Author: DES Daughter

Reforming disease definitions : a new primary care led, people-centred approach

Drug Companies Shouldn’t Help Decide Who Is Sick, 2019

Abstract

Expanding disease definitions are causing more and more previously healthy people to be labelled as diseased, contributing to the problem of overdiagnosis and related overtreatment. Often the specialist guideline panels which expand definitions have close ties to industry and do not investigate the harms of defining more people as sick. Responding to growing calls to address these problems, an international group of leading researchers and clinicians is proposing a new way to set diagnostic thresholds and mark the boundaries of condition definitions, to try to tackle a key driver of overdiagnosis and overtreatment. The group proposes new evidence-informed principles, with new process and new people constituting new multi-disciplinary panels, free from financial conflicts of interest. Image wikimedia.

Conclusion

Developing a framework for this long-term reform and facilitating a global collaboration to enact it will involve proactive and reactive efforts that we hope will drive a cultural shift and a practical change in how diseases are defined. Research teams will continue to quantify estimates of overdiagnosis arising from current disease definitions, informing priorities for action. Actions include the constitution of new panels, with new processes and new people, to review and revise existing definitions. Concurrently, primary care organisations will become more reactive to expansions in definitions seen as increasing the risk of overdiagnosis, such as the controversial 2017 hypertension widening, explicitly rejected by the American Academy of Family Physicians, and other groups, and the rejection of the expanded definition of gestational diabetes by the Royal Australian College of General Practitioners. An international meeting to review progress on our proposal and develop more detailed strategies for change will take place at the December 2019 Preventing Overdiagnosis conference in Sydney

There are important limitations, uncertainties and caveats to note as we propose this ambitious reform of disease definitions, which will provoke opposition from those whose markets are directly threatened.

  1. First, we write as a group working across a multitude of influential national and international organisations, but we do not in this instance represent them.
  2. Second, our backgrounds and thinking are largely medical, and there is clearly opportunity for this initiative to be informed by evidence, experience and theories outside medicine, including, for example, from philosophy.
  3. Third, addressing the problem of expanding disease definitions is but one of many potential solutions to overdiagnosis, and much important work is underway already to try and wind back the harms of too much medicine, safely and fairly, such as calls to action within our associations, creation of new medical curricula, scientific discussion at national and international meetings and new information materials for the public.
  4. Fourth, given the novel nature of this proposal, there is not yet a mature evidence-base to support it.
  5. Fifth, there is clear synergy between this proposal and the calls for reform of clinical practice guidelines, which has not been explored in this analysis.
  6. And finally, we acknowledge moves to expand definitions, to detect and treat people earlier, are often driven by the best of intentions, and we see great merit in identifying those who will benefit from a medical label and subsequent care.

However, notwithstanding the good intentions driving a bad system, the human person can no longer be treated as an ever-expanding marketplace of diseases, benefiting professional and commercial interests while bringing great harm to those unnecessarily diagnosed.

Transgenerational BPA exposure may contribute to autism

Transgenerational Bisphenol A Causes Deficits in Social Recognition and Alters Postsynaptic Density Genes in Mice, 2019

According to a recent mouse study, BPA exposure has transgenerational effects on gene linked to autism – social recognition test used for first time in mice showed behavioral deficit – the Endocrine Society reports.

