Genetics of Schizophrenia: Historical Insights and Prevailing Evidence.

Schizophrenia's (SZ's) heritability and familial transmission have been known for several decades; however, despite the clear evidence for a genetic component, it has been very difficult to pinpoint specific causative genes. Even so genetic studies have taught us a lot, even in the pregenomic era, about the molecular underpinnings and disease-relevant pathways. Recurring themes emerged revealing the involvement of neurodevelopmental processes, glutamate regulation, and immune system differential activation in SZ etiology. The recent emergence of epigenetic studies aimed at shedding light on the biological mechanisms underlying SZ has provided another layer of information in the investigation of gene and environment interactions. However, this epigenetic insight also brings forth another layer of complexity to the (epi)genomic landscape such as interactions between genetic variants, epigenetic marks-including cross-talk between DNA methylation and histone modification processes-, gene expression regulation, and environmental influences. In this review, we seek to synthesize perspectives, including limitations and obstacles yet to overcome, from genetic and epigenetic literature on SZ through a qualitative review of risk factors and prevailing hypotheses. Encouraged by the findings of both genetic and epigenetic studies to date, as well as the continued development of new technologies to collect and interpret large-scale studies, we are left with a positive outlook for the future of elucidating the molecular genetic mechanisms underlying SZ and other complex neuropsychiatric disorders.

Mice engineered for an obligatory Mdm4 exon skipping express higher levels of the Mdm4-S isoform but exhibit increased p53 activity.

Mdm4, a protein related to the ubiquitin-ligase Mdm2, is an essential inhibitor of tumor suppressor protein p53. In both human and mouse cells, the Mdm4 gene encodes two major transcripts: one encodes the full-length oncoprotein (designated below as Mdm4-FL), whereas the other, resulting from a variant splicing that skips exon 6, encodes the shorter isoform Mdm4-S. Importantly, increased Mdm4-S mRNA levels were observed in several human cancers, and correlated with poor survival. However, the role of Mdm4-S in cancer progression remains controversial, because the Mdm4-S protein appeared to be a potent p53 inhibitor when overexpressed, but the splice variant also leads to a decrease in Mdm4-FL expression. To unambiguously determine the physiological impact of the Mdm4-S splice variant, we generated a mouse model with a targeted deletion of the Mdm4 exon 6, thereby creating an obligatory exon skipping. The mutant allele (Mdm4(ΔE6)) prevented the expression of Mdm4-FL, but also led to increased Mdm4-S mRNA levels. Mice homozygous for this allele died during embryonic development, but were rescued by a concomitant p53 deficiency. Furthermore in a hypomorphic p53(ΔP/ΔP) context, the Mdm4(ΔE6) allele led to p53 activation and delayed the growth of oncogene-induced tumors. We next determined the effect of Mdm4(+/ΔE6) heterozygosity in a hypermorphic p53(+/Δ31) genetic background, recently shown to be extremely sensitive to Mdm4 activity. Mdm4(+/ΔE6) p53(+/Δ31) pups were born, but suffered from aplastic anemia and died before weaning, again indicating an increased p53 activity. Our results demonstrate that the main effect of a skipping of Mdm4 exon 6 is not the synthesis of the Mdm4-S protein, but rather a decrease in Mdm4-FL expression. These and other data suggest that increased Mdm4-S mRNA levels might correlate with more aggressive cancers without encoding significant amounts of a potential oncoprotein. Hypotheses that may account for this apparent paradox are discussed.

Invasive pulmonary aspergillosis due to a multi-azole resistant Aspergillus fumigatus.

A patient with invasive pulmonary aspergillosis due to an azole-resistant Aspergillus fumigatus is described. Despite treatment change from voriconazole to amphotericin B as soon as the resistance data were available, the patient died. Azole resistance is an emerging problem, which significantly complicates the management of A. fumigatus infections. It should be considered in every patient with an invasive A. fumigatus infection who is not responding to voriconazole therapy.

Spontaneous hepatic rupture in a normotensive monoamniotic twin pregnancy: case report and review of the literature.

BACKGROUND: Spontaneous liver rupture during pregnancy is extremely rare, and often associated with hypertensive disorders. Maternal outcomes are poor and morbidity is high. CASE: A 27-year-old women (G1P0), pregnant with monochorionic-monoamniotic twins, developed extensive abdominal pain while she was electively admitted at 32 weeks for fetal pulmonary maturation. Diagnosed with preterm labor, a caesarean section was performed. Postoperatively, our patient deteriorated and a second laparotomy revealed an extensive liver rupture. There was no evidence of hypertensive disorders or hepatic tumors. After perihepatic packing and embolization, our patient required long-term treatment in our intensive care unit. She survived, and both mother and children are healthy after 6 months. CONCLUSION: Despite being rare, spontaneous liver rupture in absence of hypertensive disorders during pregnancy is associated with high maternal morbidity and mortality. Adequate treatment requires a multidisciplinary approach.

