Scientists make major breakthrough in prostate cancer diagnosis

Scientists at the University of Surrey, UK, have made a major breakthrough in the early diagnosis of prostate cancer. They have developed a new way of more reliably detecting the cancer by testing a small urine sample from men, allowing faster testing that could save lives and offer the potential for huge cost savings.

A three-year study, published 1 March 2011 in the US journal Clinical Cancer Research, shows that a protein called Engrailed-2 (EN2) is made by prostate cancers and secreted into urine where it can be easily detected using the new test that is simple, quick and has the potential to be used in Primary Care clinics.

EN2 is an important protein in the development of the human embryo and, like many similar ‘early life’ proteins, its production is ‘switched off’ at birth – but analysis of urine samples from 288 patients by the team at the University of Surrey found that EN2 is switched back on in prostate cancer.

Unlike the new EN2 test the standard 30-year-old PSA test for prostate cancer involves taking a blood sample and is unable to detect a significant proportion of early prostate cancers

The new EN2 test has been proven to be more reliable and accurate than existing tests, said Professor Hardev Pandha, The Prostate Project Chair of Urological Oncology at the University of Surrey’s Postgraduate Medical School.

“In this study we showed that the new test was twice as good at finding prostate cancer as the standard PSA test. Only rarely did we find EN2 in the urine of men who were cancer free so, if we find EN2 we can be reasonably sure that a man has prostate cancer. EN2 was not detected in men with non-cancer disorders of the prostate such as prostatitis or benign enlargement. These conditions often cause a high PSA result, causing considerable stress for the patient and sometimes also unnecessary further tests such as prostate biopsies.”

Co-researcher Dr Richard Morgan, senior lecturer in Molecular Oncology at the University of Surrey, explained: “Unlike the development of drug treatments, the time taken to verify the potential of EN2 in the diagnosis of prostate cancer is relatively modest. We are preparing several large studies in the UK and in the US and although the EN2 test is not yet available several companies have expressed interest in taking it forward.” doi: 10.1158/1078-0432.CCR-10-2410

UK report shows obese at high risk under anaesthesia

A major UK study on complications of anaesthesia has shown that obese patients are twice as likely to develop serious airway problems during a general anaesthetic than non-obese patients. The study also shows that the use of a simple breathing monitor, a capnograph, could significantly reduce deaths and brain damage from such problems in intensive care units (ICUs); it found that absence of a capnograph contributed to 74% of deaths from these events in ICUs during the study.

The report, published in two parts online 29 March 2011 in the British Journal of Anaesthesia, is the result of a yearlong prospective study by the Royal College of Anaesthetists (RCoA) and the Difficult Airway Society. The full report is available on the RCoA website on the same day. The project, which identified that 2.9 million general anaesthetics are given in the UK each year, monitored all major complications of airway management that occurred in these patients and in ICUs and in emergency departments throughout the UK in 2008-2009. It studied only events serious enough to lead to death, brain damage, ICU admission or urgent insertion of a breathing tube in the front of the neck.

The report has several findings and recommendations; but those on obesity and the monitoring of breathing are among the most striking.

In addition to the two-fold increased risk of obese patients developing serious airway problems during an anaesthetic, the study also found that patients with severe obesity were four times more likely to develop such problems. In addition, obese patients were more likely to die if they sustained airway complications in ICU.

Some obese patients died from complications of general anaesthesia whilst undergoing procedures that could have been performed under local anaesthesia. In some cases this alternative appeared not to be considered.

Dr Nick Woodall, consultant anaesthetist at the Norfolk and Norwich Hospital (Norwich, UK), and an author of the report says: “Our findings show that patients who are obese have twice the risk of major airway problems during anaesthesia, compared to non-obese patients. In the very obese this risk is even higher. The report is important for patients and anaesthetists alike. The information will enable obese patients to be better informed about the risks of anaesthesia and to give informed consent. We hope our findings will encourage anaesthetists to recognise these risks and choose anaesthetic techniques with a lower risk, such as a regional anaesthesia, where possible, and also prepare for airway difficulties when anaesthetising obese patients.”

Airway problems were more likely to result in death in patients sedated on ICUs than if they occurred during anaesthesia for surgery. Half of the reports of events on ICUs described a patient death from the complication, whereas 12% died when the complication occurred during anaesthesia. Of the events reported from ICU 61% led to death or brain damage, compared to 14% of events during anaesthesia.