2019 Study Abstract

Bisphenol A (BPA) is a ubiquitous endocrine-disrupting chemical. Developmental exposure produces changes in behavior and gene expression in the brain. Here, we examined social recognition behaviors in mice from the third familial generation (F3) after exposure to gestational BPA. Second-generation mice were bred in one of four mating combinations to reveal whether characteristics in F3 were acquired via maternal or paternal exposures. After repeated habituation to the same mouse, offspring of dams from the BPA lineage failed to display increased investigation of a novel mouse. Genes involved in excitatory postsynaptic densities (PSDs) were examined in F3 brains using quantitative PCR. Differential expression of genes important for function and stability of PSDs were assessed at three developmental ages. Several related PSD genes―SH3 and multiple ankyrin repeat domains 1 (Shank1), Homer scaffolding protein 1c (Homer1c), DLG associated protein 1 (Gkap), and discs large MAGUK scaffold protein 4 (PSD95)―were differentially expressed in control- vs BPA-lineage brains. Using a second strain of F3 inbred mice exposed to BPA, we noted the same differences in Shank1 and PSD95 expression in C57BL/6J mice. In sum, transgenerational BPA exposure disrupted social interactions in mice and dysregulated normal expression of PSD genes during neural development. The fact that the same genetic effects were found in two different mouse strains and in several brain regions increased potential for translation. The genetic and functional relationship between PSD and abnormal neurobehavioral disorders is well established, and our data suggest that BPA may contribute in a transgenerational manner to neurodevelopmental diseases.

DES and the GENES

Disorders of sexual development may be more common in newborns than what we think

Frequency of Ambiguous Genitalia in 14,177 Newborns in Turkey, 2019

According to a recent study, ambiguous genitalia in newborns may be more common than previously thought, the Endocrine Society reports.

“Our research found 18 babies with ambiguous genitalia among 14,177 newborns (1.3 in 1,000 births). This frequency is higher when compared to previous studies (1 in 4,500-5,500),”

“These findings support the hypothesis that early placental dysfunction and androgen deficiency might be important in the etiology of male genital anomalies,”

said the study’s first author, Banu Kucukemre Aydin, M.D., of Istanbul University in Turkey. Image credit Intersex Human Rights Australia.

2019 Study Abstract

Context
Limited data are available on the exact incidence of disorders of sex development (DSD) with genital ambiguity at birth.

Objective
To determine frequency of ambiguous genitalia in newborns.

Design
Prospective multicenter study.

Setting
Three tertiary care hospitals.

Patients or Other Participants
All 14,177 babies born during the study period were included.

Main Outcome Measures
All newborns were examined at birth; data on weeks of gestation, birth weight, and length were collected. A structured questionnaire was used for data collection. Quigley and Prader scales were used for phenotypic grading. Clinical and genetic investigations were performed.

Results
Eighteen babies with ambiguous genitalia were found among 14,177 newborns (1.3/1000). Fifteen newborns had 46,XY DSD, one had 46,XX congenital adrenal hyperplasia, and one had 45,X/46,XY mixed gonadal dysgenesis. Karyotype analysis was not done in one baby who died in the neonatal period. The ratio of prematurity was higher in the DSD group (44% vs 11%; P < 0.001) and the ratio of small for gestational age was also higher in the DSD group (22% vs 5%; P = 0.007). Eight babies with DSD had mothers who had additional medical conditions, such as preeclampsia, depression, insulin resistance, and gestational diabetes mellitus.

Conclusion
The frequency of ambiguous genitalia was higher than in previous studies, but, as with any experiment, the finding should be met with caution because this study was conducted in tertiary care hospitals. In addition, lower birth weight in the DSD group supports the hypothesis that early placental dysfunction might be important in the etiology of male genital anomalies.

Related DES Studies

House dust can carry hormone-altering chemicals prompting body cells to accumulate fat

Chemicals in household dust may promote fat cell development, 2019

New Orleans, LA – Endocrine-disrupting chemicals present in household dust promote the development of fat cells in a cell model and could contribute to increased growth in children relative to their age, according to research presented Monday, March 25 at ENDO 2019, the Endocrine Society’s annual meeting.

“This is some of the first research investigating links between exposure to chemical mixtures present in the indoor environment and metabolic health of children living in those homes,”

said lead researcher Christopher Kassotis, Ph.D., of Duke University’s Nicholas School of the Environment in Durham, N.C.

Previous research has shown that chemical exposures can promote accumulation of triglycerides—a type of fat found in the blood—and increased obesity in animal models. Many observational studies have found a link between exposure to endocrine-disrupting chemicals believed to contribute to obesity and increased weight in humans.

