The role of PAF, TLR, and the inflammatory response in neonatal necrotizing enterocolitis

The pathogenesis of neonatal necrotizing enterocolitis remains poorly understood. Recent evidence suggests that PAF (platelet activating factor) and human toll-like receptors (TLRs) contribute to the pro-inflammatory response that is characteristic of NEC pathology. Understanding the regulation of these molecular interactions may provide new approaches for prevention or treatment of this dreaded condition.     

Progression from a stem cell–like state to early differentiation in the C. elegans germ line

Controls of stem cell maintenance and early differentiation are known in several systems. However, the progression from stem cell self-renewal to overt signs of early differentiation is a poorly understood but important problem in stem cell biology. The Caenorhabditis elegans germ line provides a genetically defined model for studying that progression. In this system, a single-celled mesenchymal niche, the distal tip cell (DTC), employs GLP-1/Notch signaling and an RNA regulatory network to balance self-renewal and early differentiation within the “mitotic region,” which continuously self-renews while generating new gametes. Here, we investigate germ cells in the mitotic region for their capacity to differentiate and their state of maturation. Two distinct pools emerge. The “distal pool” is maintained by the DTC in an essentially uniform and immature or “stem cell–like” state; the “proximal pool,” by contrast, contains cells that are maturing toward early differentiation and are likely transit-amplifying cells. A rough estimate of pool sizes is 30–70 germ cells in the distal immature pool and ≈150 in the proximal transit-amplifying pool. We present a simple model for how the network underlying the switch between self-renewal and early differentiation may be acting in these two pools. According to our model, the self-renewal mode of the network maintains the distal pool in an immature state, whereas the transition between self-renewal and early differentiation modes of the network underlies the graded maturation of germ cells in the proximal pool. We discuss implications of this model for controls of stem cells more broadly.     

Auditory-Nerve Responses to Varied Inter-Phase Gap and Phase Duration of the Electric Pulse Stimulus as Predictors for Neuronal Degeneration

After severe hair cell loss, secondary degeneration of spiral ganglion cells (SGCs) is observed—a gradual process that spans years in humans but only takes weeks in guinea pigs. Being the target for cochlear implants (CIs), the physiological state of the SGCs is important for the effectiveness of a CI. For assessment of the nerve’s state, focus has generally been on its response threshold. Our goal was to add a more detailed characterization of SGC functionality. To this end, the electrically evoked compound action potential (eCAP) was recorded in normal-hearing guinea pigs and guinea pigs that were deafened 2 or 6 weeks prior to the experiments. We evaluated changes in eCAP characteristics when the phase duration (PD) and inter-phase gap (IPG) of a biphasic current pulse were varied. We correlated the magnitude of these changes to quantified histological measures of neurodegeneration (SGC packing density and SGC size). The maximum eCAP amplitude, derived from the input–output function, decreased after deafening, and increased with both PD and IPG. The eCAP threshold did not change after deafening, and decreased with increasing PD and IPG. The dynamic range was wider for the 6-weeks-deaf animals than for the other two groups. Excitability increased with IPG (steeper slope of the input–output function and lower stimulation level at the half-maximum eCAP amplitude), but to a lesser extent for the deafened animals than for normal-hearing controls. The latency was shorter for the 6-weeks-deaf animals than for the other two groups. For several of these eCAP characteristics, the effect size of IPG correlated well with histological measures of degeneration, whereas effect size of PD did not. These correlations depend on the use of high current levels, which could limit clinical application. Nevertheless, their potential of these correlations towards assessment of the condition of the auditory nerve may be of great benefit to clinical diagnostics and prognosis in cochlear implant recipients.     