Pelvic inflammatory disease due to Streptococcus pneumoniae: a usual pathogen at an unusual place.

We report three cases of pelvic inflammatory disease (PID) due to Streptococcus pneumoniae in previously healthy young women. S. pneumoniae frequently causes bacteremia, meningitis and respiratory infections, but it very rarely infects the genital tract. All our patients presented with an acute onset of severe abdominal pain and had an intrauterine device (IUD) present. No abnormal sexual behavior was noticed. Although the relation between PID due to S. pneumoniae and the use of an IUD has been a topic for discussions, culture of IUD in all our patients and blood culture in 2 of 3 of our patients revealed S. pneumoniae. All patients recovered well with intravenous antibiotic treatment and removal of the IUD.

The RNA-binding protein Musashi-1 is produced in the developing and adult mouse eye.

PURPOSE: Musashi-1 (Msi1) is an RNA-binding protein produced in various types of stem cells including neural stem/progenitor cells and astroglial progenitor cells in the vertebrate central nervous system. Other RNA-binding proteins such as Pumilio-1, Pumilio-2, Staufen-1, and Staufen-2 have been characterized as potential markers of several types of stem or progenitor cells. We investigated the involvement of Msi1 in mouse eye development and adult mouse eye functions by analyzing the profile of Msi1 production in all ocular structures during development and adulthood. METHODS: We studied Msi1 production by in situ hybridization and immunohistochemistry of ocular tissue sections and by semi-quantitative RT-PCR and western blot analysis from the embryonic stage of 12.5 days post coitum (E12.5 dpc) when the first retinal ganglion cells (RGCs) begin to appear to the adult stage when all retinal cell types are present. RESULTS: Msi1 mRNA was present at all studied stages of eye development. Msi1 protein was detected in the primitive neuroblastic layer (NbL), the ganglion cell layer (GCL), and in all major differentiated neurons of postnatal developing and adult retinae. During postnatal developing stages, faint diffuse Msi1 protein staining is converted to a more specific distribution once mouse retina is fully differentiated. The most striking result of our study concerns the large amounts of Msi1 protein and mRNA in several unexpected sites of adult mouse eyes including the corneal epithelium and endothelium, stromal keratocytes, progenitor cells of the limbus, equatorial lens stem cells, differentiated lens epithelial cells, and differentiating lens fibers. Msi1 was also found in the pigmented and nonpigmented cells of the ciliary processes, the melanocytes of the ciliary body, the retinal pigment epithelium, differentiated retinal neurons, and most probably in the retinal glial cells such as Müller glial cells, astrocytes, and the oligodendocytes surrounding the axons of the optic nerve. Msi1 expression was detected in the outer plexiform layer, the inner plexiform layer, and the nerve fiber layer of fully differentiated adult retina. CONCLUSIONS: We provide here the first demonstration that the RNA-binding protein, Msi1, is produced in mouse eyes from embryonic stages until adulthood. The relationship between the presence of Msi1 in developing ocular compartments and the possible stem/progenitor cell characteristics of these compartments remains unclear. Finally, the expression of Msi1 in several different cell types in the adult eye is extremely intriguing and should lead to further attempts to unravel the role of Msi1 in cellular and subcellular RNA metabolism and in the control of translational processes in adult eye cells particularly in adult neuronal dendrites, axons, and synapses.

Diagnosis and outcome from suspected mesenteric ischaemia following cardiac surgery.

A three-year retrospective chart review was undertaken of all post-cardiothoracic ICU patients who underwent laparotomy for suspected mesenteric ischaemia, or who had the diagnosis confirmed at post mortem. The aim was to compare the clinical and diagnostic characteristics of cardiothoracic patients with suspected mesenteric ischaemia with patients who had a confirmed diagnosis. There were 3024 admissions to the cardiothoracic ICU over the three-year period. Twenty-six laparotomies were performed for suspected mesenteric ischaemia and 15 were positive for mesenteric ischaemia. The overall incidence of mesenteric ischaemia was 17/3024 (0.6%). Mortality for patients with mesenteric ischaemia was 13/17 (76%). Ischaemia was limited to a single segment of bowel in the four survivors. Mortality in patients who had a negative laparotomy for suspected mesenteric ischaemia was 7/11 (64%), attributable to cardiovascular failure (2/11) and multi-organ dysfunction syndrome (5/11). No clinical, biochemical or haematological test was discriminatory for mesenteric ischaemia. In patients with proven ischaemia, 7/13 plain abdominal radiographs were positive for ischaemia and 7/7 radiographs were negative for ischaemia in patients with no ischaemia (P = 0.05, PPV 1.0, NPV 0.5, sensitivity 54%, specificity 100%). Neither routine clinical investigations nor plain abdominal radiography reliably diagnose mesenteric ischaemia when the diagnosis is suspected clinically. Early laparotomy is recommended in these patients and further investigation may delay this procedure unnecessarily. The presence of mesenteric ischaemia identifies a cohort of patients with high mortality.