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Blood pressure drugs may be linked with increased risk of bowel condition

4th July 2019

Diverticulosis causes small bulges or pouches to appear in the lining of the intestine. Particularly affecting the elderly (as many as 65% of over 85s may be affected), diverticulosis can in some cases lead to a medical emergency if the pouches become infected or burst.
 
The new early-stage research finding comes from a team of scientists led by Imperial College London, who investigated the effectiveness and side effects of three common blood pressure medications: ACE-inhibitors, beta-blockers and calcium channel blockers.
 
High blood pressure affects one in ten adults across the globe, and increases the risk of heart attack and stroke. The most common treatments for high blood pressure are lifestyle changes and medications.
 
However, despite the three main medications being taken by millions, investigating their potential side effects (as well as studying their effectiveness for treating other diseases), can be difficult and often involves lengthy and expensive clinical trials.
 
To overcome this problem, the research team, led by Imperial’s School of Public Health, used genetic analyses to study the effects of the drugs.
 
By investigating versions of genes that mimic the effects of these drugs, the team were able to study the drugs’ effectiveness — and their potential side effects.
 
First, the researchers, who published their work in the journal Circulation, identified the proteins targeted by the drugs, and which help lower blood pressure. Next, they analysed genetic data from around 750,000 people and identified the so-called genetic variants that code for these proteins.
 
The team, who included researchers from LMU Munich, then studied whether these gene variants – which cause increased production of these proteins – were linked to an increased or decreased risk of other diseases.
 
The good news was that, as expected, these so-called genetic variants (which coded for proteins involved in lowering blood pressure) were linked to lower heart disease and stroke risk.
 
However after assessing the risk of around 900 different diseases – using data from the UK Biobank study – the team found that the versions of genes related to the effects of a particular type of calcium channel blocker – the non-dihydropyridine class, were linked to an increased the risk of a bowel condition called diverticulosis.
 
The team compared their findings with further genetic data, and supported the potential link with an increased risk of the bowel condition.
 
The link now needs further investigation with larger trials, explains Dr Dipender Gill, co-lead author of the research from Imperial’s School of Public Health: “This is the first time that this class of blood pressure drug has been associated with diverticulosis. We’re not sure of the underlying mechanism — although it may relate to effects on the function of intestine muscles, which perform contractions to transport food through the gut.”
 
Dr Joanna Tzoulaki, senior author from Imperial’s School of Public Health added: “The study of genetic variants that mimic the effect of drugs is evolving as a powerful concept to help prioritise clinical trials and design clinical trials more likely to be successful.”
 
Dr Gill cautions the findings should not change current prescribing guidelines and that people should not stop taking their medication unless first consulting their doctor.
 
He added: “These findings should not change clinical practice, but instead should act as a catalyst for further research.”

‘Back to school asthma’ linked to tripling in rate of health service appointments

2nd July 2019

‘Back to school asthma’- a seasonal peak in cases associated with the start of the school year in September – is linked to a tripling in the rate of general practitioner (GP) appointments across England, reveals research published online in the Journal of Epidemiology & Community Health.1

The phenomenon seems to particularly affect the under 5s and boys, national monitoring data show.

The prevalence of asthma and associated deaths and use of healthcare services in the UK are thought to be the highest in the world. And ‘back to school asthma’ accounts for up to a quarter of serious bouts of the condition in many northern hemisphere countries.

But it’s not clear where the resulting pressure points on healthcare services might be. In a bid to find out, the researchers analysed routine monitoring data for family doctor consultations about worsening asthma, both within and outside normal practice hours, as well as related visits to hospital emergency care departments between 2012 and 2016.

They looked at the time and sex specific trends for 0-4 and 5-14 year olds for the last four weeks of the summer holiday up to the first 6 to 7 weeks of the autumn term.

All three sources of data indicated similar age and sex specific patterns, with use of health services for asthma up to 2.4 times higher among boys in both age groups than among girls.

The highest rate of asthma cases was among 5 to 14 year old boys for each of the three services.

Rates of GP in hours appointments for asthma fell during school holidays, followed by an increase in the first two to three weeks of each of the autumn half terms, with the sharpest rise at the start of the school year in September.

