Methylomic changes in individuals with psychosis, prenatally exposed to endocrine disrupting compounds

Lessons from diethylstilbestrol : psychosis associated with specific methylomic modifications that could impact neurodevelopment and neuroplasticity in the DES-exposed.

2017 Study Abstract

BACKGROUND
In the Western world, between 1940 and 1970, more than 2 million people were exposed in utero to diethylstilbestrol (DES). In exposed individuals, and in their descendants, adverse outcomes have been linked to such exposure, including cancers, genital malformations, and less consistently, psychiatric disorders. We aimed to explore whether prenatal DES exposure would be associated with DNA methylation changes, and whether these epigenetic modifications would be associated with increased risk of psychosis.

METHODS
From 247 individuals born from mothers exposed to DES, we selected 69 siblings from 30 families. In each family, at least one sibling was exposed in utero to DES. We performed a methylome-wide association study using HumanMethylation450 DNA Analysis BeadChip® in peripheral blood. We analyzed methylation changes at individual CpGs or regions in exposed (n = 37) versus unexposed individuals (n = 32). We also compared exposed individuals with (n = 7) and without psychosis (n = 30).

RESULTS
There were more individuals with schizophrenia in the DES-exposed group. We found no significant differences between exposed and unexposed individuals with respect to differentially methylated CpGs or regions. The largest difference was in a region near the promoter of an ADAMTS proteoglycanase gene (ADAMTS9). Compared to exposed individuals without psychosis, exposed individuals with psychosis had differential methylation in the region encompassing the gene encoding the zinc finger protein 57 (ZFP57).

CONCLUSIONS
In utero exposure to DES was not associated with methylation changes at specific CpG or regions. In exposed individuals, however, psychosis was associated with specific methylomic modifications that could impact neurodevelopment and neuroplasticity.

  • Image credit Morgaine. Read and download the full study (free access) on the NCBI, PubMed, PMC5390994, 2017 Apr 13.
DES DiEthylStilbestrol Resources

U.S. health care quality and access index far from the top in global study

Healthcare Access and Quality Index based on mortality from causes amenable to personal health care in 195 countries and territories, 1990–2015: a novel analysis from the Global Burden of Disease Study 2015

2017 Study Summary

Background
National levels of personal health-care access and quality can be approximated by measuring mortality rates from causes that should not be fatal in the presence of effective medical care (ie, amenable mortality). Previous analyses of mortality amenable to health care only focused on high-income countries and faced several methodological challenges. In the present analysis, we use the highly standardised cause of death and risk factor estimates generated through the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to improve and expand the quantification of personal health-care access and quality for 195 countries and territories from 1990 to 2015.

Methods
We mapped the most widely used list of causes amenable to personal health care developed by Nolte and McKee to 32 GBD causes. We accounted for variations in cause of death certification and misclassifications through the extensive data standardisation processes and redistribution algorithms developed for GBD. To isolate the effects of personal health-care access and quality, we risk-standardised cause-specific mortality rates for each geography-year by removing the joint effects of local environmental and behavioural risks, and adding back the global levels of risk exposure as estimated for GBD 2015. We employed principal component analysis to create a single, interpretable summary measure–the Healthcare Quality and Access (HAQ) Index–on a scale of 0 to 100. The HAQ Index showed strong convergence validity as compared with other health-system indicators, including health expenditure per capita (r=0·88), an index of 11 universal health coverage interventions (r=0·83), and human resources for health per 1000 (r=0·77). We used free disposal hull analysis with bootstrapping to produce a frontier based on the relationship between the HAQ Index and the Socio-demographic Index (SDI), a measure of overall development consisting of income per capita, average years of education, and total fertility rates. This frontier allowed us to better quantify the maximum levels of personal health-care access and quality achieved across the development spectrum, and pinpoint geographies where gaps between observed and potential levels have narrowed or widened over time.