In this study, Kassotis and colleagues investigated the effect of chemical mixtures isolated from house dust. They collected 194 house dust samples from households in central North Carolina. They then extracted the chemicals from the dust in the lab. These extracts were tested for their ability to promote fat cell development in a cell model.

They found that very low concentrations of dust extracts were able to promote precursor fat cell proliferation and fat cell development. According to the EPA, children are estimated to consume between 60 and 100 milligrams of dust each day.

“We found that two-thirds of dust extracts were able to promote fat cell development and half promote precursor fat cell proliferation at 100 micrograms, or approximately 1,000 times lower levels than what children consume on a daily basis,”

Kassotis said.

The researchers then measured more than 100 different chemicals in the dust and looked at the relationship between their concentrations and the extent of fat cell development. They found that approximately 70 of the chemicals had a significant positive relationship with the development of dust-induced fat cells, and approximately 40 were linked with precursor fat cell development.

“This suggests that mixtures of chemicals occurring in the indoor environment might be driving these effects,”

Kassotis said.

The researchers found several chemicals were significantly elevated in the dust of homes of children who were overweight or obese. They are continuing to study these chemicals—some of which are found in common household products such as laundry detergents, household cleaners, paints and cosmetics—to determine which ones may be linked to obesity.

Reference. Image thecaspiantimes.

Tiny air pollution particles may lead to reduced sperm production

Particulate air pollution linked with reduced sperm production in mice, 2019

New Orleans, LA – Exposure to tiny air pollution particles may lead to reduced sperm production, suggests new research in mice, presented Monday, March 25 at ENDO 2019, the Endocrine Society’s annual meeting.

“Infertility rates are increasing around the world, and air pollution may be one of the main factors,”

said lead researcher Elaine Maria Frade Costa, M.D., Ph.D., of Sao Paulo University in Sao Paulo, Brazil.

The World Health Organization (WHO) estimates that approximately 15 percent of the global population has difficulty with fertility, and male infertility accounts for about half of those problems.

The study looked at the effect of particulate matter (PM) on sperm production. PM is a mixture of solid particles and liquid droplets found in the air. PM2.5 is a fine inhalable particle with diameters that are 2.5 micrometers or smaller. The average human hair is about 70 micrometers in diameters, making it 30 times larger than the biggest fine particle. PM2.5 is known to disrupt the endocrine system in humans and animals. The endocrine system is involved in reproduction, including the production of sperm.

The study included four groups of mice. One was exposed to PM2.5 from Sao Paolo before and after birth, from the day they were weaned from their mother’s milk until adulthood. The second group was exposed only during gestation. The third group was exposed after birth from weaning until adulthood; and the fourth group was exposed only to filtered air during gestation and from the time they were weaned until adulthood.

The researchers analyzed the testes of the mice and their production of sperm. DNA tests were used to evaluate gene expression, the process by which genes in DNA provide instructions for proteins.

The tubes in the testes that produce sperm of all the exposed mice showed signs of deterioration. In comparison with the mice not exposed to PM2.5, the sperm of the first group, which was exposed before and after birth, was of significantly worse quality.

The exposure to PM2.5 led to changes in the levels of genes related to testicular cell function. Exposure to PM2.5 after birth seemed to be the most harmful to testicular function, the study found.

Costa said these changes are epigenetic, which means they are not caused by changes in the DNA sequence. Epigenetic changes can switch genes on or off and determine which proteins a gene expresses.

The research demonstrates for the first time that exposure to air pollution of a large city impairs production of sperm through epigenetics, mainly in exposure after birth, Costa said.

“These findings provide more evidence that governments need to implement public policies to control air pollution in big cities,”

she said. Reference. Featured image.