Patterns for GP out of hours services were similar to those of in hour consultations. And emergency care department visits for worsening asthma also peaked at the start of the school year for both age groups.

Across the entire study period, the average delay between the start of the school year and the ‘back to school’ effect varied for each of the years, beginning as late as 17 days afterwards and as early as 7 days before.

But after taking account of these annual variations and sex differences, the daily in hours consultation rate for worsening bouts of asthma was more than three times as high in the back to school period as during the summer holidays for children up to the age of 4. And it was 2.5 times as high for 5-14 year olds.

For GP out of hours consultations, the rates were around twice as high for both age groups.

No such obvious peaks were seen for children aged 15 and older.

This is an observational epidemiological study, and as such, cannot establish cause. The coding applied to surveillance data may vary in quality, acknowledge the researchers. And it can be difficult to accurately diagnose asthma in young children because of the range of other factors than can produce similar respiratory symptoms.

But the very large number of children studied over several years lends weight to the findings, say the researchers, who suggest that multiple factors are likely to be involved.  

“The underlying aetiology of [‘back to school’] asthma is complex and in addition to the established contribution of respiratory infections, environmental determinants may be involved: the role of fungal spores (which show autumnal seasonality) could be an area for future research to investigate aetiology and thus determine potential future interventions,” suggest the researchers.

“These results support the need for further preventable work to reduce the impact of [back to school] asthma in children,” they conclude.

Reference

  1. Bundle N et al. Monitoring epidemiological trends in back to school asthma among preschool and school-aged children using real-time syndromic surveillance in England, 2012–2016. J Epidemiol Community Health 2019;jech-2018-211936 DOI: 10.1136/jech-2018-211936

Study suggests MS patients are at a greater risk of cancer

New results of a 65-year follow-up study of nearly 7000 Norwegian patients with multiple sclerosis (MS) suggest that patients may have a greater overall risk of developing cancer than the general population, with an especially high risk of cancer in respiratory organs, urinary organs and the central nervous system.
 
Cancer risk among MS patients compared with the non-MS population:
  • Respiratory cancer: 66% increase in risk
  • Central nervous system (CNS): 52% increase in risk
  • Urinary cancer: 51% increase in risk
  • Overall cancer: 14% increase in risk.
This long-term analysis was based on patient records from 6883 MS patients born between 1930-1979, who were registered with various Norwegian MS and Cancer Registries, and prevalence studies from Norway. The analysis also included data from 8918 siblings without MS, and 37,919 non-MS individuals.
 
“This study is the first to compare cancer risk in MS with non-affected siblings of MS patients. The risk assessment between these two groups is extremely interesting because they share the same genetics and environmental conditions,” noted Dr Nina Grytten, lead researcher of the study, from Haukeland University Hospital, Bergen, who presented the results at the EAN congress.
 
“Previous clinical studies of cancer risk in MS patients in various countries have shown inconsistent findings, so further research is needed to help improve our understanding in this area,” stated Dr Grytten. “This research outlines the need for greater awareness of cancer risk among MS patients, which should lead to shortened cancer diagnosis and more effective therapy in order to improve outcomes and survival.”
 
“Additional research could also identify the possible connections between haematological cancer and MS and new ways in which we could manage these conditions“, she added.
 
According to Dr. Grytten, the results of the investigation might suggest that MS and haematological cancer could share a common aetiology, which can be important for future treatment of MS and prevention of both diseases.

New method divides patients with ulcerative colitis in groups

1st July 2019

Researchers at Karolinska Institutet in Sweden have found a way of using gene expression conserved across species to divide patients with the inflammatory bowel disease, ulcerative colitis, into two distinct groups. 
 
Ulcerative colitis is an inflammatory bowel disease affecting the colon and rectum. It manifests itself differently in patients, and only 50-60% respond to the treatment with biological drugs.
 
There is therefore a need to divide patients into different groups so that new pharmaceutical targets can be identified and treatments tailored accordingly.
 
“We’ve managed to divide patients with ulcerative colitis into two molecularly distinct groups using a method that we believe can be used for other diseases too,” says the study’s corresponding author Eduardo Villablanca, associate professor at the Department of Medicine, Karolinska Institutet (Solna).
 
