A replicable strategy for mapping air pollution's community-level health impacts and catalyzing prevention.

BACKGROUND: Air pollution was responsible for an estimated 6.7 million deaths globally in 2019 and 197,000 deaths in the United States. Fossil fuel combustion is the major source. HYPOTHESIS: Mapping air pollution's health impacts at the community level using publicly available data and open-source software will provide a replicable strategy for catalyzing pollution prevention. METHODS: Using EPA's Environmental Benefits Mapping and Analysis (BenMAP-CE) software and state data, we quantified the effects of airborne fine particulate matter (PM2.5) pollution on disease, death and children's cognitive function (IQ Loss) in each city and town in Massachusetts. To develop a first-order estimate of PM2.5 pollution's impact on child IQ, we derived a concentration-response coefficient through literature review. FINDINGS: The annual mean PM2.5 concentration in Massachusetts in 2019 was 6.3 µg/M3, a level below EPA's standard of 12 µg/M3 and above WHO's guideline of 5 µg/M3. In adults, PM2.5 pollution was responsible for an estimated 2780 (Confidence Interval [CI] 2726 - 2853) deaths: 1677 (CI, 1346 - 1926) from cardiovascular disease, 2185 (CI, 941-3409) from lung cancer, 200 (CI, 66-316) from stroke, and 343 (CI, 222-458) from chronic respiratory disease. In children, PM2.5 pollution was responsible for 308 (CI, 105-471) low-weight births, 15,386 (CJ, 5433-23,483) asthma cases, and a provisionally estimated loss of nearly 2 million Performance IQ points; IQ loss impairs children's school performance, reduces graduation rates and decreases lifetime earnings. Air-pollution-related disease, death and IQ loss were most severe in low-income, minority communities, but occurred in every city and town in Massachusetts regardless of location, demographics or median family income. CONCLUSION: Disease, death and IQ loss occur at air pollution exposure levels below current EPA standards. Prevention of disease and premature death and preservation of children's cognitive function will require that EPA air quality standards be tightened. Enduring prevention will require government-incentivized transition to renewable energy coupled with phase-outs of subsidies and tax breaks for fossil fuels. Highly localized information on air pollution's impacts on health and on children's cognitive function has potential to catalyze pollution prevention.

Cerebrospinal fluid and serum glycosphingolipid biomarkers in canine globoid cell leukodystrophy (Krabbe Disease).

Globoid cell leukodystrophy (GLD, Krabbe disease, Krabbe's disease) is caused by genetic mutations in the gene encoding, galactosylceramidase (GALC). Deficiency of this enzyme results in central and peripheral nervous system pathology, and is characterized by loss of myelin and an infiltration of globoid cells. The canine model of GLD provides a translational model which faithfully recapitulates much of the human disease pathology. Targeted lipidomic analysis was conducted in serum and cerebrospinal fluid (CSF) over the lifetime of GLD affected and normal canines, and in brain tissue at humane endpoint to better understand disease progression and identify potential biomarkers of disease. Psychosine, a substrate of GALC and primary contributor to the pathology in GLD, was observed to be significantly elevated in the serum and CSF by 2 or 4 weeks of age, respectively, and steadily increased over the lifetime of affected animals. Importantly, psychosine concentration strongly correlated with disease severity. Galactosylceramide, glucosylceramide, and lactosylceramide were also found to be elevated in the CSF of affected animals and increased with age. Psychosine and galactosylceramide were found to be significantly increased in brain tissue at humane endpoint. This study identified several biomarkers which may be useful in the development of therapeutics for GLD.

Spironolactone and topical retinoids in adult female cyclical acne.

