Tag: 1/4/21

Categories : GenderTags :

Evidence for Puberty Blockers is ‘Very Low’ Says UK Guidance Body

On By ModernMedia

In an official review of studies, the UK’s National Institute of Health and Care Excellence (NICE) said that the evidence for puberty blockers is “very low”.

In an assessment of the evidence for puberty blockers commissioned by NHS England, the guidance body said that existing studies of the drugs were small and “subject to bias and confounding”. The assessment forms part of a review into gender identity services for children and young people.

NHS England said the advice would be considered by the review and it would not be commenting further.

Gonadotrophin-releasing hormone (GnRH) analogues, popularly known as puberty blockers, are prescribed to some young people with gender dysphoria – distress caused by a discrepancy between a person’s gender identity (how they see themselves regarding their gender) and their sex at birth.

The NICE evidence review looked at what impact puberty blockers had on gender dysphoria, mental health – such as depression, anger and anxiety – and quality of life.

NICE, which provides national guidance and advice to improve health and social care, said: “The quality of evidence for these outcomes was assessed as very low certainty.”

The review sought to find out how treatment with GnRH analogues compared in terms of clinical effectiveness with other interventions that may be offered to young people with gender dysphoria. These include psychological support, social transitioning to the desired gender – such as changing pronouns and clothes but without medication – or no intervention at all.

NICE found it was difficult to draw conclusions from existing studies because they were “all small” and lacked control groups. They found other issues with the studies too, such as not describing what other physical and mental health problems a young person may have alongside gender dysphoria.

The review said there was “very little data” on any additional interventions, such as counselling or other drug treatments, that the young people may have received alongside taking puberty blockers, leading to possible bias in results. Impacts of puberty blockers on bone density were another concern.

However without a “comparator group”, it was not known whether bone density changes observed “are associated with GnRH analogues or due to changes over time”.

It is argued by some that it is difficult to withhold support to create a comparator group because it would mean unfairly disadvantaging some. NICE accepted this, but said offering psychological support to compare puberty blockers “may reduce ethical concerns in future trials”.

No evidence of cost-effectiveness of treatment was found by the review.

NICE also reviewed the evidence base for gender-affirming hormones, which can be given to young people with gender dysphoria from age 16 in the NHS. These start the development of the physical sex characteristics of the gender with which they identify with the aim of improving mental health, quality of life and body image.

The review found the evidence of clinical effectiveness and safety of gender-affirming hormones was also of “very low” quality.

“Any potential benefits of gender-affirming hormones must be weighed against the largely unknown long-term safety profile of these treatments in children and adolescents with gender dysphoria,” NICE said.

Source: BBC News

Categories : Neurodegenerative DiseasesTags :

Exercise Slows Cognitive Decline in APOE4-related Parkinson’s Disease

On By ModernMedia

Results from a longitudinal study showed physical activity reduced  cognitive decline in early APOE4-related Parkinson’s disease.

Jin-Sun Jun, MD, of Hallym University in Seoul, and colleagues in Neurology presented the findings of a longitudinal study on a group of 173 recently diagnosed Parkinson’s patients. Of this group, those who with an apolipoprotein E ε4 (APOE4) allele had faster cognitive decline on the 30-point Montreal Cognitive Assessment (MoCA) scale than noncarriers (estimate -1.33, 95% CI -2.12 to -0.47, P=0.002). However, among the APOE4 carriers, higher physical activity was related to slower cognitive decline (estimate 0.007, 95% CI 0.003-0.011, P=0.001)..

Dr Jun noted that this reflects a number of studies that have demonstrated that Parkinson’s patients who exercise regularly show better clinical outcomes, including motor and cognitive function.

“These observations are supported by epidemiological data showing a link between physical activity and decreased risk for Parkinson’s disease,” Dr Jun told MedPage Today. “Because previous data indicate that physical activity modifies the APOE4 effect on the development and progression of Alzheimer’s disease, we hypothesized that physical activity also plays a role in modulating the association between APOE4 and cognition in Parkinson’s disease.”

Genetic factors interact with physical activity on other health outcomes, noted Jacob Raber, PhD, of Oregon Health and Science University in Portland, and colleagues, in an accompanying editorial.

“If similar gene-by-physical activity interactions were identified in Parkinson’s disease, they could pave the way for personalized treatment,” Raber and colleagues wrote. “While the effects of APOE4 on promoting beta-amyloid and tau pathology are well-established, recent studies show that APOE4 is also associated with more profound pathology of alpha-synuclein and higher measures of cognitive burden, both in mouse models and in humans with Parkinson’s disease.”

