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Thousands of studies could be flawed due to contaminated cells

“More than 30,000 scientific studies could be wrong due to widespread cell contamination dating back 60 years,” reports the Mail Online.

The news is based on research that suggests incorrect identification of cells grown in the lab could have distorted information in tens of thousands of published research studies. These studies have in turn been mentioned by about another half a million research papers, as recently as 2017.

The issue of misidentification of cells grown in labs (known as cell lines) due to contamination has been known to researchers for a long time. The first major report on this problem was published back in 1968.

For example, some research papers have reported results for “lung cancer cells” that turned out to be liver cancer cells. This new research gives an idea of how many scientific articles could be affected.

The Mail Online incorrectly implies that some cures or treatments could be ineffective as a consequence. The experiments that would have been affected involved the very early testing of potential drugs in laboratory conditions (in vitro research).

If these early experiments were successful, research in animals and humans would have followed. Only those drugs that were successful in all of these stages would be allowed to be used in humans.

But the findings are still of concern as they could mean more potential drugs fail when they move from tests in cells to tests in animals. And this could lead to some time consuming and expensive dead ends for researchers.

 

What are cell lines and how are they used?

Researchers often study cells they have collected from normal or diseased human or animal tissue, and then grown in the lab. They do this to understand more about how the cells work when they are in the body.

They also use them to start to get an idea of the effects of potential new drugs – for example, will they kill diseased cells but not normal cells?

The current research is about cell lines. When cells are grown in the lab, they tend to die naturally after a certain amount of time. However, if they are grown under special conditions, they can keep on growing and dividing to make new cells. At this stage these cells are called a “cell line”.

The cells can also be frozen and then revived to be grown in the lab once more. This allows the cells to be distributed and shared with other researchers.

The most famous cell line is known as the HeLa cell line, named after an African-American woman Henrietta Lacks, whose cervical cancer cells (taken without her consent) were used to establish the first ever cell line in 1951.

It is important that researchers know exactly what type of cells they are working with so each cell line is given a unique name and its characteristics recorded by researchers.

However, sometimes cell lines are misidentified, possibly because they get contaminated by other cells in the lab. If researchers don’t realise, then they could be working with the “wrong” cells, and sharing their results (and potentially the affected cell lines) with other researchers.

 

Who has done this research and why?

Researchers from the Institute for Science in Society at Radboud University in the Netherlands have looked into the issue of misidentification of cell lines.

They recognised that although attempts are being made to tighten laboratory procedures and reduce misidentification of cell lines, little has been done to make sure researchers know which affected cell lines not to use, or to flag research articles that have been affected.

They decided to carry out a study that would do three things:

  • establish how many scientific articles have been published based on misidentified cell lines
  • determine if the literature is getting any better or worse in reporting misidentified cell lines
  • suggest how to deal with the “contaminated” literature that is based on studies of these misidentified cell lines

 

How did they estimate the size of the problem?

The researchers searched the scientific databases for reports of misidentified cell lines.
In particular they were interested in cell lines where none of the original “correct” cell line (the “original stock”) is known to exist. When this is the case, there is no way to cross-check the identification of a cell line against the original stock. This means that most or all of the cells in the stock may be different to the original stock, or misidentified.

Misidentified cell lines are reported to the International Cell Line Authentication Committee’s (ICLAC) database, which lists 451 cell lines with no original stock.

The researchers then searched the following databases for articles reporting research studies using these misidentified cell lines:

  • the Cellosaurus database
  • the German Collection of Microorganisms and Cell Cultures database (DSMZ)
  • the American Type Culture Collection database (ATCC)
  • the European Collection of Authenticated Cell Cultures database (ECACC)
  • the Web of Science, a scientific literature database

They also identified any secondary published research articles that had mentioned in their references any of the studies using the misidentified cell lines.

As well as reporting on the amount of articles they found, the researchers also presented three case studies tracking publications about a single misidentified cell line to show how information based on these cell lines can spread.
Because this study has relied on researchers identifying and reporting misidentified cell lines not all cases where the problem has occurred will be captured.

 

What did they find?

The researchers identified 32,755 research articles that were “contaminated” by studying misidentified cell lines. Over half of these papers were published since the year 2000, and 58 articles were published as recently as February 2017. This suggests that the problem is not fading away.

Looking at how far the potentially incorrect information from these “contaminated” articles had spread, the researchers found:

  • overall, more than half a million research papers were estimated to mention one of the “contaminated” articles
  • almost all (about 92%) of the “contaminated” articles had been mentioned by at least one other research paper
  • 46 of the articles had been mentioned in over a thousand other research papers
  • 2,600 of the articles had been mentioned in over a hundred (but under a thousand) other research papers

To give an example of how misidentification can affect subsequent research there is a cell line called ALVA-31. This cell line was established in 1993 from a human prostate cancer, but in 2001 it was identified that the “stock” in use was identical to a different human prostate cancer cell line called PC-3.