PURPOSE: To access the efficacy of spironolactone and topical retinoids in the treatment of female cyclical acne. METHODS: A retrospective chart review on 41 female patients age 19-57 years old with cyclical acne was performed. Patients were examined over the course of 2 to 102 months while taking 50 to 200 mg of spironolactone and topical tretinoin 0.025% or adapalene 0.1% cream. All were diagnosed with acne rated mild to severe, prior to treatment, and were started on an initial dose of 50 mg po daily. If significant improvement was not seen within the first 3-6 months, the dose was either held or increased in 25 mg increments every 3 months. Patients on oral and topical antibiotics, as well as patients on photodynamic therapy were excluded from the study. The response to treatment was rated on a 0-4 scale with 0 being no response and 4 corresponding to clear skin. RESULTS: One patient (2.4%) had no response to treatment. This patient was only on 50 mg po daily for only 2 months. Only 5 (12.2%) patients had minimal response to treatment and 9 (22.0%), 12 (29.3%), and 14 (34.1%) had a good, excellent, or clear response respectively. The study showed 26 (63.4%) women on treatment with spironolactone and topical retinoids had an excellent or clear outcome, and 35 (85.4%) were considered to have a good, excellent, or clear response. CONCLUSION: The addition of spironolactone to topical retinoid treatment suggests a superior response to retinoids alone in clearance of female adult cyclical acne.

The Burden of Cardiovascular Disease from Air Pollution in Rwanda.

Background: Rwanda, like many countries in sub-Saharan Africa, is still relatively early in development. Industrialization and urbanization are major drivers of the county's economic growth. Rwanda is also undergoing an epidemiological transition, from a pattern of morbidity and mortality dominated by infectious diseases to a pattern shaped by non-communicable diseases (NCDs). The rise in NCDs is due, in part, to increasing exposures to environmental hazards. These include emissions from the growing number of motor vehicles and toxic occupational exposures. Cardiovascular disease (CVD) is now an increasingly important cause of death in Rwanda, and ambient air pollution is a CVD risk factor of growing importance. Objectives: To quantify the burden of CVD attributable to air pollution in Rwanda and identify opportunities for prevention and control of air pollution and pollution-related disease. Methods: We relied on the 2019 Global Burden of Disease (GBD) study for information on levels, sources, and trends in household and ambient air pollution and the burden of pollution-related disease in Rwanda. Information on pollution sources was obtained from the Health Effects Institute State of Global Air 2019 report. Findings: An estimated 3,477 deaths (95% Uncertainty Interval [UI]: 2,500-4,600) in Rwanda in 2019 were attributable to air pollution-related CVD. Of these, 689 (UI: 283-1,300) deaths were from ambient air pollution-related CVD, while 2,788 (UI: 1,800-3,800) deaths were from household air pollution-related CVD. Conclusion: Rwanda is experiencing increased rates of disease and premature death from NCDs, including CVD, as the country grows economically. While household air pollution is still the top pollution-related cause of disease and premature death, rising levels of ambient air pollution are an increasingly important CVD risk factor. Recommendation: Actions taken now to curb rising levels of ambient air pollution will improve health, reduce CVD, increase longevity, and produce great economic benefit for Rwanda. The single most effective intervention against air pollution will be a rapid nationwide transition to renewable energy. We recommend additionally that Rwanda prioritize air pollution prevention and control, establish a robust, nationwide air monitoring network, support research on the health effects of air pollutants, and build national research capacity. The allocation of increased resources for rural and urban public health and health care will complement air pollution control measures and further reduce CVD. To incentivize a rapid transition to renewable energy in Rwanda and other nations, we recommend the creation of a new Global Green Development Fund.

Assessing the Human Health Benefits of Climate Mitigation, Pollution Prevention, and Biodiversity Preservation.