Findings
Between 1990 and 2015, nearly all countries and territories saw their HAQ Index values improve; nonetheless, the difference between the highest and lowest observed HAQ Index was larger in 2015 than in 1990, ranging from 28·6 to 94·6. Of 195 geographies, 167 had statistically significant increases in HAQ Index levels since 1990, with South Korea, Turkey, Peru, China, and the Maldives recording among the largest gains by 2015. Performance on the HAQ Index and individual causes showed distinct patterns by region and level of development, yet substantial heterogeneities emerged for several causes, including cancers in highest-SDI countries; chronic kidney disease, diabetes, diarrhoeal diseases, and lower respiratory infections among middle-SDI countries; and measles and tetanus among lowest-SDI countries. While the global HAQ Index average rose from 40·7 (95% uncertainty interval, 39·0–42·8) in 1990 to 53·7 (52·2–55·4) in 2015, far less progress occurred in narrowing the gap between observed HAQ Index values and maximum levels achieved; at the global level, the difference between the observed and frontier HAQ Index only decreased from 21·2 in 1990 to 20·1 in 2015. If every country and territory had achieved the highest observed HAQ Index by their corresponding level of SDI, the global average would have been 73·8 in 2015. Several countries, particularly in eastern and western sub-Saharan Africa, reached HAQ Index values similar to or beyond their development levels, whereas others, namely in southern sub-Saharan Africa, the Middle East, and south Asia, lagged behind what geographies of similar development attained between 1990 and 2015.

Interpretation
This novel extension of the GBD Study shows the untapped potential for personal health-care access and quality improvement across the development spectrum. Amid substantive advances in personal health care at the national level, heterogeneous patterns for individual causes in given countries or territories suggest that few places have consistently achieved optimal health-care access and quality across health-system functions and therapeutic areas. This is especially evident in middle-SDI countries, many of which have recently undergone or are currently experiencing epidemiological transitions. The HAQ Index, if paired with other measures of health-system characteristics such as intervention coverage, could provide a robust avenue for tracking progress on universal health coverage and identifying local priorities for strengthening personal health-care quality and access throughout the world.

Sources and Press Releases
  • Healthcare Access and Quality Index based on mortality from causes amenable to personal health care in 195 countries and territories, 1990–2015: a novel analysis from the Global Burden of Disease Study 2015, the lancet, dx.doi.org/10.1016/S0140-6736(17)30818-8, May 18, 2017.
  • Image : Map of HAQ Index values, by decile, in 1990 (A) and 2015 (B) – credit lancet.
  • ‘An embarrassment’: U.S. health care far from the top in global study, washingtonpost, May 18 2017.

About The Personal Care Products Safety Act

Bill would help protect consumers from chemicals that disrupt hormones

Endocrine Society applauds new push to regulate chemicals in personal care products

Washington, DCThe Endocrine Society praised the reintroduction of a Senate bill to ensure consumers are protected from hazards associated with exposure to chemicals in personal care products such as cosmetics and lotions.

The Personal Care Products Safety Act, co-sponsored by U.S. Sens. Dianne Feinstein and Susan Collins, would set a rigorous safety standard for personal care products and provide the public with more information about the chemicals in the products they are purchasing. This is an area of concern for the Society and its 18,000 members, including researchers studying how endocrine-disrupting chemicals (EDCs) disrupt the body’s hormones.

An EDC is a chemical or mixture of chemicals that can cause adverse health effects by interfering with hormones in the body. There are more than 85,000 manufactured chemicals, of which thousands may be EDCs. EDCs are found in everyday products and throughout the environment.
The evidence is more definitive than ever before that EDCs disrupt hormones in a manner that harms human health. EDC-related health outcomes include male reproductive disorders, premature death, obesity and diabetes, neurological impacts, breast cancer, endometriosis, female reproductive disorders, immune disorders, liver cancer, osteoporosis, Parkinson’s disease, prostate cancer and thyroid disorders.

The Personal Care Products Safety Act calls for some chemicals found in shampoo, deodorant, cosmetics and other personal care products to be reviewed for safety for the first time. The Society applauded the bill’s inclusion of propyl paraben, a potential EDC linked to reproductive disorders, as one of the first five chemicals slated for review.
By providing the necessary authority and fees for the FDA to properly regulate personal care products, the Society believes that this legislation will effectively and efficiently ensure a safer marketplace for personal care products and reduce harms from exposure to EDCs and other toxic chemicals.

