Extreme Elevation of Baseline Intraoperative Parathyroid Hormone Measurements: Should Usual Protocols Apply?

INTRODUCTION: Intraoperative parathyroid hormone (IOPTH) monitoring is routinely used to facilitate minimally invasive parathyroidectomy. Many IOPTH protocols exist for predicting biochemical cure. Some patients are found to have extremely high baseline IOPTH levels (defined in this study as >500 pg/mL), which may affect the likelihood of satisfying certain final IOPTH criteria. We aimed to discover whether clinically significant differences exist in patients with extremely high baseline IOPTH and which IOPTH protocols are most appropriately applied to these patients. MATERIALS AND METHODS: This is a retrospective review of 237 patients who underwent parathyroidectomy with IOPTH monitoring for primary hyperparathyroidism (pHPT) from 2016 to 2020. Baseline IOPTH levels, drawn prior to manipulation of parathyroid glands, were grouped into categories labeled "elevated" (>65-500 pg/mL) and "extremely elevated" (>500 pg/mL). Final IOPTH levels were analyzed to determine whether there was a >50% decrease from baseline and whether a normal IOPTH value was achieved. 6-wk postoperative calcium levels were also examined. RESULTS: Of the patients in this cohort, 76% were in the elevated group and 24% in the extremely elevated group. Male sex and higher preoperative PTH levels were correlated with higher baseline IOPTH levels. Patients with extremely elevated baseline IOPTH were less likely to have IOPTH fall into normal range at the conclusion of the case (P = 0.019), and final IOPTH levels were higher (P < 0.001), but the IOPTH was equally likely to decrease >50% from baseline. There was no difference in the mean postoperative calcium levels between the two groups at 6-wk or at longer term follow-up (mean 525 d). CONCLUSIONS: Detection of baseline IOPTH levels >500 pg/mL during parathyroidectomy performed for pHPT is not uncommon. IOPTH in patients with extremely elevated baseline levels were less likely to fall into normal range, but follow-up calcium levels were equal, suggesting that applying more stringent IOPTH criteria for predicting biochemical cure may not be appropriate for this population.

Contemporary trends in the surgical management of urinary incontinence after radical prostatectomy in the United States.

PURPOSE: To identify trends, costs, and predictors in the use of different surgical procedures for post-radical prostatectomy incontinence (PPI). MATERIALS AND METHODS: We identified 21,589 men who were diagnosed with localized prostate cancer (PCa) and treated with radical prostatectomy (RP) from 2003 to 2017. The primary outcome was the incontinence procedure performances. Optum's de-identified Clinformatics® Data Mart Database was queried to define the cohort of interest. The average costs of the different incontinence procedures were obtained and compared. Also, demographic, and clinical predictors of incontinence surgery were evaluated by multivariable regression analysis. RESULTS: Of the 21,589 men with localized PCa treated with RP, 740 (3.43%) underwent at least one incontinence procedure during a median of 5 years of follow-up. In total, there were 844 unique incontinence procedures. Male slings were the most common procedure (47.5%), had an intermediate cost compared to the other treatment options, and was the first-choice treatment for the majority of patients (50%). The use of an artificial urinary sphincter (AUS) was the second most common (35.3%), but also was the most expensive treatment and was first-choice-treatment for 32.3% of patients. On multivariable analysis, metabolic syndrome related disorders, adjuvant/salvage radiation therapy as well as a history of neurological comorbidities were independently associated with an increased likelihood of incontinence surgery. CONCLUSIONS: The receipt of male slings increased and then subsequently decreased, while AUS utilization was stable, and the use of urethral bulking agents was uncommon. From a cost standpoint, AUS was the most expensive option. Finally, patient's comorbidity history and RP related factors were found to influence the choice for primary or subsequent PPI interventions.

The AICD fragment of APP initiates a FoxO3a mediated response via FANCD2.

