Summary The dentate gyrus is hypothesized to function as a “gate”, limiting the flow of excitation through the hippocampus. During epileptogenesis, adult-generated granule cells (DGC) form aberrant neuronal connections with neighboring DGC, disrupting the dentate gate. Hyperactivation of the mTOR signaling pathway is implicated in driving this aberrant circuit formation. While the presence of abnormal DGC in epilepsy has been known for decades, direct evidence linking abnormal DGC to seizures has been lacking. Here, we isolate the effects of abnormal DGC using a transgenic mouse model to selectively delete PTEN from postnatally-generated DGC. PTEN deletion led to hyperactivation of the mTOR pathway, producing abnormal DGC morphologically similar to those in epilepsy. Strikingly, animals in which PTEN was deleted from ≥9% of the DGC population developed spontaneous seizures in about four weeks, confirming that abnormal DGC – which are present in both animals and humans with epilepsy – are capable of causing the disease.

Aberrantly interconnected granule cells are characteristic of temporal lobe epilepsy. By reducing network stability, these abnormal neurons may contribute directly to disease development. Only subsets of granule cells, however, exhibit abnormalities. Why this is the case is not known. Ongoing neurogenesis in the adult hippocampus may provide an explanation. Newly generated granule cells may be uniquely vulnerable to environmental disruptions relative to their mature neighbors. Here, we determine whether there is a critical period after neuronal birth during which neuronal integration can be disrupted by an epileptogenic insult. By bromodeoxyuridine birthdating cells in green fluorescent protein-expressing transgenic mice, we were able to noninvasively label granule cells born 8 weeks before (mature), 1 week before (immature), or 3 weeks after (newborn) pilocarpineepileptogenesis. Neuronal morphology was examined 4 and 8 weeks after pilocarpine treatment. Strikingly, almost 50% of immature granule cells exposed to pilocarpine-epileptogenesis exhibited aberrant hilar basal dendrites. In contrast, only 9% of mature granule cells exposed to the identical insult possessed basal dendrites. Moreover, newborn cells were even more severely impacted than immature cells, with 40% exhibiting basal dendrites and an additional 20% exhibiting migration defects. In comparison, Ͻ5% of neurons from normal animals exhibited either abnormality, regardless of age. Together, these data demonstrate the existence of a critical period after the birth of adult-generated neurons during which they are vulnerable to being recruited into epileptogenic neuronal circuits. Pathological brain states therefore may pose a significant hurdle for the appropriate integration of newly born endogenous, and exogenous, neurons.

The functional impact of adult-generated granule cells in the epileptic brain is unclear, with data supporting both protective and maladaptive roles. These conflicting findings could be explained if new granule cells integrate heterogeneously, with some cells taking neutral or adaptive roles and others contributing to recurrent circuitry supporting seizures. Here, we tested this hypothesis by completing detailed morphological characterizations of age-and experience-defined cohorts of adult-generated granule cells from transgenic mice. The majority of newborn cells exposed to an epileptogenic insult exhibited reductions in dendritic spine number, suggesting reduced excitatory input to these cells. A significant subset, however, exhibited higher spine numbers. These latter cells tended to have enlarged cell bodies, long basal dendrites, or both. Moreover, cells with basal dendrites received significantly more recurrent mossy fiber input through their apical dendrites, indicating that these cells are robustly integrated into the pathological circuitry of the epileptic brain. These data imply that newborn cells play complex-and potentially conflicting-roles in epilepsy.