Sources and Press Releases

  • Endocrine Society applauds new push to regulate chemicals in personal care products, TheEndoSociety, May 15, 2017.
  • Senators Seek Enhanced Safety Looks at Cosmetic Ingredients, promomarketing, May 15, 2017.
  • Personal Care Products Safety Act Would Improve Cosmetics Safety, ewg.
Endocrine Disruptors

Victimes Suisses du DES : Appel à Témoin

Votre mère a-t-elle pris du Clinestrol, Cyren B, Cyren S, Estril, Estrobene, Oestrostilben ou Syntostrol ?

En 2012, l’émission 36°9, de la chaîne RTS, avait publié un excellent reportage Distilbène: un héritage empoisonné, traitant des conséquences multi-générationnelles du DES – annonçé ici.

Aujourd’hui en 2017, RTS santé recherche des victimes Suisses du DES distilbène – également commercialisé en Suisse de 1953 à 1977 sous les noms de Clinestrol, Cyren B, Cyren S, Estril, Estrobene, Oestrostilben, Syntostrol – une mère à qui on l’aurait prescrit pendant sa grossesse ou des enfants qui en subissent les conséquences.

Veuillez contacter Réseau DES France via leur site sécurisé.

Les journalistes suisses se déplaceront fin mai près de Perpignan, pour interviewer les victimes de la Dépakine et Marine Martin, présidente de l’APESAC.

Les Filles DES de la région Occitanie, prêtes à témoigner de leur parcours, peuvent contacter Réseau DES France, d’ici ce mardi 23, par courriel.

Le Distilbène DES, en savoir plus

Can common chemicals in the environment affect human foetal brain development ?

Human amniotic fluid contaminants alter thyroid hormone signalling and early brain development in Xenopus embryos

In a recent experiment conducted on tadpoles, researchers tested the hypothesis that common chemicals in the environment, singly and as a mixture, can interfere with human brain development.

2017 Study Abstract

Thyroid hormones are essential for normal brain development in vertebrates. In humans, abnormal maternal thyroid hormone levels during early pregnancy are associated with decreased offspring IQ and modified brain structure.

As numerous environmental chemicals disrupt thyroid hormone signalling, we questioned whether exposure to ubiquitous chemicals affects thyroid hormone responses during early neurogenesis.

We established a mixture of 15 common chemicals at concentrations reported in human amniotic fluid. An in vivo larval reporter (GFP) assay served to determine integrated thyroid hormone transcriptional responses.

  • Dose-dependent effects of short-term (72 h) exposure to single chemicals and the mixture were found. qPCR on dissected brains showed significant changes in thyroid hormone-related genes including receptors, deiodinases and neural differentiation markers.
  • Further, exposure to mixture also modified neural proliferation as well as neuron and oligodendrocyte size.
  • Finally, exposed tadpoles showed behavioural responses with dose-dependent reductions in mobility.

In conclusion, exposure to a mixture of ubiquitous chemicals at concentrations found in human amniotic fluid affect thyroid hormone-dependent transcription, gene expression, brain development and behaviour in early embryogenesis. As thyroid hormone signalling is strongly conserved across vertebrates the results suggest that ubiquitous chemical mixtures could be exerting adverse effects on foetal human brain development.

Sources and Press Releases
  • Human amniotic fluid contaminants alter thyroid hormone signalling and early brain development in Xenopus embryos, Nature, doi:10.1038/srep43786, 07 March 2017.
  • Everyday chemicals may affect brain development, including foetal IQ, the conversation, May 11, 2017.
  • Image credit Benny Mazur.

Can (Non-Ruptured) Breast Implants Give You Cancer ?

Anaplastic Large Cell Lymphoma (ALCL) In Women with Breast Implants

Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) — is a cancer that has affected a tiny proportion of the women who have received implants. Nearly all the cases have been linked to implants with a textured or slightly roughened surface, rather than a smooth covering. Texturing may cause inflammation that leads to cancer.

Anaplastic Large Cell Lymphoma (ALCL) In Women with Breast Implants

January 2011 Preliminary FDA Findings and Analyses

Executive Summary

Reports in the scientific community have suggested a possible association between anaplastic large cell lymphoma (ALCL) and breast implants. In this document we summarize the scientific data the FDA used to assess the possible association. It represents our current understanding, based on the published scientific literature on ALCL in women with breast implants and information gathered through the FDA’s contact with other regulatory authorities, scientific experts, and breast implant manufacturers. The document includes the FDA’s analyses of the data and steps we plan to take to better understand and characterize the possible association.