Background: Since the Industrial Revolution, humanity has amassed great wealth and achieved unprecedented material prosperity. These advances have come, however, at great cost to the planet. They are guided by an economic model that focuses almost exclusively on short-term gain, while ignoring natural capital and human capital. They have relied on the combustion of vast quantities of fossil fuels, massive consumption of the earth's resources, and production and environmental release of enormous quantities of chemicals, pesticides, fertilizers, and plastics. They have caused climate change, pollution, and biodiversity loss, the "Triple Planetary Crisis". They are responsible for more than 9 million premature deaths per year and for widespread disease - impacts that fall disproportionately upon the poor and the vulnerable. Goals: To map the human health impacts of climate change, pollution, and biodiversity loss. To outline a framework for assessing the health benefits of interventions against these threats. Findings: Actions taken by national governments and international agencies to mitigate climate change, pollution, and biodiversity loss can improve health, prevent disease, save lives, and enhance human well-being. Yet assessment of health benefits is largely absent from evaluations of environmental remediation programs. This represents a lost opportunity to quantify the full benefits of environmental remediation and to educate policy makers and the public. Recommendations: We recommend that national governments and international agencies implementing interventions against climate change, pollution, and biodiversity loss develop metrics and strategies for quantifying the health benefits of these interventions. We recommend that they deploy these tools in parallel with assessments of ecologic and economic benefits. Health metrics developed by the Global Burden of Disease (GBD) study may provide a useful starting point.Incorporation of health metrics into assessments of environmental restoration will require building transdisciplinary collaborations. Environmental scientists and engineers will need to work with health scientists to establish evaluation systems that link environmental and economic data with health data. Such systems will assist international agencies as well as national and local governments in prioritizing environmental interventions.

Development of a Canadian Food Composition Database of Gluten-Free Products.

Country-specific food composition data are needed for gluten-free (GF) food products to assess nutritional adequacy and diet quality. This research aimed to develop a comprehensive GF food composition database for key GF foods consumed in Canada. Average nutrient data from 167 products were estimated from Nutrition Fact Panel labels and the commercial ingredient list, using an iterative and systematic approach. The database reports mean values for energy and 29 nutrients per 100 g for 33 GF commercial grain-based foods. Nutrient values were evaluated with Health Canada's nutrient content claims per standard reference serving. On average, GF products were, at minimum, a source of thiamin (73%), riboflavin (70%), niacin (58%), iron (58%), fibre (55%), magnesium (48%), folate (36%), zinc (19%), and calcium (15%). Most GF products were low in saturated fat (85%) and cholesterol (64%) but only 15% were low in total fat and 6% were free of sugar. Micronutrient enrichment and the use of nutrient-dense whole grain flours, legume flours, oil seed husks, and functional fibre ingredients varied within and between categories and brands but appeared to contribute to nutrient content. This database provides a new tool to enhance GF diet assessment in individuals or populations in Canada.

Air Pollution, Political Corruption, and Cardiovascular Disease in the Former Soviet Republics.

Background: Ambient air pollution is a serious problem in many Eastern European countries. Elevated levels of fine airborne particulate matter (PM2.5) pollution in the former Soviet republics relative to the rest of Europe contribute to elevated rates of disease, especially cardiovascular disease (CVD). Objective: Information on the underlying social and political causes of air pollution in Eastern Europe is important for pollution control and disease prevention. Methods: To quantify relationships between pollution, and air-pollution-related CVD, and political corruption throughout Europe and particularly in the former Soviet republics, we relied on the State of Global Air report for information on air pollution levels; on the 2019 Global Burden of Disease study (GBD) for estimates of the burden of air-pollution-related CVD; and on Transparency International (TI) for rankings of governmental corruption. Findings: Air-pollution-related CVD was responsible for an estimated 178,000 (UI: 112,000-251,000) premature deaths and for the loss of 4,010,000 (UI: 2,518,000--5,611,000) productive years of life (DALYs) in 2019 in the former Soviet republics. A significant positive correlation (R = 0.72, p 1.7e-8) was found across Europe between air-pollution-related CVD mortality rates and national corruption rankings. Conclusions: We conclude that lack of governmental transparency, inadequate air pollution monitoring, and opposition by vested interests have hindered air pollution control and perpetuated high rates of pollution-related morbidity and mortality in the former Soviet republics. Ending corruption and modernizing industrial production will be key to air pollution and related diseases.