The amyloid precursor protein (APP) is a cell surface protein of uncertain function that is notable for being the parent protein of beta-amyloid. Research around this protein has focussed heavily on the link to Alzheimer's disease and neurodegeneration. However, there is increasing evidence that APP may be linked to neuronal loss through mechanisms independent of beta-amyloid. FoxO3a is a transcription factor associated with neuronal longevity and apoptosis. In neurons, FoxO3a is associated with cell death through pathways that include BIM, a BCL-2 family member. In this study we have shown that APP overexpression increased the cellular levels and activity of FoxO3a. This increased expression and activity is not a result of decreased phosphorylation but is more likely a result of increased nuclear stability due to increased levels of FANCD2, a binding partner of FoxO3a. The changes caused by APP overexpression were shown to be due to the AICD fragment of APP possibly directly inducing transcription increase in FANCD2. These findings strengthen the link between APP metabolism and FoxO3a neuronal activity. This link may be crucial in better understanding the cellular role of APP and its link to neurodegeneration and aging.

Is Stone-free Status After Surgical Intervention for Kidney Stones Associated With Better Health-related Quality of Life? - A Multicenter Study From the North American Stone Quality of Life Consortium.

OBJECTIVE: To compare the health-related quality of life (HRQOL) of patients with residual fragments after surgical intervention for kidney stones to patients that are stone-free using the disease-specific Wisconsin stone quality of life (WISQOL) questionnaire. Kidney stones contribute to impaired HRQOL, which is increasingly recognized as an important healthcare outcome measurement. MATERIALS AND METHODS: With institutional review board approval, 313 adult patients who underwent surgical intervention for kidney stones at 4 sites completed a WISQOL questionnaire. We retrospectively collected surgical data including presence of residual fragments on post-operative imaging. We calculated standardized WISQOL total and domain scores (0-100), which included items related to social functioning (D1), emotional functioning (D2), stone-related impact (D3), and vitality (D4). Scores were compared between patients with residual fragments to those who were stone-free after surgical intervention. RESULTS: Demographics did not differ between groups, overall mean age 54.6 ± 13.5 and 55.4% female. There was no significant difference in total WISQOL score for patients with residual fragments (n = 124) compared to patients that were stone-free (n = 189), 110.5 ± 27.8 vs 115.4 ± 23.6 respectively, (P = .12). Interestingly, patients with residual fragments who underwent secondary surgery were found to have significantly lower total WISQOL score (88.4 ± 30.1 vs 116.6 ± 25.0, P <.0001). CONCLUSION: Stone-free status after surgical intervention is not associated with better HRQOL when compared with patients whose surgeries left residual fragments. Indeed, further surgical intervention on residual fragments to achieve stone-free status may actually result in worse HRQOL.

Clinical management of patients with Cushing syndrome treated with mifepristone: consensus recommendations.

BACKGROUND: While surgery is the first-line treatment for patients with endogenous hypercortisolism (Cushing syndrome [CS]), mifepristone has been shown to be a beneficial medical treatment option, as demonstrated in the SEISMIC (Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing Syndrome) trial. Mifepristone is a competitive glucocorticoid receptor antagonist and progesterone receptor antagonist that is associated with several treatment effects and adverse events that clinicians need to be aware of when considering its use. The objective of this review was to provide updated clinical management recommendations for patients with CS treated with mifepristone. METHODS: A panel of endocrinologists from the US with extensive experience in treating patients with CS, including with mifepristone, convened as part of a clinical advisory board to develop a consensus on the practical, real-world clinical management of patients on mifepristone. RESULTS: Comprehensive considerations and recommendations are provided for managing mifepristone-associated effects, including symptoms of cortisol withdrawal, hypokalemia, and change in thyroid function; effects related to its antiprogesterone activity; and rash. Additional management strategies to address concomitant medications and special clinical situations, such as surgery and use in specific populations, are also provided. CONCLUSION: Safe and effective use of mifepristone requires clinical judgment and close patient monitoring to ensure optimal clinical outcomes. These consensus recommendations provide useful, practical guidance to clinicians using mifepristone.