Although ALCL is extremely rare, the FDA believes that women with breast implants may have a very small but increased risk of developing this disease in the scar capsule adjacent to the implant. Based on available information, it is not possible to confirm with statistical certainty that breast implants cause ALCL. At this time, data appear to indicate that the incidence of ALCL is very low, even in breast implant patients. Currently it is not possible to identify a type of implant (silicone versus saline) or a reason for implant (reconstruction versus aesthetic augmentation) associated with a smaller or greater risk.

The FDA is interested in learning more about the actual incidence of ALCL in women with breast implants, the characteristics of breast implants that might increase the risk of ALCL, and the pathological characteristics and clinical features of ALCL in women with breast implants. To this end, FDA is collaborating with the American Society of Plastic Surgeons to establish a registry of cases of women with breast implants who have been diagnosed with ALCL.

Health care providers should be aware ALCL in women with breast implants is a very rare condition; when it occurs, it has been identified most frequently in patients undergoing implant revision operations for late onset, persistent seroma. The FDA does not recommend prophylactic breast implant removal in patients without symptoms or other abnormalities. Current recommendations are described below. As we learn more about ALCL in women with breast implants, these recommendations may change.

  • Consider the possibility of ALCL when you have a patient with late onset, persistent peri-implant seroma. In some cases, patients presented with capsular contracture or masses adjacent to the breast implant. If you have a patient with suspected ALCL, refer her to an appropriate specialist for evaluation. When testing for ALCL, collect fresh seroma fluid and representative portions of the capsule and send for pathology tests to rule out ALCL. Diagnostic evaluation should include cytological evaluation of seroma fluid with Wright Giemsa stained smears and cell block immunohistochemistry testing for cluster of differentiation (CD) and Anaplastic Lymphoma Kinase (ALK) markers.
  • Report all confirmed cases of ALCL in women with breast implants to the FDA. In some cases, the FDA may contact you for additional information. The FDA will keep the reporter’s and the patient’s identity confidential.
  • Develop an individualized treatment plan in coordination with the patient’s multi-disciplinary care team. Because of the small number of cases worldwide and variety of available treatment options, there is no single defined consensus treatment regimen.

Some researchers have suggested that breast implant-associated ALCL may represent a new clinically entity with less-aggressive (indolent) behavior (Li, 2010; Miranda et al, 2009; Thompson et al, 2010). Because of the small number of cases and the short median duration of follow-up, the FDA believes it is premature to draw conclusions regarding the prognosis of ALCL in women with breast implants.

Because the risk of ALCL appears very small, FDA believes that the totality of evidence continues to support a reasonable assurance that FDA-approved breast implants are safe and effective when used as labeled.

More Information
  • A Shocking Diagnosis: Breast Implants ‘Gave Me Cancer’, NYtimes, MAY 14, 2017.
  • Anaplastic Large Cell Lymphoma (ALCL) In Women with Breast Implants: Preliminary FDA Findings and Analyses, FDA, January 2011.
  • Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL), FDA, Last Updated: 03/23/2017.
  • Questions and Answers about Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL), FDA, Last Updated: 03/21/2017.

JAMA 2017 Guidance for Modifying the Definition of Diseases

Loose disease definitions cause millions misdiagnoses and excess testing/treatment. Checklist stops disease mongering

A landmark paper addressing overdiagnosis, published yesterday in the journal JAMA Internal Medicine, outlines the first serious attempt to set some global rules for those experts who move diagnostic goalposts that label more people as sick.

Abstract

Importance
No guidelines exist currently for guideline panels and others considering changes to disease definitions. Panels frequently widen disease definitions, increasing the proportion of the population labeled as unwell and potentially causing harm to patients. We set out to develop a checklist of issues, with guidance, for panels to consider prior to modifying a disease definition.

Observations

“Medical science is making so much great progress soon none of us will be well”
Allen Frances

We assembled a multidisciplinary, multicontinent working group of 13 members, including members from the Guidelines International Network, Grading of Recommendations Assessment, Development and Evaluation working group, and the World Health Organisation. We used a 5-step process to develop the checklist:

  1. a literature review of issues,
  2. a draft outline document,
  3. a Delphi process of feedback on the list of issues,
  4. a 1-day face-to-face meeting,
  5. and further refinement of the checklist.