In their study, the researchers followed recently diagnosed patients in the Parkinson’s Progression Markers Initiative cohort who were not treated for Parkinson’s and who had abnormal dopamine transporter (DAT) imaging.

Self-reported physical activity was begun 2 years after enrollment and scored on the Physical Activity Scale of the Elderly. Cognitive function was measured annually with the MoCA, which is well-suited for Parkinson’s patients, and DAT imaging was performed at years 2 and 4. Assessments performed at years 2, 3, and 4 were used for analysis.

There was no significant interaction seen between physical activity and APOE4 involving change in striatal DAT activities. This suggests that striatal dopaminergic function may not be a major factor in physical activity’s protective effect on APOE4-related cognitive decline, Dr Jun and colleagues noted. “These negative results may be explained by the modest effect of APOE4 on the nigrostriatal dopaminergic system,” they wrote. “Furthermore, our follow-up duration may be too short to comprehend the impact of APOE4 on this system, considering the slow progressive nature of alpha-synucleinopathy.”

The researchers also pointed out that the exercise could offer benefits through mechanisms unrelated to the disease. “Although we cannot conclude what types or amounts of exercise help to slow progression from this study design, even non-high-intensity physical activity positively modified the impact of APOE4 on cognitive function,” Jun said.

The study’s limitations included physical activity being self-reported, cognitive function being based only on MoCA scores, and a short follow-up time. Though motor scores in the off-medication state were adjusted for, physical activity may have been less due to disease progression.

Source: MedPage Today

Categories : NeurologyTags :

Sugar-sweetened Drinks During Adolescence Impacts Cognition in Adulthood

On By ModernMedia

New research has shown that, in rats, daily consumption of sugar-sweetened drinks during adolescence impairs performance on a learning and memory task during adulthood. 

The researchers also demonstrated that changes in the bacteria in the gut may be the key to the sugar-induced memory impairment. Evidence in support of this comes from the observation of similar memory deficits even when the bacteria, called Parabacteroides, were experimentally enriched in the guts of animals that had never consumed sugar.

“Early life sugar increased Parabacteroides levels, and the higher the levels of Parabacteroides, the worse the animals did in the task,” said first author Emily Noble, assistant professor, College of Family and Consumer Sciences, University of Georgia. “We found that the bacteria alone was sufficient to impair memory in the same way as sugar, but it also impaired other types of memory functions as well.”

Data from the Centers for Disease Control and Prevention show American children between the ages 9-18 exceed the recommendation of limiting added sugars to less than 10 percent of calories per day, with the bulk of the calories coming from sugar-sweetened beverages.

Since the hippocampus is still developing into late adolescence and plays a role in a variety of cognitive functions, researchers sought to understand more about its susceptibility to a high-sugar diet via gut microbiota.

Juvenile rats were given their normal chow and an 11% sugar solution, comparable to commercially available sugar-sweetened beverages. Researchers then had the rats perform a hippocampus-dependent memory task designed to measure episodic contextual memory, or remembering the context where they had seen a familiar object before.

“We found that rats that consumed sugar in early life had an impaired capacity to discriminate that an object was novel to a specific context, a task the rats that were not given sugar were able to do,” Prof Noble said.

A second memory task measured basic recognition memory, a hippocampal-independent memory function that involves the animals’ ability to recognise something they had seen previously. Sugar had no effect on the animals’ recognition memory.

“Early life sugar consumption seems to selectively impair their hippocampal learning and memory,” Prof Noble said.

Further analysis revealed that high sugar consumption led to elevated levels of Parabacteroides in the gut microbiome, the more than 100 trillion microorganisms in the gastrointestinal tract that play a role in human health and disease.

To determine the mechanism by which bacteria impacted memory and learning, researchers experimentally increased levels of Parabacteroides in the microbiome of rats that had never consumed sugar. Those animals showed impairments in both hippocampal dependent and hippocampal-independent memory tasks.

“(The bacteria) induced some cognitive deficits on its own,” Prof Noble said.

Future research is needed to better identify these gut-brain signaling specific pathways.

“The question now is how do these populations of bacteria in the gut alter the development of the brain?” Prof Noble said. “Identifying how the bacteria in the gut are impacting brain development will tell us about what sort of internal environment the brain needs in order to grow in a healthy way.”

Source: News-Medical.Net

Journal information: Noble, E. E., et al. (2021) Gut microbial taxa elevated by dietary sugar disrupt memory function. Translational Psychiatry. doi.org/10.1038/s41398-021-01309-7.