Exposure assessment of adults living near unconventional oil and natural gas development and reported health symptoms in southwest Pennsylvania, USA.

Recent research has shown relationships between health outcomes and residence proximity to unconventional oil and natural gas development (UOGD). The challenge of connecting health outcomes to environmental stressors requires ongoing research with new methodological approaches. We investigated UOGD density and well emissions and their association with symptom reporting by residents of southwest Pennsylvania. A retrospective analysis was conducted on 104 unique, de-identified health assessments completed from 2012-2017 by residents living in proximity to UOGD. A novel approach to comparing estimates of exposure was taken. Generalized linear modeling was used to ascertain the relationship between symptom counts and estimated UOGD exposure, while Threshold Indicator Taxa Analysis (TITAN) was used to identify associations between individual symptoms and estimated UOGD exposure. We used three estimates of exposure: cumulative well density (CWD), inverse distance weighting (IDW) of wells, and annual emission concentrations (AEC) from wells within 5 km of respondents' homes. Taking well emissions reported to the Pennsylvania Department of Environmental Protection, an air dispersion and screening model was used to estimate an emissions concentration at residences. When controlling for age, sex, and smoker status, each exposure estimate predicted total number of reported symptoms (CWD, p<0.001; IDW, p<0.001; AEC, p<0.05). Akaike information criterion values revealed that CWD was the better predictor of adverse health symptoms in our sample. Two groups of symptoms (i.e., eyes, ears, nose, throat; neurological and muscular) constituted 50% of reported symptoms across exposures, suggesting these groupings of symptoms may be more likely reported by respondents when UOGD intensity increases. Our results do not confirm that UOGD was the direct cause of the reported symptoms but raise concern about the growing number of wells around residential areas. Our approach presents a novel method of quantifying exposures and relating them to reported health symptoms.

Propranolol Sensitizes Vascular Sarcoma Cells to Doxorubicin by Altering Lysosomal Drug Sequestration and Drug Efflux.

Angiosarcoma is a rare cancer of blood vessel-forming cells with a high patient mortality and few treatment options. Although chemotherapy often produces initial clinical responses, outcomes remain poor, largely due to the development of drug resistance. We previously identified a subset of doxorubicin-resistant cells in human angiosarcoma and canine hemangiosarcoma cell lines that exhibit high lysosomal accumulation of doxorubicin. Hydrophobic, weak base chemotherapeutics, like doxorubicin, are known to sequester within lysosomes, promoting resistance by limiting drug accessibility to cellular targets. Drug synergy between the beta adrenergic receptor (ß-AR) antagonist, propranolol, and multiple chemotherapeutics has been documented in vitro, and clinical data have corroborated the increased therapeutic potential of propranolol with chemotherapy in angiosarcoma patients. Because propranolol is also a weak base and accumulates in lysosomes, we sought to determine whether propranolol enhanced doxorubicin cytotoxicity via antagonism of ß-ARs or by preventing the lysosomal accumulation of doxorubicin. ß-AR-like immunoreactivities were confirmed in primary tumor tissues and cell lines; receptor function was verified by monitoring downstream signaling pathways of ß-ARs in response to receptor agonists and antagonists. Mechanistically, propranolol increased cytoplasmic doxorubicin concentrations in sarcoma cells by decreasing the lysosomal accumulation and cellular efflux of this chemotherapeutic agent. Equivalent concentrations of the receptor-active S-(-) and -inactive R-(+) enantiomers of propranolol produced similar effects, supporting a ß-AR-independent mechanism. Long-term exposure of hemangiosarcoma cells to propranolol expanded both lysosomal size and number, yet cells remained sensitive to doxorubicin in the presence of propranolol. In contrast, removal of propranolol increased cellular resistance to doxorubicin, underscoring lysosomal doxorubicin sequestration as a key mechanism of resistance. Our results support the repurposing of the R-(+) enantiomer of propranolol with weak base chemotherapeutics to increase cytotoxicity and reduce the development of drug-resistant cell populations without the cardiovascular and other side effects associated with antagonism of ß-ARs.