The most important finding was that the absence of a breathing monitor (capnograph) contributed to 74% of airwayrelated deaths reported from ICUs. The authors say that if the monitor had been used it would have identified problems at an earlier stage and so could have prevented some of the deaths altogether. The capnograph, which detects exhaled carbon dioxide, is used almost universally in anaesthesia but only sporadically in ICUs. Several authors and organisations have recommended that it should be used routinely in ICUs.

Ref: Part 1 Anaesthesia. doi:10.1093/bja/aer058

Part 2 Intensive Care and Emergency Departments. doi:10.1093/bja/aer059

The full report is called: “4th National Audit Project of the Royal College of Anaesthetists and the Difficult Airway Society: Major complications of Airway Management in the UK.”

Researchers find new mechanism for development of diabetes in obese

Max Planck researchers have discovered a new mechanism that leads to the development of type 2 diabetes in obesity. Body weight influences the risk of developing diabetes: between 80% and 90% of patients with type 2 diabetes are overweight or obese. According to scientists at the Max Planck Institute for Neurological Research in Cologne and the Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases (CECAD), short ribonucleic acid molecules, known as micro-RNAs, appear to play an important role in this mechanism.

The researchers discovered that the obese mice form increased levels of the regulatory RNA molecule miRNA-143. miRNA-143 inhibits the insulin-stimulated activation of the enzyme AKT. Without active AKT, insulin cannot unfold its blood-sugar-reducing effect and the blood sugar level is thrown out of kilter. This newly discovered mechanism could provide the starting point for the development of new drugs for the treatment of diabetes.

The molecular processes in the body’s cells responsible for the connection between body weight and diabetes are largely unknown. However, in all tissues that respond to insulin, Micro-RNAs can be found. The Cologne-based scientists working with Jens Brüning, director at the Max Planck Institute for Neurological Research and scientific coordinator of the Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases at the University of Cologne assume, therefore, that micro-RNAs may also play a role in type 2 diabetes. These short ribonucleic acid molecules can regulate the activity of genes and thus control protein production.

The research group in Cologne has now discovered a new mechanism that leads to insulin resistance of the cells. Accordingly, obese mice form excess miRNA-143 in their livers. This RNA molecule silences genes that are responsible for the activation of the enzyme AKT and therefore inhibits insulin from activating AKT. “AKT is important for glucose transport in the cell and for the inhibition of glucose synthesis in the liver. When the enzyme is inhibited, insulin fails to take effect and the blood sugar remains elevated,” explains Jens Brüning.

- doi: 10.1038/ncb2211

Study shows heart rate turbulence linked to cardiac disease in low risk individuals

Abnormal heart rate turbulence is associated with an increased risk of heart disease death in otherwise low-risk older individuals, according to a study funded by the US National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.

Heart rate turbulence refers to how smoothly the heart rate returns to normal after a premature ventricular contraction, a fairly common event in which the second portion of a heart beat is triggered too soon. This study appears in the 15 February edition of the Journal of Cardiovascular Electrophysiology.

Among the nearly 1,300 study participants, heart rate turbulence, which reflects how well the heart reacts to occasional premature contractions, was an even stronger heart disease risk factor than elevated levels of C-reactive protein. CRP is a potential heart disease biomarker that has emerged in recent years.

Study participants considered at low risk of heart disease based on traditional risk factors were on average 8 to 9 times more likely to die of heart disease during the roughly 14-year follow-up period if they had abnormal heart rate turbulence values. Traditional risk factors include age, gender, high blood cholesterol, high blood pressure, obesity, diabetes, and smoking. Lowrisk individuals with elevated CRP in their blood were about 2.5 times more likely to die than those with normal or low CRP.

“These findings suggest that apparently healthy people might be at increased risk of death from cardiovascular disease, and heart rate turbulence may help us identify them,” said Susan B. Shurin, MD, acting director of the NHLBI. “It will be important to see if we can replicate this finding in other populations.”

By analysing the heart’s electrical signals, physicians can measure the magnitude of the initial heart rate jump (turbulence onset) and the speed at which heart rate returns to normal (turbulence slope), and then determine if the heart rate turbulence response is normal or abnormal.

Researchers don’t yet know if abnormal heart rate turbulence can be treated or prevented. However, interest might grow within the medical community in measuring heart rate turbulence in clinical practice, said study author Phyllis K. Stein, PhD, a research associate professor of medicine and director of the Heart Rate Variability Laboratory at Washington University School of Medicine in St Louis. Currently, this type of measurement is not widely available.