Categories : Cancer PaediatricsTags :

Blood Mutation Explains High Leukaemia Rates in Children with Down’s

On By ModernMedia

According to a new study by researchers at the Linda Crnic Institute for Down Syndrome, the reason that children with Down syndrome have a drastically elevated risk of leukaemia is due to a more prevalent condition increasing blood stem cell mutation.

Children with Down syndrome are 20-times more likely to develop acute lymphocytic leukaemia (ALL) and 150-times more likely to develop acute myeloid leukaemia (AML) compared to their typical peers. The researchers found that the reason for this is that they are more likely to present with clonal haematopoiesis (CH), a process in which a blood stem cell acquires a genetic mutation that promotes replication.  

The findings add to a growing body of evidence linking immune dysregulation to a very different disease spectrum, whereby people with Down syndrome are highly predisposed to certain diseases such as leukaemia and autoimmune disorders, while being highly protected from others, such as solid tumours.

“We found a higher-than expected rate of CH in individuals with Down syndrome between the age of one to 20 years old,” said study author Dr Alexander Liggett, who as a doctoral candidate led the study in the lab of Dr James DeGregori, Professor of Biochemistry and Molecular Genetics. “It is a surprising finding, as the phenomenon is typically only observed in elderly people.”

The researchers used an advanced sequencing technique that they had developed, called FERMI, to blood samples from the Crnic Institute Human Trisome Project Biobank. Mutations were more likely to be detected in Down’s syndrome and also more likely to be oncogenic. In elderly people, oncogenic mutations are commonly found in the genes DNMT3A, TET2, ASXL1, TP53, and JAK2. In people with Down’s syndrome, oncogenic CH was found to be dominated by mutations of the TET2 gene.

“Given the increased risk of leukaemia that accompanies clonal expansion of blood cells carrying oncogenic mutations, these expansions may become an important biomarker of cancer risk in the future,” said Dr Liggett.

The study also found that CH in Down syndrome is associated with immune dysregulation biosignatures linked to diseases co-occurring with Down’s syndrome, including thyroiditis, Alzheimer’s disease, and leukaemia. This discovery opens new avenues in understanding the way CH impacts an array of health outcomes in Down syndrome and how to potentially counteract its effects.

“This is truly transformative. This team has identified a new trait of Down syndrome that has strong implications for understanding the appearance of comorbidities more common in this population, such as leukaemia and premature ageing,” said Dr. Joaquin Espinosa, Executive Director of the Crnic Institute. “The next step is to define the long-term impacts of this precocious clonal hematopoiesis and how to prevent its harmful effects.”

Source: News-Medical.Net

Journal information: Liggett, L.A., et al. (2021) Precocious clonal hematopoiesis in Down syndrome is accompanied by immune dysregulation. Gut. doi.org/10.1182/bloodadvances.2020003858.

Categories : COVIDTags :

COVID Surges Driven by New Variants

On By ModernMedia

A study of SARS-CoV-2 genomes and epidemic case data has shown that COVID outbreaks emerge with new variants.

“As variants emerge, you’re going to get new outbreaks,” said Bart Weimer, professor of population health and reproduction at the UC Davis School of Veterinary Medicine. The study combined classical epidemiology with genomics, providing a tool for public health authorities to predict the course of pandemics.

SARS-CoV-2  only has 15 genes, but is mutating constantly. The majority of these changes have little impact, but occasionally they result in the virus becoming more or less transmissible.

Together with graduate student DJ Darwin R Bandoy, Prof Weimer at first analysed the genomes of 150 SARS-CoV-2 strains, mostly from outbreaks in Asia prior to March 1, 2020, along with epidemiology and transmission information on those outbreaks. 

The classified outbreaks by stage: index (no outbreak), takeoff, exponential growth and decline. Virus transmissibility is set by the value R, or reproductive number, where R is the average number of new infections caused by each infected person.

They combined all this information into a metric called GENI, for pathogen genome identity. Comparing GENI scores with epidemic phases showed that an increase in genetic variation immediately preceded exponential growth in cases, for example in South Korea in late February. In Singapore, however, bursts of variation were associated with smaller outbreaks that were quickly brought under control.

Prof Weimer and Bandoy then looked at 20 000 sequences of SARS-CoV-2 viruses collected over February to April 2020 in the United Kingdom, and compared them with COVID cases data.

They found that the GENI variation score rose steadily with the number of cases. When a national lockdown was imposed in late March, the number of new cases stabilised but the GENI score continued to rise. This shows that control measures such as banning gatherings, mask mandates and social distancing are effective in controlling spread of disease in the face of rapid virus evolution.

