Comparing a novel hand held device (Peritron+) to standard urodynamics in measuring intravesical pressure.

AIMS: Peritron+ is a new handheld device, which can be attached to a urethral catheter to measure intravesical pressures (Pves). The goal of this study was to assess if Pves recorded by standard urodynamics (UDs) are comparable to those recorded by the Peritron+. METHODS: Patients with voiding dysfunction and an indication for UD underwent measurement of Pves with nonvideo UD and Peritron+. Pves were recorded at volumes of 50, 100, and 200 mL for the supine and sitting positions. A failure of the Peritron+ was considered to be a discrepancy of Pves values >3 cmH2 O between Peritron+ and UD recordings. Two-way ANOVA was used to assess for statistical significance. P-values < 0.05 were considered significant. RESULTS: Ten female patients, mean age 51 years old, were enrolled in the study. The difference in Pves measurements between Peritron+ and UD were ≤3 cmH2 O at all bladder volumes measured in a supine and sitting positions. There were no adverse events and there were no malfunctions of the Peritron+ device during the study. CONCLUSIONS: Peritron+ handheld device accurately assessed Pves at different intravesical volumes when compared to UD measurements. The Peritron+ is a simple and safe device, which can be used in the office by a clinician and at home by a patient to monitor Pves and help to select patients who may require standard UD re-evaluation. This will be a valuable tool in managing patients with neurogenic and nonneurogenic bladders who are at a risk of upper urinary tract deterioration.

E2F4 is required for early eye patterning.

Increasingly, studies reveal novel functions for cell cycle proteins during development. Here, we investigated the role of E2F4 in eye development. E2F4-deficient mouse embryos exhibit severe early eye patterning defects, which are evident from embryonic day 11.5 and characterized by aberrant shape of the optic cup, coloboma as well as abnormal eye pigmentation. Loss of E2F4 is associated with proximal-distal patterning defects in the optic vesicle. These defects are characterized by the expansion of optic stalk marker gene expression to the optic cup and reduced expression of ventral optic cup markers. These defects are associated with a split of Shh expression domain at the ventral midline of the forebrain and expansion of the Shh activity into the ventral optic cup. Despite these patterning defects, early neuronal differentiation and Shh expression in the retina are not affected by E2F4 deletion. Overall, the results of our studies show a novel role of E2F4 in the early eye development.

Mcl-1 is a key regulator of apoptosis during CNS development and after DNA damage.

Despite the importance of Mcl-1, an anti-apoptotic Bcl-2 family member, in the regulation of apoptosis, little is known regarding its role in nervous system development and injury-induced neuronal cell death. Because germline deletion of Mcl-1 results in peri-implantation lethality, we address the function of Mcl-1 in the nervous system using two different conditional Mcl-1 mouse mutants in the developing nervous system. Here, we show for the first time that Mcl-1 is required for neuronal development. Neural precursors within the ventricular zone and newly committed neurons in the cortical plate express high levels of Mcl-1 throughout cortical neurogenesis. Loss of Mcl-1 in neuronal progenitors results in widespread apoptosis. Double labeling with active caspase 3 and Tuj1 reveals that newly committed Mcl1 deficient neurons undergo apoptosis as they commence migration away from the ventricular zone. Examination of neural progenitor differentiation in vitro demonstrated that cell death in the absence of Mcl1 is cell autonomous. Although conditional deletion of Mcl-1 in cultured neurons does not trigger apoptosis, loss of Mcl-1 sensitizes neurons to an acute DNA damaging insult. Indeed, the rapid reduction of Mcl-1 mRNA and protein levels are early events after DNA damage in neurons, and maintaining high Mcl-1 levels can protect neurons against death. Together, our results are the first to demonstrate the requirement of Mcl-1, an anti-apoptotic Bcl-2 family protein, for cortical neurogenesis and the survival of neurons after DNA damage.

Cell cycle regulator E2F4 is essential for the development of the ventral telencephalon.

Early forebrain development is characterized by extensive proliferation of neural precursors coupled with complex structural transformations; however, little is known regarding the mechanisms by which these processes are integrated. Here, we show that deficiency of the cell cycle regulatory protein, E2F4, results in the loss of ventral telencephalic structures and impaired self-renewal of neural precursor cells. The mechanism underlying aberrant ventral patterning lies in a dramatic loss of Sonic hedgehog (Shh) expression specifically in this region. The E2F4-deficient phenotype can be recapitulated by interbreeding mice heterozygous for E2F4 with those lacking one allele of Shh, suggesting a genetic interaction between these pathways. Treatment of E2F4-deficient cells with a Hh agonist rescues stem cell self-renewal and cells expressing the homeodomain proteins that specify the ventral telencephalic structures. Finally, we show that E2F4 deficiency results in impaired activity of Shh forebrain-specific enhancers. In conclusion, these studies establish a novel requirement for the cell cycle regulatory protein, E2F4, in the development of the ventral telencephalon.

Unique requirement for Rb/E2F3 in neuronal migration: evidence for cell cycle-independent functions.

The cell cycle regulatory retinoblastoma (Rb) protein is a key regulator of neural precursor proliferation; however, its role has been expanded to include a novel cell-autonomous role in mediating neuronal migration. We sought to determine the Rb-interacting factors that mediate both the cell cycle and migration defects. E2F1 and E2F3 are likely Rb-interacting candidates that we have shown to be deregulated in the absence of Rb. Using mice with compound null mutations of Rb and E2F1 or E2F3, we asked to what extent either E2F1 or E2F3 interacts with Rb in neurogenesis. Here, we report that E2F1 and E2F3 are both functionally relevant targets in neural precursor proliferation, cell cycle exit, and laminar patterning. Each also partially mediates the Rb requirement for neuronal survival. Neuronal migration, however, is specifically mediated through E2F3, beyond its role in cell cycle regulation. This study not only outlines overlapping and distinct functions for E2Fs in neurogenesis but also is the first to establish a physiologically relevant role for the Rb/E2F pathway beyond cell cycle regulation in vivo.