The researchers first used openly accessible data on gene expression – transcription data – from colon biopsies from 102 patients with ulcerative colitis. But the variation between patients proved too great to break the patients down into meaningful groups.
 
They then hit on the idea of excluding irrelevant genes in the patient material by only looking at genes whose expression is changed in both humans and mice. To do this, the group analysed gene expressions in colon biopsies from a mouse model with ulcerative colitis. They found 57 genes in common from the mouse and patient material.
 
Using these 57 genes, the researchers were able to identify two groups of patients, which they term UC1 and UC2. UC1 patients are characterised by the higher expression of genes involved in the recruitment of neutrophils, which are a type of immune cell. Over 87 per cent of the patients in this group also responded poorly to treatment with two of the most widely used biological drugs for ulcerative colitis. About 60 per cent of the patients in the UC2 group, however, responded to this treatment.
 
“We demonstrate the principle that it’s possible to combine datasets from mice and humans to group previously indistinguishable patients,” says Dr Villablanca. “The results provide new knowledge on inflammatory bowel diseases and can contribute to the more tailored treatment of ulcerative colitis.”
 
Reference
  1. Czarnewski P et al. Conserved transcriptomic profile between mouse and human colitis allows unsupervised patient stratification. Nature Communications 2019;online 28 June: doi: 10.1038/s41467-019-10769-x

New genetic test helps predict side effects of chemotherapy

The Cancer and Haematology Centre at the Churchill Hospital in Oxford and the Horton General Hospital in Banbury have introduced a genetic test that helps predict dangerous side-effects of chemotherapy.
 
As a result of an agreement between Oxford University Hospitals (OUH) NHS Foundation Trust, which runs the hospitals, and Oxford Cancer Biomarkers (OCB) Ltd, 600 patients receiving chemotherapy each year for colon, breast, oesophagus and other cancers will have a blood test prior to treatment. The test predicts the side effects of two commonly used chemotherapy drugs, and will allow the cancer teams to tailor the chemotherapy dose for each patient.
 
Capecitabine and 5-FU cause a range of side effects, including low blood counts, diarrhoea and heart problems that can be fatal in some instances.
 
Using a broader genetic analysis of the blood samples, OCB’s ToxNav test may better predict who is at risk of some of these significant side effects, with the aim of ensuring capecitabine and 5-FU treatments are safer.
 
The test looks at 19 different genetic changes (variants) of a gene called DPYD that indicate susceptibility with the toxicity of these drugs. DPYD activity is important as it normally acts to breakdown 5-FU.
 
The variants identified in the ToxNav test are associated with lower DPYD activity, and so higher and more dangerous levels of 5-FU after treatment. Approximately 5-8% of the population have such DPYD variants, that are only unmasked when the drugs are administered.
 
Prof Bass Hassan, Clinical Director at the Oxford Cancer and Haematology Centre, said: “The ToxNav test is a step-change for personalised treatment of cancer patients in Oxfordshire. It marks an exciting and important milestone in the development of the technology, in a unique collaborative initiative with Oxford Cancer Biomarkers, a local company that we have contracted in a close working agreement.”
 
Research at OUH and the University of Oxford is leading to a range of genetic tests for many diseases, including cancer. Through clinical trials run in the NHS, many of these validated discoveries are then taken to the market by local spin-out companies such as OCB, in this case lead by University academics, Prof David Kerr and Prof Nick La Thangue.
 
There is no routine reporting of deaths and toxicities associated with 5FU and capecitabine, but OCB estimates from UK medical and research data that at least 150 people in the UK die each year from various complications due to these drugs, and many more will suffer severe side-effects.
 
“We are very hopeful that we will see a reduction in the chemotherapy mortality rate in Oxford, as well as a fall in the number of bed admissions by adopting this innovation,” Prof Hassan said.
 
“The next steps for our cancer team in Oxford are to confirm the cost-effectiveness of the ToxNav test in routine NHS care, so that this information can help it be adopted by other NHS cancer hospitals.”