It could also help explain “superspreader” events when large numbers of infections result from relaxed precautions at an event.

Prof Weimer said he hopes that health authorities will adopt this method of measuring virus variation and linking it to the local transmission rate, R.

“In this way you can get a very early warning of when a new outbreak is coming,” he said. “Here’s a recipe for how to go about it.”

Source: Medical Xpress

Journal information: Scientific Reports (2021). DOI: 10.1038/s41598-021-86265-4

Categories : CancerTags :

The Effect of Hypoxia on Cancer Cells is a Matter of Timing

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A new study from the University of Colorado School of Medicine shows that the effect of hypoxia on cancer cells varies in the short term versus the long term, opening new possibilities for cancer treatment.

How cancer cells adapt to hypoxia, where insufficient oxygen reaches cells, is a key aspect of cancer biology.

“Most tumours cannot grow unless they figure out a way to induce formation of new blood vessels to supply them with oxygen and other nutrients,” explained Matthew Galbraith, PhD. “So, what happens inside of solid tumours is they undergo intermittent periods of low oxygen between rounds of new blood vessel formation.”

Previous research focussed on hypoxia in the long term, characterising it as oncogenic, or cancer promoting. However some studies showed that hypoxia-sensing factors, known as hypoxia inducible factors, or HIFs, can in some situations suppress tumour growth. To solve this, senior researcher Joaquin Espinosa, PhD and colleagues studied the immediate acute response to hypoxia.

“We employed a cutting-edge genomics technology that nobody had employed in this field before that allowed us to see what happens to cancer cells within minutes of depriving them of oxygen,” Dr Espinosa said.

Employing this technology, they identified hundreds of hypoxia-inducible genes activated shortly upon oxygen deprivation. Using computational biology approaches on large, publicly available datasets, they inferred the function of these genes on hundreds of lab-grown cancer cell lines and hundreds of tumour samples from cancer patients.

They found that when a cell is hypoxic, it reacts by ceasing growth to preserve its existing nutrients and oxygen. Thus, hypoxia causes a tumour-suppressive reaction at this point, mostly by preventing protein synthesis. Only after prolonged periods of hypoxia do cells metastasise and spread out in search of oxygen.

“There’s been a lot of debate about whether these hypoxia-inducible factors promote tumour growth or prevent tumour growth,” Dr Espinosa said. “The conclusion we came to is that everyone was right to a degree. Hypoxia-inducible factors can suppress tumour growth by preventing protein synthesis early on, but they can also advance tumour growth at later stages by promoting the ability of cancer cells to invade neighboring tissues. It depends on when you’re looking at it.”

The tumour suppression and promotion mechanisms elicited by HIFs can be exploited as drug targets. Tumour suppression is mediated by inhibition of an enzyme known as mTOR, which in turn can be inhibited by available drugs often used in cancer therapies. “mTOR inhibitors could mimic the tumour suppressive effects of HIFs,” Dr Galbraith explained.

When deprived of oxygen for a longer amount of time, the HIFs switch on a set of enzymes that can degrade the extracellular matrix that holds them in place, allowing the cancer cells to escape the oxygen-deprived tumour. The cancer cells can then enter the bloodstream and invade nearby tissues.

“These results emphasise the importance of developing inhibitors of hypoxia-inducible enzymes that degrade collagen and other components of the extracellular matrix,” Espinosa said.

Dr Espinosa and his team hope that their research will help new cancer treatments to be developed, which also target the cancer at the right times. 

“People have been trying to target the hypoxia-inducible factors with different therapeutics, but this research would suggest that you may want to exercise some caution about when you apply those therapeutics, given that the HIFs can be tumour suppressive in the early stages of hypoxia,” Dr Galbraith said.

“Since the hypoxic response can be tumour suppressive in some contexts and oncogenic in other contexts, it’s not a good idea to issue a blanket statement that we should always try to shut it down,” Dr Espinosa added. “Instead, we should be thinking about what aspect of the hypoxic response to target, and that’s the aspect where hypoxia drives invasion and metastasis.”

Hoping that other researchers would make use of the map his team developed, Dr Espinosa said, “I would say this is a definitive improvement in the mapping of the early events of hypoxia. And the beauty of that is that once you have a good map of the land, a lot of people can use it.”

Source:  Medical Xpress

Journal information: Zdenek Andrysik et al, Multi-omics analysis reveals contextual tumor suppressive and oncogenic gene modules within the acute hypoxic response, Nature Communications (2021). DOI: 10.1038/s41467-021-21687-2