Air pollution and development in Africa: impacts on health, the economy, and human capital.

BACKGROUND: Africa is undergoing both an environmental and an epidemiological transition. Household air pollution is the predominant form of air pollution, but it is declining, whereas ambient air pollution is increasing. We aimed to quantify how air pollution is affecting health, human capital, and the economy across Africa, with a particular focus on Ethiopia, Ghana, and Rwanda. METHODS: Data on household and ambient air pollution were from WHO Global Health Observatory, and data on morbidity and mortality were from the 2019 Global Burden of Disease Study. We estimated economic output lost due to air pollution-related disease by country, with use of labour income per worker, adjusted by the probability that a person (of a given age) was working. Losses were expressed in 2019 international dollars and as a proportion of gross domestic product (GDP). We also quantified the contribution of particulate matter (PM)2·5 pollution to intelligence quotient (IQ) loss in children younger than 10 years, with use of an exposure-response coefficient based on previously published data. FINDINGS: Air pollution was responsible for 1·1 million deaths across Africa in 2019. Household air pollution accounted for 697 000 deaths and ambient air pollution for 394 000. Ambient air pollution-related deaths increased from 361 000 in 2015, to 383 000 in 2019, with the greatest increases in the most highly developed countries. The majority of deaths due to ambient air pollution are caused by non-communicable diseases. The loss in economic output in 2019 due to air pollution-related morbidity and mortality was $3·02 billion in Ethiopia (1·16% of GDP), $1·63 billion in Ghana (0·95% of GDP), and $349 million in Rwanda (1·19% of GDP). PM2·5 pollution was estimated to be responsible for 1·96 billion lost IQ points in African children in 2019. INTERPRETATION: Ambient air pollution is increasing across Africa. In the absence of deliberate intervention, it will increase morbidity and mortality, diminish economic productivity, impair human capital formation, and undercut development. Because most African countries are still early in development, they have opportunities to transition rapidly to wind and solar energy, avoiding a reliance on fossil fuel-based economies and minimising pollution. FUNDING: UN Environment Programme.

Ocean acidification disrupts the orientation of postlarval Caribbean spiny lobsters.

Anthropogenic inputs into coastal ecosystems are causing more frequent environmental fluctuations and reducing seawater pH. One such ecosystem is Florida Bay, an important nursery for the Caribbean spiny lobster, Panulirus argus. Although adult crustaceans are often resilient to reduced seawater pH, earlier ontogenetic stages can be physiologically limited in their tolerance to ocean acidification on shorter time scales. We used a Y-maze chamber to test whether reduced-pH seawater altered the orientation of spiny lobster pueruli toward chemical cues produced by Laurencia spp. macroalgae, a known settlement cue for the species. We tested the hypothesis that pueruli conditioned in reduced-pH seawater would be less responsive to Laurencia spp. chemical cues than pueruli in ambient-pH seawater by comparing the proportion of individuals that moved to the cue side of the chamber with the proportion that moved to the side with no cue. We also recorded the amount of time (sec) before a response was observed. Pueruli conditioned in reduced-pH seawater were less responsive and failed to select the Laurencia cue. Our results suggest that episodic acidification of coastal waters might limit the ability of pueruli to locate settlement habitats, increasing postsettlement mortality.

Human Health and Ocean Pollution.