Faecal marker could help diagnose early signs of chronic gut conditions

Small molecules found in faecal matter could provide clues to the early inflammation found in chronic gut conditions, such as intestinal bowel disease (IBD), and serve as new biomarkers for diagnosis, according to a study led by the Institute for Biomedical Sciences at Georgia State University.
 
The researchers found that faecal miRNA, small nucleic acid sequences, could be used as a tool to assess the healthiness of gut microbiota and provide early clues to intestinal inflammation in mice.
 
Studies have shown that some microbiotas can play a role in the development of intestinal inflammation. Since disruption of the symbiosis between the microbiota and the intestine is associated with various inflammatory diseases, such as IBD and metabolic syndrome, it is essential to identify new biomarkers of microbiota healthiness. The findings, published in the journal Theranostics, are some of the first to show connections between faecal miRNAs and gut microbiota. Earlier studies to find biomarkers for IBD or inflammation have mostly been done from tissue and blood.
 
“We found that miRNA from faeces are indicative of inflammation level as well as microbiota function,” said Dr. Emilie Viennois, first author of the study and assistant professor in the Institute for Biomedical Sciences. “It can indeed indicate if the microbiota is more prone to induce inflammation or is more protective against inflammation, and it could also determine the ability of patients to respond to therapeutics.”
 
“Further study will need to be done in humans, but we think that faecal miRNA can also be a way to indicate the status of the microbiota in IBD patients,” Viennois said. “We know that some microbiotas are more prone to induce inflammation than others, and using miRNA as a tool to determine that would be extremely useful.”
 
Reference
  1. Viennois E et al. Host-derived fecal microRNAs can indicate gut microbiota healthiness and ability to induce inflammation. Theranostics 2019;9(15):4542 DOI: 10.7150/thno.35282

Expert view: Correct diagnosis of rhinitis is key to management

Allergic rhinitis is one of the most frequently neglected and underappreciated diseases. When the symptoms are limited to sneezing and itchy eyes, many sufferers decide to treat themselves with do-it-yourself remedies or remedies recommended by friends and relatives; however, this is a mistake.
 
In Europe, 113 million patients suffer from allergic rhinitis. According to data from the European Federation of Allergy and Airway Disease Patient Association, 30–35% of the total European population suffers from respiratory allergies during their lifetime, and 20% of the entire population is affected by allergic rhinitis. In light of these high numbers, however, there are still too many allergy sufferers who treat themselves without having received an accurate diagnosis, and who utilise over the counter symptom relief. A total of 45% of the subjects complaining of allergic symptoms never arrive at a certain diagnosis because they do not report the symptoms to the doctor, and 18% of patients experience a worsening of the disease with severe symptoms.
 
A study by Canonica et al analysed perceptions of patients and physicians regarding the symptoms and impact of allergic rhinitis in a prospective, cross‐sectional, international survey, and reported the results from Germany, France, Italy, Spain and the UK.1 They found that allergic rhinitis was a significant health problem and that there was a poor correlation between patients and physicians in the reporting of disease severity.
 
Even when rhinitis is mild, and therefore does not bring with it the above consequences, it is important to accurately diagnose its pathology, understand which allergens trigger it, and follow the therapy prescribed by the clinician to avoid the condition deteriorating and becoming worse. 
 
For the diagnosis of allergic rhinitis, it is sufficient to perform a skin prick test or the dosage of specific IgE for inhalant allergens. In the first case, the allergist or paediatrician can directly perform the skin test; in the second case, a blood sample is necessary and the result will come from the lab.
 
Based on the duration of symptoms, allergic rhinitis can be classified as intermittent or persistent, whereas it can be defined as mild or moderate to severe based on symptom severity. The intermittent/seasonal forms are less problematic, as they are generally related to pollen allergies and therefore depend on the flowering of certain plants (usually in the Spring). The more enduring forms are instead often linked to allergens derived from dust mites and pets, which are present throughout the year.
 
Rhinitis is considered moderate or severe when the symptoms cause consequences such as an alteration of sleep patterns, limitations on sporting or leisure time, or repercussions on work or school performance.
 
Badly/inadequately treated allergic rhinitis is an important risk factor for the development of asthma but can also lead to other pathologies such as rhinosinusitis, nasal polyposis, otitis and conjunctivitis.
 