Changes in the Electrically Evoked Compound Action Potential over time After Implantation and Subsequent Deafening in Guinea Pigs

The electrically evoked compound action potential (eCAP) is a direct measure of the responsiveness of the auditory nerve to electrical stimulation from a cochlear implant (CI). CIs offer a unique opportunity to study the auditory nerve’s electrophysiological behavior in individual human subjects over time. In order to understand exactly how the eCAP relates to the condition of the auditory nerve, it is crucial to compare changes in the eCAP over time in a controlled model of deafness-induced auditory nerve degeneration. In the present study, 10 normal-hearing young adult guinea pigs were implanted and deafened 4 weeks later, so that the effect of deafening could be monitored within-subject over time. Following implantation, but before deafening, most examined eCAP characteristics significantly changed, suggesting increasing excitation efficacy (e.g., higher maximum amplitude, lower threshold, shorter latency). Conversely, inter-phase gap (IPG) effects on these measures – within-subject difference measures that have been shown to correlate well with auditory nerve survival – did not vary for most eCAP characteristics. After deafening, we observed an initial increase in excitability (steeper slope of the eCAP amplitude growth function (AGF), lower threshold, shorter latency and peak width) which typically returned to normal-hearing levels within a week, after which a slower process, probably reflecting spiral ganglion cell loss, took place over the remaining 6 weeks (e.g., decrease in maximum amplitude, AGF slope, peak area, and IPG effect for AGF slope; increase in IPG effect for latency). Our results suggest that gradual changes in peak width and latency reflect the rate of neural degeneration, while peak area, maximum amplitude, and AGF slope reflect neural population size, which may be valuable for clinical diagnostics.

     

Neurotrophins and their role in the cochlea

Spiral ganglion cell (SGC) degeneration following hair cell loss can be prevented by administration of exogenous neurotrophic factors. Many of these neurotrophic factors, in particular the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), have been described to be involved in the development of the rodent cochlea. While expression of most of the neurotrophins has decreased to below detectable levels during adulthood (only NT-3 remains highly expressed), their respective receptors remain present in SGCs. Indeed much less is known about the function of neurotrophins in the mature cochlea. Such knowledge is crucial in the search for tools to improve SGC survival following cochlear implantation. In this review, we will critically regard the current experimental findings of neurotrophic treatment of the SGCs in the perspective of fundamental cellular mechanisms underlying neurotrophin signaling. We conclude that, in order to fully apprehend the effects of neurotrophic treatment of degenerating SGCs and in order to consider clinical application of neurotrophins, future research should focus (a) on characterizing the expression pattern of neurotrophins in the cochlea after deafening, (b) on more detailed characterization of functional and morphological changes of SGCs associated with both deafening and neurotrophic treatment and (c) on the possible self-supporting state of SGCs after cessation of short-term neurotrophic treatment.     

Maternal exposure to Great Lakes sport-caught fish and dichlorodiphenyl dichloroethylene, but not polychlorinated biphenyls, is associated with reduced birth weight

Fish consumption may be beneficial for a developing human fetus, but fish may also contain contaminants that could be detrimental. Great Lakes sport-caught fish (GLSCF) are contaminated with polychlorinated biphenyls (PCBs) and dichlorodiphenyl dichloroethylene (DDE), but the effects of these contaminants on birth outcome are not clear. To distinguish potential contaminant effects, we examined (1) whether the decrease over time in contaminant levels in GLSCF is paralleled by an increase in birth weight of children of GLSCF-consuming mothers and (2) the relation between maternal serum concentrations of these contaminants and birth weight. Mothers (n=511) were interviewed from 1993 to 1995, and maternal serum was collected from 1994 to 1995 (n=143). Potential confounders considered were child gender, maternal age at delivery, maternal prepregnancy body mass index, maternal cigarette and alcohol use during pregnancy, maternal education level, maternal parity, and maternal breastfeeding. Children born during 1970-1977, 1978-1984, and 1985-1993 to mothers who ate more than 116 meals of GLSCF before pregnancy were, on average, 164 g lighter, 46 g heavier, and 134 g heavier, respectively, than children of mothers who ate no GLSCF before pregnancy (P trend=0.05). GLSCF-consuming mothers had higher serum PCB and DDE concentrations, but only increased DDE was associated with lower birth weight. The data suggest that fetal DDE exposure (as indicated by maternal serum DDE concentration) may decrease birth weight and that decreased birth weight effects associated with GLSCF consumption have decreased over time.