Assessing exposure to unconventional natural gas development: using an air pollution dispersal screening model to predict new-onset respiratory symptoms.

Various exposure estimates have been used to assess health impact of unconventional natural gas development (UNGD). The purpose of this study was to (1) use an air pollution dispersal screening model and wind direction to characterize the air emissions from UNGD facilities at each residence and (2) assess association of this exposure estimate with respiratory symptoms. Respiratory symptoms were abstracted from health records of a convenience sample of 104 adults from one county in southwestern PA who had completed a standard clinical interview with a nurse practitioner. Using publicly available air emission data, we applied a "box" air pollution dispersion screening model to estimate the median ambient air level of CO, NOx, PM 2.5, VOCs, and formaldehyde at the residence during the year health symptoms were reported. Sources and median emissions were categorized as north, south, east, or west of the residence to account for the effect of wind direction on dispersion. Binary logistic regression was performed for each respiratory symptom. Number of sources had varying magnitudes of association with some symptoms (i.e., cough, shortness of breath, and "any respiratory symptom") and no association with others (i.e., sore throat, sinus problems, wheezing). Air emissions were not associated with any symptom.

Prevalence of master plans supportive of active living in US municipalities.

Community planning documents can play an important role in promoting the design and maintenance of walkable communities. This study estimates the prevalence among US municipalities of (1) community wide planning documents and (2) inclusion of plan objectives supportive of active living within these documents. Data from the 2014 National Survey of Community-Based Policy and Environmental Supports for Healthy Eating and Active Living (CBS HEAL), a survey of local officials, were analyzed (n = 2005). Prevalence of comprehensive or general plans, 3 specific plan types, and 3 objectives supportive of active living were analyzed using survey weights to create national estimates. Overall, 64% of municipalities had a comprehensive/general plan, 46% had a transportation plan, 48% had a bicycle or pedestrian plan and 76% had a land use plan. Of municipalities with a plan, 78% included at least one of the three objectives measured supportive of active living. Differences in presence of plans and objectives were observed by population size of the municipality, urban status, region, and median education. Helping communities, especially smaller or rural municipalities and those with lower median education levels, create and adopt planning documents supportive of active living may be an important step in creating more walkable communities.

Setback distances for unconventional oil and gas development: Delphi study results.

Emerging evidence indicates that proximity to unconventional oil and gas development (UOGD) is associated with health outcomes. There is intense debate about "How close is too close?" for maintaining public health and safety. The goal of this Delphi study was to elicit expert consensus on appropriate setback distances for UOGD from human activity. Three rounds were used to identify and seek consensus on recommended setback distances. The 18 panelists were health care providers, public health practitioners, environmental advocates, and researchers/scientists. Consensus was defined as agreement of ≥70% of panelists. Content analysis of responses to Round 1 questions revealed four categories: recommend setback distances; do not recommend setback distances; recommend additional setback distances for vulnerable populations; do not recommend additional setback distances for vulnerable populations. In Round 2, panelists indicated their level of agreement with the statements in each category using a five-point Likert scale. Based on emerging consensus, statements within each category were collapsed into seven statements for Round 3: recommend set back distances of <» mile; »-½ mile; 1-1 » mile; and ≥ 2 mile; not feasible to recommend setback distances; recommend additional setbacks for vulnerable groups; not feasible to recommend additional setbacks for vulnerable groups. The panel reached consensus that setbacks of < » mile should not be recommended and additional setbacks for vulnerable populations should be recommended. The panel did not reach consensus on recommendations for setbacks between » and 2 miles. The results suggest that if setbacks are used the distances should be greater than » of a mile from human activity, and that additional setbacks should be used for settings where vulnerable groups are found, including schools, daycare centers, and hospitals. The lack of consensus on setback distances between 1/4 and 2 miles reflects the limited health and exposure studies and need to better define exposures and track health.

Model Senescent Microglia Induce Disease Related Changes in α-Synuclein Expression and Activity.

