High Expression of Nicotinamide N-Methyltransferase in Patients with Sporadic Alzheimer's Disease.

We have previously shown that the expression of nicotinamide N-methyltransferase (NNMT) is significantly increased in the brains of patients who have died of Parkinson's disease (PD). In this study, we have compared the expression of NNMT in post-mortem medial temporal lobe, hippocampus and cerebellum of 10 Alzheimer's disease (AD) and 9 non-disease control subjects using a combination of quantitative Western blotting, immunohistochemistry and dual-label confocal microscopy coupled with quantitative analysis of colocalisation. NNMT was detected as a single protein of 29 kDa in both AD and non-disease control brains, which was significantly increased in AD medial temporal lobe compared to non-disease controls (7.5-fold, P < 0.026). There was no significant difference in expression in the cerebellum (P = 0.91). NNMT expression in AD medial temporal lobe and hippocampus was present in cholinergic neurones with no glial localisation. Cell-type expression was identical in both non-disease control and AD tissues. These results are the first to show, in a proof-of-concept study using a small patient cohort, that NNMT protein expression is increased in the AD brain and is present in neurones which degenerate in AD. These results suggest that the elevation of NNMT may be a common feature of many neurodegenerative diseases. Confirmation of this overexpression using a larger AD patient cohort will drive the future development of NNMT-targetting therapeutics which may slow or stop the disease pathogenesis, in contrast to current therapies which solely address AD symptoms.

Novel Regulatory Mechanisms for the SoxC Transcriptional Network Required for Visual Pathway Development.

What pathways specify retinal ganglion cell (RGC) fate in the developing retina? Here we report on mechanisms by which a molecular pathway involving Sox4/Sox11 is required for RGC differentiation and for optic nerve formation in mice in vivo, and is sufficient to differentiate human induced pluripotent stem cells into electrophysiologically active RGCs. These data place Sox4 downstream of RE1 silencing transcription factor in regulating RGC fate, and further describe a newly identified, Sox4-regulated site for post-translational modification with small ubiquitin-related modifier (SUMOylation) in Sox11, which suppresses Sox11's nuclear localization and its ability to promote RGC differentiation, providing a mechanism for the SoxC familial compensation observed here and elsewhere in the nervous system. These data define novel regulatory mechanisms for this SoxC molecular network, and suggest pro-RGC molecular approaches for cell replacement-based therapies for glaucoma and other optic neuropathies.SIGNIFICANCE STATEMENT Glaucoma is the most common cause of blindness worldwide and, along with other optic neuropathies, is characterized by loss of retinal ganglion cells (RGCs). Unfortunately, vision and RGC loss are irreversible, and lead to bilateral blindness in ∼14% of all diagnosed patients. Differentiated and transplanted RGC-like cells derived from stem cells have the potential to replace neurons that have already been lost and thereby to restore visual function. These data uncover new mechanisms of retinal progenitor cell (RPC)-to-RGC and human stem cell-to-RGC fate specification, and take a significant step toward understanding neuronal and retinal development and ultimately cell-transplant therapy.

Serum PCB concentrations in residents of Calcasieu and Lafayette Parishes, Louisiana with comparison to the U.S. population.

In 2002, a cross-sectional study designed to compare the serum dioxin toxic equivalent concentrations (TEQ) of a population-based sample of Calcasieu Parish, Louisiana residents, to Lafayette Parish was conducted. The mono-ortho polychlorinated biphenyls (PCBs) were measured in order to calculate the TEQ. We compared the sum of lipid adjusted serum concentrations of 27 PCB congeners (total PCBs) in residents of these two parishes and also by their demographic characteristics. The geometric means (GM) [standard errors (SE)] of the concentrations (ngg(-1) lipids) of total PCBs in participants from Calcasieu Parish and Lafayette Parish were 154 (11.8) and 168.6 (20.8) (T-test p=0.54), respectively. Various percentiles of the distribution of serum total PCB concentrations were similar in the two parishes. After adjusting by age and race in the ANCOVA regression model, the adjusted GM for the lipid adjusted total PCBs was statistically higher in the residents in Lafayette than in Calcasieu Parish regardless of age or race (P=0.007). The adjusted GM of lipid adjusted total PCBs for African Americans was significantly higher than for Whites (p<0.001). Serum total PCB levels in residents of both parishes increased linearly with age (P<0.001). The congener profiles were similar in residents of both parishes. We also compared the GMs of a sum of 8 PCBs in Calcasieu and Lafayette Parish residents to those from a representative sample of the U.S. general population in 2001-2002 and they were not significantly different between parishes or between the parish data and the U.S. general population.

Comparison of blood volatile organic compound levels in residents of Calcasieu and Lafayette Parishes, LA, with US reference ranges.