Background: Pollution - unwanted waste released to air, water, and land by human activity - is the largest environmental cause of disease in the world today. It is responsible for an estimated nine million premature deaths per year, enormous economic losses, erosion of human capital, and degradation of ecosystems. Ocean pollution is an important, but insufficiently recognized and inadequately controlled component of global pollution. It poses serious threats to human health and well-being. The nature and magnitude of these impacts are only beginning to be understood. Goals: (1) Broadly examine the known and potential impacts of ocean pollution on human health. (2) Inform policy makers, government leaders, international organizations, civil society, and the global public of these threats. (3) Propose priorities for interventions to control and prevent pollution of the seas and safeguard human health. Methods: Topic-focused reviews that examine the effects of ocean pollution on human health, identify gaps in knowledge, project future trends, and offer evidence-based guidance for effective intervention. Environmental Findings: Pollution of the oceans is widespread, worsening, and in most countries poorly controlled. It is a complex mixture of toxic metals, plastics, manufactured chemicals, petroleum, urban and industrial wastes, pesticides, fertilizers, pharmaceutical chemicals, agricultural runoff, and sewage. More than 80% arises from land-based sources. It reaches the oceans through rivers, runoff, atmospheric deposition and direct discharges. It is often heaviest near the coasts and most highly concentrated along the coasts of low- and middle-income countries. Plastic is a rapidly increasing and highly visible component of ocean pollution, and an estimated 10 million metric tons of plastic waste enter the seas each year. Mercury is the metal pollutant of greatest concern in the oceans; it is released from two main sources - coal combustion and small-scale gold mining. Global spread of industrialized agriculture with increasing use of chemical fertilizer leads to extension of Harmful Algal Blooms (HABs) to previously unaffected regions. Chemical pollutants are ubiquitous and contaminate seas and marine organisms from the high Arctic to the abyssal depths. Ecosystem Findings: Ocean pollution has multiple negative impacts on marine ecosystems, and these impacts are exacerbated by global climate change. Petroleum-based pollutants reduce photosynthesis in marine microorganisms that generate oxygen. Increasing absorption of carbon dioxide into the seas causes ocean acidification, which destroys coral reefs, impairs shellfish development, dissolves calcium-containing microorganisms at the base of the marine food web, and increases the toxicity of some pollutants. Plastic pollution threatens marine mammals, fish, and seabirds and accumulates in large mid-ocean gyres. It breaks down into microplastic and nanoplastic particles containing multiple manufactured chemicals that can enter the tissues of marine organisms, including species consumed by humans. Industrial releases, runoff, and sewage increase frequency and severity of HABs, bacterial pollution, and anti-microbial resistance. Pollution and sea surface warming are triggering poleward migration of dangerous pathogens such as the Vibrio species. Industrial discharges, pharmaceutical wastes, pesticides, and sewage contribute to global declines in fish stocks. Human Health Findings: Methylmercury and PCBs are the ocean pollutants whose human health effects are best understood. Exposures of infants in utero to these pollutants through maternal consumption of contaminated seafood can damage developing brains, reduce IQ and increase children's risks for autism, ADHD and learning disorders. Adult exposures to methylmercury increase risks for cardiovascular disease and dementia. Manufactured chemicals - phthalates, bisphenol A, flame retardants, and perfluorinated chemicals, many of them released into the seas from plastic waste - can disrupt endocrine signaling, reduce male fertility, damage the nervous system, and increase risk of cancer. HABs produce potent toxins that accumulate in fish and shellfish. When ingested, these toxins can cause severe neurological impairment and rapid death. HAB toxins can also become airborne and cause respiratory disease. Pathogenic marine bacteria cause gastrointestinal diseases and deep wound infections. With climate change and increasing pollution, risk is high that Vibrio infections, including cholera, will increase in frequency and extend to new areas. All of the health impacts of ocean pollution fall disproportionately on vulnerable populations in the Global South - environmental injustice on a planetary scale. Conclusions: Ocean pollution is a global problem. It arises from multiple sources and crosses national boundaries. It is the consequence of reckless, shortsighted, and unsustainable exploitation of the earth's resources. It endangers marine ecosystems. It impedes the production of atmospheric oxygen. Its threats to human health are great and growing, but still incompletely understood. Its economic costs are only beginning to be counted.Ocean pollution can be prevented. Like all forms of pollution, ocean pollution can be controlled by deploying data-driven strategies based on law, policy, technology, and enforcement that target priority pollution sources. Many countries have used these tools to control air and water pollution and are now applying them to ocean pollution. Successes achieved to date demonstrate that broader control is feasible. Heavily polluted harbors have been cleaned, estuaries rejuvenated, and coral reefs restored.Prevention of ocean pollution creates many benefits. It boosts economies, increases tourism, helps restore fisheries, and improves human health and well-being. It advances the Sustainable Development Goals (SDG). These benefits will last for centuries. Recommendations: World leaders who recognize the gravity of ocean pollution, acknowledge its growing dangers, engage civil society and the global public, and take bold, evidence-based action to stop pollution at source will be critical to preventing ocean pollution and safeguarding human health.Prevention of pollution from land-based sources is key. Eliminating coal combustion and banning all uses of mercury will reduce mercury pollution. Bans on single-use plastic and better management of plastic waste reduce plastic pollution. Bans on persistent organic pollutants (POPs) have reduced pollution by PCBs and DDT. Control of industrial discharges, treatment of sewage, and reduced applications of fertilizers have mitigated coastal pollution and are reducing frequency of HABs. National, regional and international marine pollution control programs that are adequately funded and backed by strong enforcement have been shown to be effective. Robust monitoring is essential to track progress.Further interventions that hold great promise include wide-scale transition to renewable fuels; transition to a circular economy that creates little waste and focuses on equity rather than on endless growth; embracing the principles of green chemistry; and building scientific capacity in all countries.Designation of Marine Protected Areas (MPAs) will safeguard critical ecosystems, protect vulnerable fish stocks, and enhance human health and well-being. Creation of MPAs is an important manifestation of national and international commitment to protecting the health of the seas.