Aging is the most prominent risk factor for most neurodegenerative diseases. However, incorporating aging-related changes into models of neurodegeneration rarely occurs. One of the significant changes that occurs in the brain as we age is the shift in phenotype of the resident microglia population to one less able to respond to deleterious changes in the brain. These microglia are termed dystrophic microglia. In order to better model neurodegenerative diseases, we have developed a method to convert microglia into a senescent phenotype in vitro. Mouse microglia grown in high iron concentrations showed many characteristics of dystrophic microglia including, increased iron storage, increased expression of proteins, such as ferritin and the potassium channel, Kv1.3, increased reactive oxygen species production and cytokine release. We have applied this new model to the study of α-synuclein, a protein that is closely associated with a number of neurodegenerative diseases. We have shown that conditioned medium from our model dystrophic microglia increases α-synuclein transcription and expression via tumor necrosis factor alpha (TNFα) and mediated through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The conditioned medium also decreases the formation of α-synuclein tetramers, associated ferrireductase activity, and increases aggregates of α-synuclein. The results suggest that we have developed an interesting new model of aged microglia and that factors, including TNFα released from dystrophic microglia could have a significant influence on the pathogenesis of α-synuclein related diseases.

Altered Processing of ß-Amyloid in SH-SY5Y Cells Induced by Model Senescent Microglia.

The single greatest risk factor for neurodegenerative diseases is aging. Aging of cells such as microglia in the nervous system has an impact not only on the ability of those cells to function but also on cells they interact with. We have developed a model microglia system that recapitulates the dystrophic/senescent phenotype, and we have combined this with the study of ß-amyloid processing. The model is based on the observation that aged microglia have increased iron content. By overloading a human microglial cell line with iron, we were able to change the secretory profile of the microglia. When combining these senescent microglia with SH-SY5Y cells, we noted an increase in extracellular ß-amyloid. The increased levels of ß-amyloid were due to a decrease in the release of insulin-degrading enzyme by the model senescent microglia. Further analysis revealed that the senescent microglia showed both decreased autophagy and increased ER stress. These studies demonstrate the potential impact of an aging microglial population in terms of ß-amyloid produced by neurons, which could play a causal role in diseases like Alzheimer's disease. Our results also further develop the potential utility of an in vitro model of senescent microglia for the study of brain aging and neurodegenerative disease.

Racial and ethnic differences in perceived safety barriers to walking, United States National Health Interview Survey - 2015.

Barriers to safe walking may prevent people from being physically active, and previous reports have identified differences in barriers to safe walking across racial and ethnic groups. The purpose of this research was to determine the role demographic characteristics play on racial/ethnic differences in perceived barriers to safe walking and determine if racial/ethnic differences vary by urban/rural residence and Census region. Participants in the 2015 National Health Interview Survey Cancer Control Supplement (n = 31,433 adults ≥18 years) reported perceived barriers to safe walking (traffic, crime, and animals) and demographic characteristics. Urban/rural residence and Census region were based on home addresses. We calculated adjusted prevalence of barriers by race/ethnicity using logistic regression; geographic differences in barriers across racial/ethnic groups were examined via interaction terms. After adjustment for demographic characteristics, non-Hispanic blacks (blacks) and Hispanics reported crime and animals as barriers more frequently than non-Hispanic whites (whites) (crime: blacks, 22.2%; Hispanics, 16.7%; whites, 9.0%; animals: blacks, 18.0%; Hispanics, 12.4%; whites, 8.5%). Racial/ethnic differences in perceived crime as a barrier were more pronounced in the Northeast and Midwest than in the South and West. Urban-dwelling blacks (all regions) and Hispanics (Midwest and South) reported animals as barriers more frequently than whites. Racial/ethnic differences in perceived barriers to safe walking remained after adjusting for demographic characteristics and varied by geographic location. Addressing perceived crime and animals as barriers to walking could help reduce racial/ethnic differences in physical activity, and several barriers may need to be assessed to account for geographic variation.