Endocrine disruptors alter pubertal timing

Endocrine disrupters and possible contribution to pubertal changes

Puberty represents a crucial milestone in one’s reproductive life. For this reason, any effect of the environment on pubertal timing might announce later consequences on reproduction. For the last 20 years, data has accumulated suggesting changes in pubertal timing and a possible role for exposure to endocrine disrupting chemicals (EDCs). This review will summarize the recent data regarding secular trends in age at puberty in boys and girls as well as the likely increase in central precocious puberty incidence in girls. Finally, we will review the epidemiological and animal data suggesting a role for endocrine disrupting chemicals in the reported changes in pubertal timing.

Abstract

The onset of puberty strongly depends on organizational processes taking place during the fetal and early postnatal life. Therefore, exposure to environmental pollutants such as Endocrine disrupting chemicals (EDCs) during critical periods of development can result in delayed/advanced puberty and long-term reproductive consequences. Human evidence of altered pubertal timing after exposure to endocrine disrupting chemicals is equivocal. However, the age distribution of pubertal signs points to a skewed distribution towards earliness for initial pubertal stages and towards lateness for final pubertal stages. Such distortion of distribution is a recent phenomenon and suggests environmental influences including the possible role of nutrition, stress and endocrine disruptors. Rodent and ovine studies indicate a role of fetal and neonatal exposure to EDCs, along the concept of early origin of health and disease. Such effects involve neuroendocrine mechanisms at the level of the hypothalamus where homeostasis of reproduction is programmed and regulated but also peripheral effects at the level of the gonads or the mammary gland.

Endocrine disruptors alter female reproduction throughout multiple generations

OR23-1 Transgenerational Effects of Endocrine Disrupting Chemicals on Pubertal Timing through Epigenetic Reprogramming of the Hypothalamus

According to a recent animal study, endocrine disruptors, hormone-altering chemicals that are widespread in our environment, can shape the brain through four generations, altering offspring’s maternal behavior, sexual development and reproduction, The Endocrine Society reports.

Abstract

Endocrine disrupting chemicals (EDCs) are a rising concern for public health due to their ubiquitous presence as complex mixtures affecting development throughout generations. Our goal was to study the effect of a mixture of EDCs on female sexual development during 3 generations. Female rats (F0 generation) were orally exposed to a mixture of 14 anti-androgenic and estrogenic EDCs or corn oil for 2 weeks before and throughout gestation and until weaning. The mixture was composed of plasticizers (BPA, DBP, DEHP), fungicides/pesticides (Vinclozolin, Procymidon, Prochloraz, Epoxynazole, Linurone, p-p’-DDT), UV filters (4-MBC, OMC), Butyl Paraben and the analgesic Acetaminophen. The doses were in the micrograms/kg range in order to represent human exposure. Sexual development (vaginal opening, GnRH interpulse interval and estrous cyclicity) as well as maternal behavior were studied from F1 to F3 generations. At PND21 the mediobasal hypothalamus of the F1 and F3 were removed for gene expression analysis by RNAseq and RT-qPCR as well as for Chromatin Immunoprecipitation of histone modifications at regulatory regions of target genes. While F2 and F3 females showed delayed vaginal opening, decreased percentage of regular estrous cycles and decreased GnRH interpulse interval, no such changes were detected in F1 animals. These reproductive phenotypes were associated with alterations in both transcriptional and histone posttranslational modifications of hypothalamic genes involved in reproductive competence and behavior like kisspeptin (Kiss1), oxytocin (Oxt), estrogen (Esr1), glutamate (Grin2d), dopamine signaling (Th and Drd1) as well as glucocorticoid activity (Nr3c1 and Crh). Concomitant with a decrease in transcriptional activity, we have observed either a decrease of active histone marks (H3K4me3, H3K9ac) for Esr1 and Oxt promoter regions, an increase of repressive histone modifications (H3K27me3, H3K9me3) for Grin2D, Th and Nr3c1 promoter regions or both for the Kiss1 promoter. Up-regulated genes (Pomc, and CRH) showed decreased H3K9me3 and increased H3K9ac at their 5’regulatory regions. F1 females that were exposed in utero to the EDC mixture, showed a reduction in Th mRNA expression and decreased grooming/licking behavior while spending more time resting alone. These alterations on maternal behavior are known to cause transgenerational alterations of the development of the corticotropic and gonadotropic axis. Overall, our data shows that gestational and lactational exposure to an environmentally relevant EDC mixture transgenerationally affects sexual development throughout epigenetic reprogramming of the hypothalamus. Such effects could be mediated by alterations of maternal behavior caused by exposure of the first generation to the EDC mixture.