Consequently, the treatment needs to take into account the duration and intensity of the events. In addition to oral antihistamine therapy – often considered the only remedy for allergies – there are other therapeutic approaches that can be used in case of rhinitis, such as nasal corticosteroids.
 
Reference
  1. Canonica W et al. A survey of the burden of allergic rhinitis in Europe. Allergy 2007; doi.org/10.1111/j.1398-9995.2007.01549.x

Antioxidants implicated in new understanding of how lung cancer spreads

Lung cancer cells use antioxidants, endogenous or dietary, to spread in the body by activating a protein called BACH1 and increasing the uptake and use of sugar, Swedish and American researchers report in two independent studies. 
 
It is a known fact that cancer cells are exposed to oxidative stress caused by free oxygen radicals. It is also well-known that cancer cells are characterised by the high uptake and use of glucose, or sugar, and that this is one of many factors that govern their ability to divide and metastasise. Studying mice and human tissue, two independent research teams have now discovered how these circumstances interact when cancer cells metastasise to other parts of the body.
 
The process begins when the cancer cells manage to reduce their oxidative stress, which can happen in one of two ways: the cancer cells can either obtain antioxidants, such as vitamins A, C or E, from the diet, or synthesise their own. In about one in every three cases of lung cancer, the tumour cells have special mutations, linked to the NRF2 and KEAP1 genes, which enable them to start producing their own antioxidants.
 
It is when the oxidative stress has subsided that the fundamental process of the new discovery occurs: the protein BACH1 is stabilised and accumulates in the cancer cells. This protein presses several start buttons in the cancer cell which stimulates metastasis mechanisms, including one that orders the cancer cell to increase both the metabolism of glucose into cell fuel and lactic acid, and the stockpiling of glucose from the blood stream. The higher rate of glucose use then greatly boosts the ability of the cancer cells to spread.
 
“There is nothing to suggest, however, that the amount of glucose in the blood has anything to do with this; rather, it is the tumour cells’ ability to utilise glucose that is essential to the accelerating metastasis,” says Martin Bergo, professor at the Department of Biosciences and Nutrition at Karolinska Institutet, who led the Swedish study.
 
“We now have important new information on lung cancer metastasis, making it possible for us to develop new treatments, such as ones based on inhibiting BACH1,” says Professor Bergo. “In this present study, we show that the aggressive metastasising induced by antioxidants can be blocked by stopping the production of BACH1 or by using drugs that suppress the breakdown of sugar. Our American colleagues show how inhibiting another enzyme, heme oxygenase, which is linked to BACH1, can also curb the metastasis process.”
 
Professor Bergo and his Swedish colleagues have previously shown that antioxidants, such as vitamin E, in dietary supplement doses accelerate tumour growth. When the first studies to show this were presented in 2014 they drew a great deal of media attention and sparked a fierce debate, since it was generally believed that antioxidant supplements had beneficial effects on cancer. What the researchers have done now is to explain how antioxidants go about expediting the course of the disease – specifically, in the case of the present study, lung cancer.
 
“This is one of the most exciting findings we’ve made,” says Volkan Sayin, assistant professor at the Department of Clinical Sciences, University of Gothenburg, and co-corresponding author. “Our results also provide a new explanation for how the so-called Warburg effect is activated. The Warburg effect describes how cancer cells absorb sugar and convert it into energy and lactic acid under normal aerobic conditions. Since this is one of the most well-known hallmarks of cancer, our results provide a crucial new piece in the oncological puzzle.”
 
References
  1. Will C et al. BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis. Cell 2019: DOI: 10.1016/j.cell.2019.06.005
  2. Lignitto L et al. Nrf2 Activation Promotes Lung Cancer Metastasis by Inhibiting the Degradation of Bach1. Cell 2019; DOI: 10.1016/j.cell.2019.06.003

One in five haematological cancer patients suffer blood clots or bleeding

An average of one in five haematological cancer patients suffer blood clots or bleeding, according to new Danish research that aims to help direct focus towards this serious complication. 