Symposium review: Microbial endocrinology-Why the integration of microbes, epithelial cells, and neurochemical signals in the digestive tract matters to ruminant health.

The union of microbiology and neurobiology, which has been termed microbial endocrinology, is defined as the study of the ability of microorganisms to produce and respond to neurochemicals that originate either within the microorganisms themselves or within the host they inhabit. It serves as the basis for an evolutionarily derived method of communication between a host and its microbiota. Mechanisms elucidated by microbial endocrinology give new insight into the ways the microbiota can affect host stress, metabolic efficiency, resistance to disease, and other factors that may prove relevant to the dairy industry.

Levels of α- and ß-synuclein regulate cellular susceptibility to toxicity from α-synuclein oligomers.

α-Synuclein (α-syn) is associated with a range of diseases, including Parkinson disease. In disease, α-syn is known to aggregate and has the potential to be neurotoxic. The association between copper and α-syn results in the formation of stellate toxic oligomers that are highly toxic to cultured neurons. We further investigated the mechanism of toxicity of α-syn oligomers. Cells that overexpress α-syn showed increased susceptibility to the toxicity of the oligomers, while those that overexpressed ß-syn showed increased resistance to the toxic oligomers. Elevated α-syn expression caused an increase in expression of the transcription factor Forkhead box O3a (FoxO3a). Inhibition of FoxO3a activity by the overexpression of DNA binding domain of FoxO3a resulted in significant protection from α-syn oligomer toxicity. Increased FoxO3a expression in cells was shown to be caused by increased ferrireductase activity and Fe(II) levels. These results suggest that α-syn increases FoxO3a expression as a result of its intrinsic ferrireductase activity. The results also suggest that FoxO3a plays a pivotal role in the toxicity of both Fe(II) and toxic α-syn species to neuronal cells.-Angelova, D. M., Jones, H. B. L., Brown, D. R. Levels of α- and ß-synuclein regulate cellular susceptibility to toxicity from α-synuclein oligomers.

Prevalence of Modifiable Cancer Risk Factors Among U.S. Adults Aged 18-44 Years.

INTRODUCTION: Carcinogen exposure and unhealthy habits acquired in young adulthood can set the stage for the development of cancer at older ages. This study measured the current prevalence of several cancer risk factors among young adults to assess opportunities to intervene to change the prevalence of these risk factors and potentially reduce cancer incidence. METHODS: Using 2015 National Health Interview Survey data (analyzed in 2016), the prevalence of potential cancer risk factors was estimated among U.S. adults aged 18-44 years, based on responses to questions about diet, physical activity, tobacco product use, alcohol, indoor tanning, sleep, human papillomavirus vaccine receipt, and obesity, stratified by sex, age, and race/ethnicity. RESULTS: The prevalence of some risk factors varied by age and race/ethnicity. Obesity (one in four people) and insufficient sleep (one in three people) were common among men and women. Physical inactivity (one in five men, one in four women); binge drinking (one in four men, one in eight women); cigarette smoking (one in five men, one in seven women); and frequent consumption of red meat (one in four men, one in six women) also were common. More than half of the population of adults aged 18-44 years consumed sugar-sweetened beverages daily and processed meat at least once a week. Most young adults had never had the human papillomavirus vaccine. CONCLUSIONS: Findings can be used to target evidence-based environmental and policy interventions to reduce the prevalence of cancer risk factors among young adults and prevent the development of future cancers.

Steady-State Kinetics of α-Synuclein Ferrireductase Activity Identifies the Catalytically Competent Species.