Pollution and children's health.

FINDINGS: The Lancet Commission on Pollution and Health found that pollution - air, water, soil, and chemical pollution - was responsible in 2016 for 940,000 deaths in children worldwide, two-thirds of them in children under the age of 5. Pollution is inequitably distributed, and the overwhelming majority of pollution-related deaths in children occurred in low- and middle-income countries (LMICs). Most were due to respiratory and gastrointestinal diseases caused by polluted air and water. Pollution is linked also to multiple non-communicable diseases (NCDs) in children including low birth weight, asthma, cancer and neurodevelopmental disorders, and these diseases are on the rise. The full impact of pollution, especially chemical pollution on the global burden of pediatric disease is not yet known, but almost certainly is undercounted because patterns of chemical exposure are not well charted and the potential toxicity of many chemical pollutants has not been characterized. The list of pediatric NCDs attributed to pollution will likely expand as the health effects of newer chemical pollutants are better defined and additional associations between pollution and disease are discovered. CONCLUSION: Pollution prevention presents a major, largely unexploited opportunity to improve children's health and prevent NCDs, especially in LMICs. Failure to incorporate pollution prevention into NCD control programs is a major missed opportunity for disease prevention.

Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC).

The family histories of 130 individuals with documented hereditary non-polyposis colorectal cancer (HNPCC) (caused by mutations in mismatch-repair (MMR) genes MSH2 (n = 64), MLH1 (n = 62) or MSH6 (n = 4)) were obtained, and incidence of cancers in those families was compared to that in the general population. There were a total of 982 cancers in 723 individuals. Colorectal cancer (CRC) was the commonest type (64% and 55% in individuals from families with germline MLH1 and MSH2 mutations respectively). Median age at diagnosis of first CRC in MSH6 mutation families was 59 years compared to 45 years in both MLH1 and MSH2 mutation families. The relative risk (RR) of endometrial cancer was 55 in MSH2 mutation families, compared with 27 in MLH1 mutation families, and 37 in MSH6 mutation families; median age at diagnosis 49 years. Even within MSH2 families, endometrial cancer tended to cluster, with 28 of the 58 cases coming from families with three or more cases (P < 0.001). Absolute risk of endometrial cancer in MLH1 families was still greater than any other cancer (other than CRC). 5% of cancers in both MLH1 and MSH2 mutation families were gastric (RR = 12); 53% of these were diagnosed before 50 years. Seven cases of small intestinal cancer occurred in MSH2 and MLH1 mutation families (RR = 26). There were 13 cases of cancer of the ureter; all were in MSH2 families. These cancers tended to cluster within families (P < 0.001); three of seven families with urothelial cancer had such cases in two or more individuals; two others had kidney cancer. Nineteen of 27 ovarian cancers (70%) were in MSH2 mutation families and 70% of these were diagnosed before age 50 years. There were 9 cases of sebaceous skin cancer, 3 in two MLH1 and 6 in four MSH2 mutation families. Of 22 pancreatic cancers, 14 were known to be diagnosed before 60 years. Breast cancer RR was 1.7 overall. The type of mutation (truncating or other type, and site of mutation) showed no obvious correlation with the presence or absence of extra-colonic cancers in families.