Medulloblastoma (MB), originating in the cerebellum, is the most common malignant brain tumor in children. MB consists of four major groups where constitutive activation of the Sonic Hedgehog (SHH) signaling pathway is a hallmark of one group. Mouse and human SHH MBs exhibit increased expression of microRNAs encoded by the miR-17~92 and miR-106b~25 clusters compared to granule progenitors and post-mitotic granule neurons. Here, we assessed the therapeutic potential of 8-mer seed-targeting LNA-modified antimiR oligonucleotides, termed tiny LNAs, that inhibit microRNA seed families expressed by miR-17~92 and miR-106b~25 in two mouse models of SHH MB. We found that tumor cells (MB cells) passively took up 8-mer LNA-antimiRs, and specifically inhibited targeted microRNA seed-sharing family members. Inhibition of miR-17 and miR-19a seed families by antimiR-17 and antimiR-19, respectively, resulted in diminished tumor cell proliferation in vitro. Treatment of mice with systemic delivery of antimiR-17 and antimiR-19 reduced tumor growth in flank and brain allografts in vivo and prolonged the survival of mice with intracranial transplants, suggesting that inhibition of the miR-17~92 cluster family by 8-mer LNA-antimiRs might be considered for the treatment of SHH MBs.

Saba senegalensis (SS) is a well-known and commonly eaten fruit in Western Africa, especially in the rainy season when it is abundant. The ingestion of its seeds may cause abdominal pain and bowel obstruction. This cause might not be recognized by radiologists who are not aware of SS CT features. We thus present the characteristic CT features of SS as found in patients presenting with abdominal pain and incidentally in others. We also discuss the differential diagnosis with the cowries (ornament) and other similar fruits as imaged on CT. From 2009 through 2015 a series of 14 patients, aged 4-65 years (10 males) were referred to our hospital. The reasons for abdominal/lumbar CT were: abdominal pain only, signs of bowel occlusion, neoplasm, trauma, scoliosis and spondylodiscitis. In all these patients, we found in the bowel, objects appearing as oval-shaped foreign bodies, spontaneously hyperdense with a midline hypodense line along its long axis (Figure 1A, B). The multiplicity, same shape and density of the objects led us to search for something swallowed. In most of the cases we reached the final diagnosis of tropical fruits ingestion after questioning the relatives. Our own investigations Figure 1: Axial CT images showing (A) SS seeds, incidentally found in the bowel (arrows), and (B) A seed impacted in the ileocecal valve (arrow), responsible for occlusion; Photograph (C) and CT (D) of SS; seed (dark arrow): maximum long diameter: 16 mm, high density of the shell (256 HU) and the midline linear hypodensity (92 HU).

SUMMARY Four distinct subgroups of cerebellar medulloblastomas (MBs) differ in their histopathology, molecular profiles, and prognosis. c-Myc (Myc) or MycN overexpression in granule neuron progenitors (GNPs) induces Group 3 (G3) or Sonic Hedgehog (SHH) MBs, respectively. Differences in Myc and MycN transcriptional profiles depend, in part, on their interaction with Miz1, which binds strongly to Myc but not MycN, to target sites on chromatin. Myc suppresses ciliogenesis and “reprograms” the transcriptome of SHH-dependent GNPs through Miz1-dependent gene repression to maintain “stemness”. Genetic disruption of the Myc/Miz1 interaction inhibited G3 MB development. Target genes of Myc/Miz1 are repressed in human G3 MBs, but not in other subgroups. Therefore, the Myc/Miz1 interaction is a defining hallmark of G3 MB development.

Hypothesis: Hepatic radiofrequency ablation (RFA) is effective in treating patients with unresectable hepatic malignancies. Design: Case series of 123 patients with unresectable hepatic tumors or tumors with histological findings not traditionally treated by means of hepatic resection were considered for hepatic RFA. Median follow-up was 20 months.

Detection of bowel and mesenteric injury can be challenging in patients after blunt abdominal trauma. Early diagnosis and treatment are critical to decrease patient morbidity and mortality. Computed tomography (CT) has become the primary modality for the imaging of these patients. Signs of bowel perforation such as free air and contrast material are virtually pathognomonic. Bowel-wall thickening, free fluid, and mesenteric infiltration may be seen with this type of injury and partial thickness injuries. The authors present and discuss the range of CT findings seen with bowel and mesenteric injuries. Examples of observation and interpretation errors are also provided to highlight pitfalls encountered in the evaluation of abdominopelvic CT scans in patients after blunt trauma.