- doi: 10.1111/j.1540-8167.2010.01967.x

Researchers find molecular switch for insulin secretion

Researchers at Johns Hopkins believe they have uncovered the molecular switch for the secretion of insulin, providing for the first time an explanation of this process, which may lead to better treatments for type 2 diabetes.

“Our research cracks open a decadeslong mystery,” said Mehboob Hussain, MD, associate professor of pediatrics, medicine and biological chemistry.

“Before our discovery, the mechanism behind how exactly the insulin-producing beta cells in the islet of Langerhans of the pancreas fail in type 2 diabetes was incompletely understood, making it difficult to design new and better therapies.”

In a study designed to figure out more precisely how the pancreas releases insulin, Hussain’s group looked at how other cells in the body release chemicals. One particular protein, Snapin, found in nerve cells, caught their eye because it‘s used by nerve cells to release chemicals necessary for cell communication. Snapin also is found in the insulin-secreting pancreatic beta cells.

To test the role of Snapin, researchers engineered a change to the Snapin gene in mice to keep Snapin permanently “on” in the pancreas. Researchers removed the pancreas cells and grew them in a dish for a day, then added glucose to the cells and took samples to measure how much insulin was released.

When the scientists compared that measurement to what was released by pancreas cells in normal mice, they found that normal mice released about 2.8 billionths of a gram of insulin per cell, whereas the cells from “Snapin-on” mice released 7.3 billionths of a gram of insulin per cell – about three times the normal amount.

“We were surprised to find that the Snapin-on mice didn’t have more or bigger pancreas cells, they just made more insulin naturally,” says Hussain. “This means all our insulin-secreting cells have this amazing reserve of insulin that we didn’t really know existed and a switch that controls it.”

To see if permanently turning off Snapin would reduce insulin release and further demonstrate that Snapin controls the process, the researchers first grew normal mouse pancreas cells in a dish, and treated them with a chemical that stopped them from making the Snapin protein. They again bathed the cells in glucose and measured how much insulin was released by the cells. Normal cells released 5.8 billionths of a gram of insulin, whereas cells with no Snapin only released 1.1 billionths of a gram of insulin – about 80% less.

“These results convinced us that Snapin is indeed the switch that releases insulin from the pancreas,” says Hussain.

Hussain then questioned whether Snapin could be used to fix the defects in cells from a diabetic animal.

Since the cells with Snapin on made too much insulin, researchers wanted to see if they could use this to restore these mice’s ability to secrete the initial burst of insulin. After growing pancreatic beta cells from type 2 diabetes mice in a dish and engineering them to make the Snapin-on protein, the researchers fed the cells glucose and found that they did indeed regain the ability to release that initial insulin burst.

“While keeping Snapin on in these mouse cells corrects the problem in this animal model of type 2 diabetes, we’re still a long way from knowing if the same mechanism will work in people, but this gives us an encouraging start,” says Hussain.

Ref: M.A. Hussain et al. “Snapin Mediates Incretin Action and Augments Glucose-Dependent Insulin Secretion”, Cell Metabolism, Volume 13, Issue 3, 308- 319, 2 March 2011

Link between migraines and patent foramen ovale

Roughly 15% of children suffer from migraines, and approximately one-third of these affected children have migraines with aura, a collection of symptoms that can include weakness, blind spots, and even hallucinations. Although the causes of migraines are unclear, a new study published in The Journal of Pediatrics suggests a connection between migraine headaches in children and a heart defect called patent foramen ovale, which affects 25% of people in the US.

Dr Rachel McCandless and colleagues from the Primary Children’s Medical Center and the University of Utah studied 109 children 6-18 years old who were diagnosed with migraines between 2008 and 2009.

The researchers took two-dimensional echocardiograms of each child’s heart, looking for a patent foramen ovale (PFO), a common defect in the wall between the two upper chambers of the heart. Although a PFO is not necessarily dangerous, it can allow unfiltered blood to bypass the lungs and circulate throughout the body. As Dr McCandless explains: “Some adult studies have suggested a link between having a PFO and migraine headaches.”

Of the studied children who had migraines with aura, 50% also had a PFO; this is nearly double the PFO rate of the general population. However, only 25% of children who had migraines without aura had a PFO. Dr McCandless and colleagues hypothesize that if a causal relationship can be established, closure of a PFO with a catheter device may help in the treatment of certain kinds of migraines, specifically migraines with aura.

It is her hope that “our study will help guide future research about this difficult problem”.