Fifty six published articles referring to the ALVA-31 cell line were found. Of these, 22 were published after the discovery that the ALVA-31 cell line had been misidentified. Of those 22 articles, only two mentioned the potential misidentification of ALVA-31. Some of these papers were published in 2016 – 15 years after the misidentification was reported.

The 56 articles on ALVA-31 had been mentioned in 2,615 other research papers.

 

What is the impact of this contamination?

The first concerns about contaminated literature were raised over half a century ago. Given some of the contaminated literature found in this study was published this year, clearly this issue remains a pressing one for researchers.

Although some articles mentioning the “contaminated” research may be doing so to point out the misidentification, the sheer mass of research potentially built on false grounds is still alarming.

The contaminated literature may have important impacts. The findings of these studies may lead researchers to draw incorrect conclusions, and perform additional studies based on these. As a result, these studies could waste both valuable research time and money.

On the other hand, the researchers recognise that not all of the papers they identified found serious errors. In some cases, the exact origin or characteristics of a cell line may not actually affect the results of an experiment that much.

 

What steps can be taken to remedy this problem?

This is a known problem and ICLAC has published guidelines aimed at minimising misidentification issues.

Good researchers are likely to already carry out checks to make sure their cell lines are what they think they are. They also take steps to make sure they don’t contaminate their cells. This study shows why it is important for researchers to consistently take these steps.

The authors of the current research make a number of suggestions for additional improvements to the current situation, including that:

  • papers reporting on the discovery of misidentified cell lines need to be clearly labelled so that other researchers can easily find them
  • to make sure they don’t “spread” misleading research in their own publications
  • those aiming to clean up the contamination problem should write about the contamination, using social media campaigns and general media coverage to highlight the issue and inspire greater research scrutiny
  • in cases where uses of misidentified cell lines produce a false conclusion papers should be officially withdrawn

The findings should not cause unnecessary concern about existing drug treatments. Not all of these “contaminated” studies would have assessed potential new drugs. If they did, any that showed promise would then have had to undergo rigorous testing in animals, and then humans, before they could be used in routine practice.

Links To The Headlines

More than 30,000 scientific studies could be WRONG due to widespread cell contamination dating back 60 years, new report warns. Mail Online, October 17 2017

Links To Science

Horbach SPJM, Halffman W. The ghosts of HeLa: How cell line misidentification contaminates the scientific literature. PLOS One. Published online October 12 2017

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‘Magic mushrooms’ may help ‘reset’ depressive brains, study claims

“Magic mushrooms can ‘reboot’ brain to treat depression,” reports the Daily Telegraph.

The news is based on a small UK study that looked at the effects of psilocybin, a chemical found in magic mushrooms, on patients with severe depression.

All 19 patients said their depression improved immediately after taking psilocybin and almost half said they still felt the benefits 5 weeks later.
However, the study didn’t include a comparison group, so it’s hard to know whether this benefit can be attributed to the chemical.

The patients were also given special psychological care during and after taking psilocybin, as an integral part of their treatment.

The effects of psilocybin were measured using a functional MRI scan, an advanced MRI machine that measures blood flow in the brain.

The researchers believe psilocybin helps to change how networks of nerves communicate in the brain, which might disrupt negative thought patterns.

The suggestion of “re-setting” or “rebooting” the brain is attractive in an age when we are all used to fixing computers by turning them off and on again.

However, we need to see further, larger studies to know whether this treatment offers a comparable solution to the brain as the off switch does for computers.

The authors of the study warn that people with depression should not try psilocybin or other psychedelic drugs to treat themselves.

Psilocybin and the mushrooms that contain it are illegal to possess, give away or sell in the UK, outside of clinical trials. They could be dangerous if used without medical support.

Where did the story come from?

The researchers were mostly based at Imperial College in London, with some at Hammersmith Hospital, Cardiff University and University College London. The study was published in the peer-reviewed journal Nature Scientific Reports and is free to read online.

Although for the most part the UK media reported the study accurately, none of the reports pointed out the lack of comparison group in the study, which makes it hard to attribute the study results to the drug. The Guardian otherwise gave a good explanation of the study methods and results.

The Mail Online carried comments from the researchers suggesting that people in the study had reduced depression six months later, but this information was not included in the study so can’t be checked.

The Independent wrongly stated that the study showed: “Eating magic mushrooms can help treat depression,” and wrongly claimed that the researchers gave mushrooms to patients, rather than administering the extract psilocybin.

What kind of research was this?

This was a small experimental study with no control group. The researchers wanted to see how psilocybin affected brain activity and if that was linked to depression.