Kasper Adelborg, a medical doctor and PhD from Aarhus University and Aarhus University Hospital, studied the cases of 32,000 haematological cancer patients between the years 2000 and 2013. Haematological cancer includes leukaemia, bone marrow cancer and cancers of the lymph nodes.

“This is a broad group of patients with very different disease experiences depending on the type of haematological cancer. Some patients have a particular risk of suffering blood clots, while others have instead a higher risk of bleeding such as, for example, gastrointestinal bleeding,” says Adelborg, before stating that the new knowledge can be used for even better prevention and individualised treatment:

“If a person has a high risk of suffering a blood clot, treatment with anticoagulant medicine can benefit some patients. But anticoagulant medicine is not desirable if the risk of suffering bleeding is higher. This is a difficult clinical problem, but our study can set goals for what carries most weight for each individual type of cancer,” he says.

One example is the disease myelodysplastic syndrome (MDS). Here the study showed that the risk of bleeding within ten years was approximately 15%, while the risk of suffering a blood prop was lower.

“This means that doctors who help these patients should be aware that they have a high risk of bleeding and should therefore not prescribe too much anticoagulant medicine,” says Adelborg.

He adds that with each individual patient there is still a need to weigh up the overall risk of a blood prop and bleeding, which includes taking into account the patient’s age, medical history, other diseases, lifestyle etc. before choosing a treatment.

The study, which has been published in the Journal of Thrombosis and Haemostasis, corroborates previous studies, though researchers have not previously looked at the entire group of haematological cancer patients together – and neither were there any studies covering so many years. Additionally, previous studies have either focused solely on blood clots or bleeding.

Adelborg emphasises that there are major differences in the prognoses for the different patient groups. For example. only a few children develop a blood prop or suffer bleeding in the years after suffering from leukaemia, while far more patients with, for example, bone marrow cancer develop blood props and/or bleeding.

“The potential for prevention is particularly large in the latter group,” he says.

In relation to the population as a whole, the study shows the heightened risk for haematological cancer patients:

  • Blood clot in the heart: 40% higher
  • Blood clot in the brain: 20% higher
  • Blood clot in the legs and lungs: over 300% higher
  • Bleeding: 200% higher.

New knowledge on the development of asthma

Researchers at Karolinska Institutet in Sweden have studied which genes are expressed in overactive immune cells in mice with asthma-like inflammation of the airways. Their results, which are published in the journal Immunity, suggest that the synthesis and breakdown of fats plays an important part in the process.
 
Th2 cells plays a vital part in asthma-related inflammation, but the rarity of these cells and a lack of sensitivity technology has made these cells hard to study in any detail.
 
Researchers at Karolinska Institutet have now used single-cell RNA sequencing to analyse which genes are active in individual T cells. For the study, the team exposed mice to house dust mites, a common allergen to which most asthmatics are sensitive and which induces asthma-like lung inflammation. They then monitored gene expression in T cells before and after exposure to the allergens in the lymph glands to the point of inflammation in the lungs.
 
They found that in the mouse lung, the T cells express a unique profile of hundreds of genes, many of which are linked to how the cells make and break down fat. When they then gave mice a drug to block fat metabolism, the lung inflammation decreased relative to controls.
 
“Our results suggest that fats can help to aggravate the T-cell activated inflammation in the lungs that is seen in asthma,” says the study’s corresponding author Jonathan Coquet, researcher at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet. “We now plan to systematically test the importance of the hundreds of uniquely expressed genes in order to find those that can trigger or prevent the development of the disease.”
 
Another feature of the study was that when T cells reached the lungs from the lymph glands, they received signals that switched on the production of two powerful inflammatory substances: the cytokines interleukin 5 and 13. These cytokines are responsible for many of our normal asthma symptoms, such as respiratory tract inflammation, muscle contraction and mucus discharge.
 
“Our observation is that the T cells change a great deal over time and seem to undergo a kind of reprogramming in the lungs that makes them highly inflammatory,” says Dr Coquet.
 
Reference
  1. Tibbitt C et al. Single-Cell RNA Sequencing of the T Helper Cell Response to House Dust Mites Defines a Distinct Gene Expression Signature in Airway Th2 Cells. Immunity 2019;DOI:10.1016/j.immuni.2019.05.014

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