- doi: 10.1016/j.jpeds.2011.01.062

iPhone app helps doctors save lives

Doctors who used a free iPhone application provided by the UK Resuscitation Council performed significantly better in a simulated medical emergency than those who did not, according to a UK study. More than 60,000 free copies of the iResus application have been downloaded. “A healthcare professional recently told us that they had used it when they were involved in an out-of-hospital paediatric emergency" says Dr Daniel Low, the consultant anaesthetist who developed the application. "Being able to refer to paediatric drug doses they were unfamiliar with helped them to save a child’s life.” The study provides further support for the current evidence that CPR prompt devices improve skills and can lead to a better outcome when a patient suffers a cardiac arrest.

doi: 10.1111/j.1365-2044.2011. 06649.x iRhesus

Weight gain and obesity linked with endometrial cancer risk

Women who put on substantial weight in early adulthood were diagnosed with endometrial cancer at much younger ages than their peers who gained weight later in life, new research by the Yale School of Public Health has found. The findings are published in the International Journal of Cancer.

In addition, long-term obesity significantly increased the risk of this cancer, which develops in the lining of the uterus and is the most commonly diagnosed gynaecological cancer in the United States. Some 42,000 American women are diagnosed with endometrial cancer annually, and nearly 8,000 die from the disease. The number of women developing the disease has risen steadily in recent years.

In general, the risk for endometrial cancer doubles for overweight women compared to women with healthier weights. The risk doubles again for obese women.

Researchers gathered data from 668 endometrial cancer patients and another 665 women of comparable ages without the disease. The heights and weights of the participants were tracked during each decade of adulthood.

Data show that endometrial cancer patients who had a substantial weight increase as young adults tended to be diagnosed at much younger ages. Women in their twenties who experience a weight gain of 35% are likely to have endometrial cancer diagnosed 10 years earlier than women who experienced less than 5% weight gain during the same period.

A significant trend was also observed between the length of time that a woman was overweight and her risk of endometrial cancer. Women who were consistently overweight between the ages of 20 and 50 had a nearly five-fold increased risk of endometrial cancer. “These data indicate the significant impact of lifestyle in early adult life on health later on,” said Herbert Yu, MD, PhD, the study’s lead researcher, a professor at the School of Public Health and member of Yale Cancer Center.

After menopause, adipose tissue (which stores fat) produces oestrogen but the ovaries no longer make progesterone. The “unopposed” oestrogen is believed to play a crucial role in the development of endometrial cancer. Additionally, the fat tissue may have other biological effects on the uterus as it produces growth factors and other molecules which can stimulate cell proliferation and pro-inflammatory reactions that are believed to facilitate the process of tumour development.

- doi: 10.1002/ijc.26046

Hands-free water faucets found to hinder infection control

A study of newly installed, hands-free faucets at The Johns Hopkins Hospital, all equipped with the latest electronic-eye sensors to automatically detect hands and dispense preset amounts of water, shows they were more likely to be contaminated with one of the most common and hazardous bacteria in hospitals compared to old-style fixtures with separate handles for hot and cold water.

“Newer is not necessarily better when it comes to infection control in hospitals, especially when it comes to warding off potential hazards from water-borne bacteria, such as Legionella species,” says senior study investigator and infectious disease specialist Lisa Maragakis, MD, MPH. “New devices, even faucets, however wellintentioned in their make-up and purpose, have the potential for unintended consequences, which is why constant surveillance is needed,” says Maragakis, director of hospital epidemiology and infection control at Hopkins Hospital and an assistant professor at the Johns Hopkins University School of Medicine.

Although the high-tech faucets cut daily water consumption by well over half, Johns Hopkins researchers identified Legionella growing in 50% of cultured water samples from 20 electronic-eye faucets in or near patient rooms on three different inpatient units, but in only 15% of water cultures from 20 traditional, manual faucets in the same patient care areas. Weekly water culture results also showed half the amount of bacterial growth of any kind in the manual faucets than in the electronic models.

While the precise reasons for the higher bacterial growth in the electronic faucets still need clarification, the researchers say it appears that standard hospital water disinfection methods, which complement treatments by public utilities, did not work well on the complex valve components of the newer faucets. They suspect that the valves simply offer additional surfaces for bacteria to become trapped and grow.

Researchers say their next steps are to work with manufacturers of electronic and manual faucets to help remedy their flaws and to design components that can be cleaned more easily and save water.

- Johns Hopkins Hospital Epidemiology and Infection Control

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