A meta-analysis of blood lead levels in India and the attributable burden of disease.

Multiple studies in India have found elevated blood lead levels (BLLs) in target populations. However the data have not yet been evaluated to understand population-wide exposure levels. We used arithmetic mean blood lead data published from 2010 to 2018 on Indian populations to calculate the average BLLs for multiple subgroups. We then calculated the attributable disease burden in IQ decrement and Disability Adjusted Life Years (DALYs). Our Pubmed search yielded 1066 articles. Of these, 31 studies representing the BLLs of 5472 people in 9 states met our study criteria. Evaluating these, we found a mean BLL of 6.86 µg/dL (95% CI: 4.38-9.35) in children and 7.52 µg/dL (95% CI: 5.28-9.76) in non-occupationally exposed adults. We calculated that these exposures resulted in 4.9 million DALYs (95% CI: 3.9-5.6) in the states we evaluated. Population-wide BLLs in India remain elevated despite regulatory action to eliminate leaded petrol, the most significant historical source. The estimated attributable disease burden is larger than previously calculated, particularly with regard to associated intellectual disability outcomes in children. Larger population-wide BLL studies are required to inform future calculations. Policy responses need to be developed to mitigate the worst exposures.

LC3 Immunostaining in the Inferior Olivary Nuclei of Cats With Niemann-Pick Disease Type C1 Is Associated With Patterned Purkinje Cell Loss.

The feline model of Niemann-Pick disease, type C1 (NPC1) recapitulates the clinical, neuropathological, and biochemical abnormalities present in children with NPC1. The hallmarks of disease are the lysosomal storage of unesterified cholesterol and multiple sphingolipids in neurons, and the spatial and temporal distribution of Purkinje cell death. In feline NPC1 brain, microtubule-associated protein 1 light chain 3 (LC3) accumulations, indicating autophagosomes, were found within axons and presynaptic terminals. High densities of accumulated LC3 were seen in subdivisions of the inferior olive, which project to cerebellar regions that show the most Purkinje cell loss, suggesting that autophagic abnormalities in specific climbing fibers may contribute to the spatial pattern of Purkinje cell loss seen. Biweekly intrathecal administration of 2-hydroxypropyl-beta cyclodextrin (HPßCD) ameliorated neurological dysfunction, reduced cholesterol and sphingolipid accumulation, and increased lifespan in NPC1 cats. LC3 pathology was reduced in treated animals suggesting that HPßCD administration also ameliorates autophagic abnormalities. This study is the first to (i) identify specific brain regions exhibiting autophagic abnormalities in any species with NPC1, (ii) provide evidence of differential vulnerability among discrete brain nuclei and pathways, and (iii) show the amelioration of these abnormalities in NPC1 cats treated with HPßCD.

An individual with Muir-Torre syndrome found to have a pathogenic MSH6 gene mutation.

Mutations reported to cause Muir-Torre syndrome (MTS) have previously been reported in the mismatch repair genes MLH1 and MSH2 and more recently, in MYH [1]. We report siblings, one of whom has a clinical diagnosis of MTS, who have a pathogenic MSH6 gene mutation. This finding demonstrates that MSH6 gene analysis should be considered in MTS families where no MSH2 or MLH1 gene mutations have been found.