The literature review identified 12 potential issues. From these, the group developed an 8-item checklist that consisted of definition changes, number of people affected, trigger, prognostic ability, disease definition precision and accuracy, potential benefits, potential harms, and the balance between potential harms and benefits. The checklist is accompanied by an explanation of each item and the types of evidence to assess each one. We used a panel’s recent consideration of a proposed change in the definition of gestational diabetes mellitus (GDM) to illustrate use of the checklist.

Conclusions and Relevance
We propose that the checklist be piloted and validated by groups developing new guidelines. We anticipate that the use of the checklist will be a first step to guidance and better documentation of definition changes prior to introducing modified disease definitions.

Sources and Media Releases
  • Changes in Disease Definition and Prevalence of a ConditionWiser Healthcare, 04:59 – 16 mai 2017.

    How does a new disease definition impact the prevalence of a condition ?
  • Checklist of Items to Consider When Modifying a Disease DefinitionWiser Healthcare, 03:31 – 16 mai 2017.

    Preventing #overdiagnosis: a checklist to guide modification of #disease definitions
  • Guidance for Modifying the Definition of Diseases, A Checklist, JAMA Internal Medicine Special Communication, doi:10.1001/jamainternmed.2017.1302, May 15, 2017.
  • How to rein in the widening disease definitions that label more healthy people as sick, the conversation, May 15, 2017.

Exposure to heavy pesticide use during peak periods can impact neurobehavioral performance in children

Potential short-term neurobehavioral alterations in children associated with a peak pesticide spray season: The Mother’s Day flower harvest in Ecuador

Researchers from the University of California San Diego, School of Medicine, in collaboration with scientists from Ecuador and Minnesota, have found that exposure to heavy pesticide use during peak periods can impact neurobehavioral performance in children. The study focused on exposure to organophosphate pesticides, which have been associated with a broad range of diseases in both children and adults.

2017 Study Highlights

  • Little is known about acute neurobehavior change related to pesticide spray periods.
  • Ecuador’s Mother’s Day (MD) flower production is a period of high pesticide use.
  • We examined 308 non-worker children aged 4–9y, once between 63 and 100 days after MD.
  • Neurobehavioral scores were worse in children examined sooner (vs later) after MD.
  • Associations were strongest with attention/inhibition, visuospatial, and sensorimotor.

Abstract

Background
Exposures to cholinesterase inhibitor pesticides (e.g. organophosphates) have been associated with children’s neurobehavioral alterations, including attention deficit and impulsivity. Animal studies have observed transient alterations in neurobehavioral performance in relation to cholinesterase inhibitor pesticide exposures; however, limited evidence exists regarding transient effects in humans.

Methods
We estimated the associations between neurobehavioral performance and time after Mother’s Day flower harvest (the end of a heightened pesticide usage period) among 308 4-to 9-year-old children living in floricultural communities in Ecuador in 2008 who participated in the ESPINA study. Children’s neurobehavior was examined once (NEPSY-II: 11 subtests covering 5 domains), between 63 and 100 days (SD: 10.8 days) after Mother’s Day harvest (blood acetylcholinesterase activity levels can take 82 days to normalize after irreversible inhibition with organophosphates).

Results
The mean (SD) neurobehavioral scaled scores across domains ranged from 6.6 (2.4) to 9.9 (3.3); higher values reflect greater performance. Children examined sooner after Mother’s Day had lower neurobehavioral scores than children examined later, in the domains of (score difference per 10.8 days, 95%CI): Attention/Inhibitory Control (0.38, 0.10–0.65), Visuospatial Processing (0.60, 0.25–0.95) and Sensorimotor (0.43, 0.10–0.77). Scores were higher with longer time post-harvest among girls (vs. boys) in Attention/Inhibitory Control.

Conclusions
Our findings, although cross-sectional, are among the first in non-worker children to suggest that a peak pesticide use period may transiently affect neurobehavioral performance, as children examined sooner after the flower harvest had lower neurobehavioral performance than children examined later. Studies assessing pre- and post-exposure measures are needed.