Agency for Toxic Substances and Disease Registry conducted a study to evaluate body burden levels of volatile organic compounds (VOCs) among residents of highly industrialized Calcasieu Parish, LA, USA, in 2002. Blood VOC levels in a representative sample of participants in Calcasieu Parish were compared with a similar group of participants in the less-industrialized Lafayette Parish. Participants' ages ranged from 15 to 91 years, 46% were men, and 89% were Caucasian. VOC levels in these two populations were also compared at the national levels. Solid-phase microextraction coupled with gas chromatography mass spectrometry was used to measure levels of 30 VOCs in blood samples collected from 283 self-described non-smoking study participants. Of the 30 VOCs, 6 had quantifiable levels in at least 25% of the blood samples analyzed. The frequency of detection was >95% for benzene and m-/p-xylene, >60% for 1,4-dichlorbenzene and toluene, 27% for ethylbenzene, and 39% for styrene. Calcasieu and Lafayette Parish participants had similar distributions for six VOCs in key percentiles and geometric means. When compared with a representative sampling of the 1999-2000 US general population, no significant differences were found between the parish data and the US general population.

Tissue engineering the retinal ganglion cell nerve fiber layer.

Retinal degenerative diseases, such as glaucoma and macular degeneration, affect millions of people worldwide and ultimately lead to retinal cell death and blindness. Cell transplantation therapies for photoreceptors demonstrate integration and restoration of function, but transplantation into the ganglion cell layer is more complex, requiring guidance of axons from transplanted cells to the optic nerve head in order to reach targets in the brain. Here we create a biodegradable electrospun (ES) scaffold designed to direct the growth of retinal ganglion cell (RGC) axons radially, mimicking axon orientation in the retina. Using this scaffold we observed an increase in RGC survival and no significant change in their electrophysiological properties. When analyzed for alignment, 81% of RGCs were observed to project axons radially along the scaffold fibers, with no difference in alignment compared to the nerve fiber layer of retinal explants. When transplanted onto retinal explants, RGCs on ES scaffolds followed the radial pattern of the host retinal nerve fibers, whereas RGCs transplanted directly grew axons in a random pattern. Thus, the use of this scaffold as a cell delivery device represents a significant step towards the use of cell transplant therapies for the treatment of glaucoma and other retinal degenerative diseases.

Serum dioxin levels in residents of Calcasieu and Lafayette parishes, Louisiana with comparison to the US population.

The Agency for Toxic Substances and Disease Registry (ATSDR) used a cross-sectional study to compare the serum dioxin toxic equivalent (TEQ) levels of a population-based representative sample of Calcasieu Parish residents aged 15 years and older to a similar group of residents of Lafayette Parish with less industrial facilities. Serum dioxins consisted of polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and dioxin-like polychlorinated biphenyls. Overall, the mean and distribution of serum dioxin TEQ level in residents of both parishes were similar by age groups (15-29 years, 30-44 years, 45-59 years, and 60 year and older). When the Calcasieu Parish area was further divided based on distance to three industrial areas, the mean dioxin TEQ levels were similar. Serum dioxin TEQ levels in residents of both parishes increased with age. Calcasieu Parish residents who reported having eaten locally caught fish, smoked cigarettes, worked in an occupation with potential exposure, or used pesticides had dioxin levels similar to Lafayette Parish residents who reported these activities. African Americans had higher dioxin levels than Caucasians in Lafayette Parish and both races in Calcasieu Parish. The congener profiles were similar in residents of both parishes. When the combined Calcasieu and Lafayette Parish data were compared by age group to the National Health and Nutrition Examination Survey (NHANES) 2001-2002 data, the geometric means for the dioxin levels in the combined Parish data set were significantly lower than the NHANES data in all age groups (all P-values <0.0001), except the oldest age group where the significance level is marginal (P=0.067). The various percentiles of the youngest age group of the combined parish data were also significantly lower than those in NHANES. Since the combined parish dioxin levels were below a representative sampling of the US population, there is no increase in serum dioxin concentrations in both the parishes.

Confirming the utility of four kidney biomarker tests in a longitudinal follow-up study.

In this follow-up study, 526 persons were followed for almost 5 years to assess the reversibility and predictive value of four kidney biomarkers in a field epidemiology setting. This study examined (a) whether elevations in urinary albumin, N-acetyl-beta-D-glucosaminidase, retinol-binding protein, and alanine aminopeptidase remained elevated at follow-up and (b) whether these initial elevations were predictive of kidney disease (as measured by markers of kidney dysfunction: serum creatinine, serum cystatin C, creatinine clearance, and urine osmolality) at follow-up. Study participants were 8-76 years of age at baseline and were followed for an average of 4.5 years. Approximately 50% of adults who had an elevated biomarker did not have an elevation at followup. Youths with elevated biomarkers at baseline, but who completed adolescence by the time of the follow-up, no longer had any elevations in biomarkers at follow-up. Adult participants who had elevated biomarkers and selected health conditions at baseline (diabetes and, to a lesser extent, heart disease, hypertension, gout, and urinary tract disease) were more likely to show early indicators of kidney impairment at follow-up. Participants with these health conditions and normal kidney biomarker values at baseline had kidney test results at follow-up that were similar to results of study participants who did not have these health conditions at baseline. The presence or absence of elevated biomarkers at baseline among generally healthy participants was not associated with the development of early indicators of kidney impairment at follow-up. This longitudinal study confirmed the utility of these four kidney biomarker tests as markers of preclinical organ dysfunction among adults with certain preexisting medical conditions.