Contribution of cyclin d1 (CCND1) and E-cadherin (CDH1) polymorphisms to familial and sporadic colorectal cancer.

The molecular basis for most non-HNPCC familial colorectal cancer cases is unknown, but there is increasing evidence that common genetic variants may play a role. We investigated the contribution of polymorphisms in two genes implicated in the pathogenesis of colorectal cancer, cyclin D1 (CCND1) and E-cadherin (CDH1), to familial and sporadic forms of the disease. The CCND1 870A/G polymorphism is thought to affect the expression of CCND1 through mRNA splicing and has been reported to modify the penetrance of HNPCC. Inactivation of E-cadherin is common in colorectal cancer, and truncating germline mutations have been reported to confer susceptibility to colorectal as well as diffuse gastric cancer. The -160A/C CDH1 polymorphism appears to affect expression of CDH1 and may therefore also confer an increased risk. We found a significantly higher frequency of CCND1 870A allele in 206 familial cases compared to 171 controls (P=0.03). Odds ratios in heterozygotes and homozygotes were 1.7 (95% CI: 1.0-2.66) and 1.8 (95% CI: 1.0-3.3) respectively. The difference was accounted for by an over-representation of A allele in non-HNPCC familial cases (P=0.007). Over-representation of the CCND1 A allele was also seen in sporadic colorectal cancer cases compared to controls but this did not attain statistical significance (P=0.08). No significant differences between the frequency of CDH1 -160A/C genotypes in familial, sporadic colorectal cancer cases and controls were seen, although a possible association between the low expressing A allele and right-sided tumours was detected in familial cases.

Monocrotaline, an alternative to retrorsine-based hepatocyte transplantation in rodents.

Retrorsine has been used extensively to inhibit proliferation of resident hepatocytes in various transplantation models. Here we report a successful alternative to currently unavailable retrorsine that can be used in cellular transplantation models. Based on structural and molecular similarities, we investigate the use of monocrotaline (MCT) in cell transplantation studies in rodents. In this study, MCT was given to rats intraperitoneally in two injections 2 weeks apart. Two weeks after the final injection, a partial hepatectomy followed by splenic hepatocyte transplantation was performed. The results indicate that MCT, at two doses of 30 mg/kg, highly enhances liver repopulation by donor hepatocytes following partial hepatectomy and produces 15.3 +/- 4.9% liver repopulation within the first 6 weeks following transplantation. Additionally, we tested the effectiveness of MCT in a murine model. Using two injections of 50 mg/kg each, given 2 weeks apart, hepatocyte proliferation in the native liver was inhibited and subsequent oval cell transplants engrafted at 18 +/- 21.3% after 16 weeks posttransplantation. In conclusion, MCT can be used as an effective selective pressure for donor hepatocytes in cell transplantation to the liver in rodents.

A microfluidic-based genetic screen to identify microbial virulence factors that inhibit dendritic cell migration.

Microbial pathogens are able to modulate host cells and evade the immune system by multiple mechanisms. For example, Salmonella injects effector proteins into host cells and evades the host immune system in part by inhibiting dendritic cell (DC) migration. The identification of microbial factors that modulate normal host functions should lead to the development of new classes of therapeutics that target these pathways. Current screening methods to identify either host or pathogen genes involved in modulating migration towards a chemical signal are limited because they do not employ stable, precisely controlled chemical gradients. Here, we develop a positive selection microfluidic-based genetic screen that allows us to identify Salmonella virulence factors that manipulate DC migration within stable, linear chemokine gradients. Our screen identified 7 Salmonella effectors (SseF, SifA, SspH2, SlrP, PipB2, SpiC and SseI) that inhibit DC chemotaxis toward CCL19. This method is widely applicable for identifying novel microbial factors that influence normal host cell chemotaxis as well as revealing new mammalian genes involved in directed cell migration.