Sources
  • Potential short-term neurobehavioral alterations in children associated with a peak pesticide spray season: The Mother’s Day flower harvest in Ecuador, science direct, doi.org/10.1016/j.neuro.2017.02.002, 7 February 2017.
  • Exposure to Heavy Pesticide Use Can Impact Neurobehavioral Performance in Children, Beyond Pesticides, May 12, 2017.
  • Image credit wikimedia.

The New War on Cancer

50-Year War on Cancer: Can We Win?

The signing of the National Cancer Act by President Richard M. Nixon on December 23, 1971, was considered a declaration of war on cancer.

In a multi-part series, the National Post explores why we need a new war on cancer.

Cancer nation

Where you live could affect your odds of getting cancer or dying from it.

Interactive map: Cancer is an indiscriminate disease, affecting rich and poor, old and young. Still, Canadians’ odds of getting sick depend surprisingly on where they live.

Why we need a new war on cancer

Over-treating and over-screening is doing patients more harm than good

The issue: Advances in screening and diagnosis are sending some cancer patients down aggressive treatment paths that they shouldn’t be on.
The solution: A new war on cancer and a rethinking of resources.

Drug money

Some cancer treatments cost as much as $33,000 a month, but fall well short of being wonder cures

A Post analysis of 17 cancer drugs that cost between $4,700 and $33,000 a month reveals only three had evidence that they extended lives when approved by Health Canada.

Bankrupt by cancer

Cancer is not just a life-threatening disease ― but a financial disaster.

In Canada, a country that prides itself on looking after the sick, no matter their ability to pay, Canadians are declaring bankruptcy because of cancer.

The fundraising complex

Of the $2.7 billion that cancer charities spent in 2013, only 45 per cent went towards fighting cancer.

The Post’s analysis of cancer funding reveals the depth of inefficiencies in the sector. In 2013, more than half of total funds went to salaries and overhead.

Learning to live with cancer

As science gets better at controlling cancer for longer periods of time, it might be best to kill the battle rhetoric

Nowhere else in medicine is the battle rhetoric more entrenched than in cancer. And its defeating people. Who wants to go war with their own bodies?

Prevention as the ultimate cure

Prevention saves more lives than any cancer drug

However, in the multi-billion-dollar cancer business, efforts to stop people from contracting the illness account for as little as five per cent of what’s spent.

Why Dissent Matters

Because Some People See Things the Rest of Us Miss

The thalidomide tragedy was averted in the United States because Dr. Kelsey, alone and in the face of fierce opposition, did her job. Her perspective was educated, fresh and unique. If there had been no thalidomide crisis, the United States, with the rest of the world following, would still at some time have brought pharmaceutical regulation into the 20th century. But thalidomide created one of those moments when something had to be done. It could not be ignored in 1961-62, and it led immediately to a better and stronger regulatory system. Maybe someone else would have stopped thalidomide in the United States had Dr. Kelsey not been assigned the NDA, but, interestingly, no one else stopped it anywhere else until it was too late. Dr. Kelsey was the only person in the entire world who said no. She said no to a bad drug application, she said no to an overbearing pharmaceutical company and she said no to vested interests who put profits first. She was one brave dissenter. In the end, the question is not what made Frances Kelsey, but why aren’t there more like her?

Because Some People See Things the Rest of Us Miss

The nature writer Rachel Carson identified an emerging environmental disaster and pulled the fire alarm. Public protests, individual dissenters, judges, and juries can change the world – and they do.

A wide-ranging and provocative work on controversial subjects, Why Dissent Matters tells a story of dissent and dissenters – people who have been attacked, bullied, ostracized, jailed, and, sometimes when it is all over, celebrated.

William Kaplan shows that dissent is noisy, messy, inconvenient, and almost always time-consuming, but that suppressing it is usually a mistake – it’s bad for the dissenter but worse for the rest of us. Drawing attention to the voices behind international protests such as Occupy Wall Street and Boycott, Divest, and Sanction, he contends that we don’t have to do what dissenters want, but we should listen to what they say. Our problems are not going away. There will always be abuses of power to confront, wrongs to right, and new opportunities for dissenting voices to say, “Stop, listen to me.” Why Dissent Matters may well lead to a different and more just future.

Read This is Dr. Frances Kelsey’s story, the globe and mail, MAY 11, 2017.