About DES and the GENES

T-shaped uterus and subtle uterine variances

A need for reliable criteria, Fertility and Sterility, August 2019

Abstract

The ASRM Class VII, the ESHRE/ESGE Class U1, and the T-shaped uterus have a uniquely interesting history. The T-shaped uterus was first described as a diethylstilbestrol– (DES-) related congenital uterine anomaly based on findings from hysterosalpingography by Kaufman in 1977. Together with two similar morphologic forms of the uterus—constricting bands in the uterine cavity and a widening of the lower two-thirds of the uterus—this was included as a separate class of DES-related anomalies by the Buttram and Gibbons 1979 classification, and its further modification—the American Fertility Society classification.

In 2013, ESHRE/ESGE singled out a subtle uterine variance with a thickened lateral wall and a T-shaped uterus. As a result, the diagnosis of subtle uterine variances has increased with the designation of a T-shaped uterus or dysmorphic uterus and surgical repair is offered to enhance fertility. However, there is insufficient evidence to offer it in daily practice even in women with recurrent pregnancy loss, where historically metroplasty of the T-shaped uterus is rarely reported and its surgical correction is always questionable.

In this issue Alonso Pacheco et al. present a nicely done video using three-dimensional ultrasound and hysteroscopy in three cases of what they believe is a T-shaped uterus that is representative in distinguishing three of its subclasses. The authors used three-dimensional ultrasound and hysteroscopy to suggest that T-shaped uterus can be subclassified as T-shaped, Y-shaped, or I-shaped uterus. However, the division still remains arbitrary based on subjective impression of the presence of thickened wall and letter-shaped uterine cavities in these conditions. Discussion.

Bisphenol-A can promote fibroids growth, study says

Bisphenol A promotes the proliferation of leiomyoma cells by GPR30‐EGFR signaling pathway, 2019

Abstract

Aim
To study the molecular mechanism of G protein‐coupled receptor 30‐epidermal growth factor receptor (GPR30‐EGFR) signaling pathway on the proliferation of leiomyoma cells exposed with bisphenol A.

Methods
Primary cultures and subcultures of human uterine leiomyoma (UL) cells. The expressions of messenger RNA and proteins of GPR30 and EGFR in 15 leiomyoma tissue specimens and all groups were detected by real‐time quantitative polymerase chain reaction assay and Western blot assay. The protein of mitogen‐activated protein kinases (MAPK)/extracellular signal–regulated kinases (ERK)/c‐fos signaling pathway members was detected by Western blot assay.

Results
Bisphenol A promoted the growth of UL cells and the expressions of GPR30, EGFR, c‐fos and p‐ERK1/2.

Conclusion
Bisphenol A was found to be a promoter specifically to proliferate the human UL cells by activating the transcription and translation of GPR30‐EGFR and MAPK/ERK/c‐fos signaling pathway members.

The shocking truth behind the widely used drug sodium valproate

Inside Out London, 22.01.2018 Full Version

We expose the government documents that we obtained concerning Sodium Valproate and the defect risk when taken during pregnancy and the worrying transgenerational link it will affect our grand children.

In a special edition of Inside Out London, Tarah Welsh investigates the shocking truth behind an anti-epilepsy drug which has harmed thousands of children. She uncovers new medical evidence suggesting that birth defects caused by the drug could be passed down through generations of the same family. Archives.