α-Synuclein (α-syn) is a cytosolic protein known for its association with neurodegenerative diseases, including Parkinson's disease and other synucleinopathies. The potential cellular function of α-synuclein may be of consequence for understanding the pathogenesis of such diseases. Previous work has suggested that α-synuclein can catalyze the reduction of iron as a ferrireductase. We performed a detailed analysis of the steady-state kinetics of recombinant α-syn ferrireductase activity and for disease-associated variants. Our study illustrates that the ferrireductase activity we observed is clearly commensurate with bona fide enzyme activity and suggests a mechanistic rationale for the activity and the relationship to cellular regulation of the pool of Fe(III) and Fe(II). Using cell-based studies, we examined the functionally active conformation and found that the major catalytically active form is a putative membrane-associated tetramer. Using an artificial membrane environment with recombinant protein, we demonstrate that secondary structure folding of α-synuclein is insufficient to allow enzyme activity and the absolute specificity of the tertiary/quaternary structure is the primary requirement. Finally, we explored the steady-state kinetics of a range of disease α-synuclein variants and found that variants involved in neurodegenerative disease exhibited major changes in their enzymatic activity. We discuss these data in the context of a potential disease-associated mechanism for aberrant α-synuclein ferrireductase activity.

α-Synuclein increases ß-amyloid secretion by promoting ß-/γ-secretase processing of APP.

α-Synuclein misfolding and aggregation is often accompanied by ß-amyloid deposition in some neurodegenerative diseases. We hypothesised that α-synuclein promotes ß-amyloid production from APP. ß-Amyloid levels and APP amyloidogenic processing were investigated in neuronal cell lines stably overexpressing wildtype and mutant α-synuclein. γ-Secretase activity and ß-secretase expression were also measured. We show that α-synuclein expression induces ß-amyloid secretion and amyloidogenic processing of APP in neuronal cell lines. Certain mutations of α-synuclein potentiate APP amyloidogenic processing. γ-Secretase activity was not enhanced by wildtype α-synuclein expression, however ß-secretase protein levels were induced. Furthermore, a correlation between α-synuclein and ß-secretase protein was seen in rat brain striata. Iron chelation abolishes the effect of α-synuclein on neuronal cell ß-amyloid secretion, whereas overexpression of the ferrireductase enzyme Steap3 is robustly pro-amyloidogenic. We propose that α-synuclein promotes ß-amyloid formation by modulating ß-cleavage of APP, and that this is potentially mediated by the levels of reduced iron and oxidative stress.

Catecholamine-Directed Epithelial Cell Interactions with Bacteria in the Intestinal Mucosa.

The catecholamines epinephrine, norepinephrine and dopamine are present in or have access to mucous membranes in the digestive, respiratory and genitourinary tracts, which represent the first sites of microbial colonization and infection within the body. Epithelial cells at mucosal surfaces establish and maintain symbiotic microbial communities and serve as the initial cellular point of contact for pathogens with the animal host. These cells express receptors that are capable of detecting and responding to microbe-associated molecular patterns and in most host species express G protein-coupled receptors for catecholamines. Although it is increasingly recognized that substances produced and released from nerves and endocrine cells can exert immuno-modulatory actions at mucosal sites, there have been few investigations focused specifically on the catecholaminergic modulation of interactions between the mucosal epithelium and bacteria or other mucosa-associated microorganisms. The potential biomedical importance of this phenomenon cannot be understated. For example, psychological stress or other conditions that activate the sympathetic nervous system to release epinephrine and norepinephrine may act to produce short-term changes in luminal and mucosal microbial communities or alter the course of a bacterial infection. This chapter will briefly review this developing and important research area of mucosa-microbe interactions with a focus on intestinal host defense.

Prion infection in cells is abolished by a mutated manganese transporter but shows no relation to zinc.

The cellular prion protein has been identified as a metalloprotein that binds copper. There have been some suggestions that prion protein also influences zinc and manganese homeostasis. In this study we used a series of cell lines to study the levels of zinc and manganese under different conditions. We overexpressed either the prion protein or known transporters for zinc and manganese to determine relations between the prion protein and both manganese and zinc homeostasis. Our observations supported neither a link between the prion protein and zinc metabolism nor any effect of altered zinc levels on prion protein expression or cellular infection with prions. In contrast we found that a gain of function mutant of a manganese transporter caused reduction of manganese levels in prion infected cells, loss of observable PrP(Sc) in cells and resistance to prion infection. These studies strengthen the link between manganese and prion disease.