This type of study can yield interesting information in the early stages of exploring potential medical treatments, but needs to be backed up by more reliable randomised controlled trials (RCTs) before we can say whether the treatment works.

What did the research involve?

Researchers recruited 20 patients with depression that no longer responded to standard antidepressants. They scanned their brains and measured their depression using a symptom questionnaire. They then administered two doses of psilocybin, one week apart.

They scanned the participants’ brains and measured depression symptoms the day after the second treatment, then measured depression symptoms again 5 weeks later.

Finally, the researchers looked to see whether the brain scans showed differences in activity before and after taking psilocybin, and whether these changes were linked to people’s depression scores.

The brain scans used functional MRI. They measured two things:

  • cerebral blood flow – how much blood flowed around the brain. This is used as a general measure of brain activity
  • resting state functional connectivity. This is used to monitor how much activity takes place through nerve networks in different areas of the brain. The researchers focused on four areas that had previously been identified as potentially important

Depression was measured using the Quick Inventory Depression Score (QIDS-SR16). Psilocybin doses were 10mg followed by 25mg. Patients were given psychological support during and after taking their medication.

The researchers analysed whether changes seen on brain scans correlated with depression symptom scores the day after the second treatment, and with patients’ chances of showing a treatment response 5 weeks later. A positive treatment response was defined as a halving of their initial QIDS-SR16 score.

What were the basic results?

One person dropped out of the study, and some of the brain images were not good enough quality to use. Of the 19 patients who took part in the whole study, all had improved QIDS-SR16 scores on the day after the second treatment, and in 47% the effects were still there after 5 weeks.

Based on brain scans from 16 people, the researchers said that cerebral blood flow to the brain was decreased the day after the second treatment, compared to before treatment. They said they found no instances where blood flow increased.

They said that comparisons between blood flow to the amygdala (an area of the brain that controls many emotions, such as fear and stress) and symptom scores the day after scanning showed a “significant relationship” between the two.

Based on brain scans from 15 people, the researchers said that resting-state functional connectivity increased in two of the regions studied, and decreased in one region. They found no difference in connectivity in a fourth region.

For the three regions that did show changes, two of them were linked to a positive treatment response at 5 weeks. None of the brain regions showed changes that correlated with improved symptom scores the day after treatment.

How did the researchers interpret the results?

The researchers said their findings suggested that psilocybin might have a similar action to electroconvulsive therapy (ECT).

They say their findings showed that “default mode network” – the resting patterns of connectivity between brain regions – may have “decreased acutely, then increased (or normalised) post-acutely, accompanied by improvements in mood. This process might be likened to a ‘reset’ mechanism.”

They call for further testing to assess the “relative contributions” of psilocybin and the accompanying psychological support.

Conclusion

For people with depression who are not helped by conventional treatment such as antidepressants and talking therapies, studies such as this one may offer a glimmer of hope. This and previous studies on psilocybin suggest it may one day become a treatment option for people with a range of psychiatric conditions.

It’s important to note that this is experimental, early-stage research. The study lacked a control group, so it’s hard to know whether the improvement in mood, or the changes seen on MRI scans, can be attributed to the drug.

The study is very small and we should bear in mind that half of those taking part did not see a 50% reduction in depression symptoms after 5 weeks, suggesting they gained little real benefit.

Changes in brain function may help explain the effect of psilocybin and similar drugs. Previous studies with healthy (non-depressed) volunteers have shown changes in brain function after people took psychedelic drugs.

The suggestion of a “re-set” or “reboot” sounds plausible, especially in an age when we are all used to fixing computers by turning them off and on again. The idea of temporarily “powering down” the brain to fix problems is intuitively easy to grasp. However, we need to see further studies to know whether this treatment offers a comparable solution to the brain as the off switch does for computers.

Your GP is the first port of call if you have, or think you may have, depression. We strongly advise against self-medicating with any drug for depression. Psilocybin and magic mushrooms are class A drugs in the UK.

Links To The Headlines

Magic mushrooms can ‘reset’ depressed brain. BBC News, October 14 2017

Magic mushrooms can ‘reboot’ brain to treat depression – study. The Daily Telegraph, October 14 2017

Eating magic mushrooms can treat depression, study finds. The Independent, October 14 2017

Magic mushrooms may ‘reset’ the brains of depressed patients, study shows. Mail Online, October 13 2017

Magic mushrooms ‘reboot’ brain in depressed people – study. The Guardian, October 13 2017

Links To Science

Carhart-Harris RL, Roseman L, Bolstridge M et al. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Scientific Reports. Published online on October 13 2017

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Site last updated October 19, 2017 @ 6:00 pm; This content last updated December 11, 2011 @ 12:55 pm