The leading cause of death in the world remains cardiovascular diseases, which are responsible for more than one third of overall mortality, according to the World Health Organization. Obesity and diet are obvious culprits behind heart disease but, over the past decade, research has also pointed to genetic factors, specifically mutations in cell adhesion components—the forces that bind cells together.

In a new study, scientists from the Florida campus of The Scripps Research Institute offer new molecular insights into how the interaction between specific genetic mutations and a cytoskeletal protein critical for the proper development and maintenance of heart tissue can lead to conditions such as dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM)—and ultimately heart failure.

The new study, which was led by Associate Professor T. Izard of the Florida campus of TSRI. The new insights could aid in the development of drug therapies to strengthen the hearts of patients suffering from age-related heart failure.

The study focuses on the protein vinculin and a variant form known as metavinculin, which is found only in muscle tissue. Vinculin has been shown to reinforce the myocardial cell cytoskeleton, improving heart muscle contractility and prolonging life, while metavinculin plays an essential role in the development and function of the heart.

Both vinculin and metavinculin regulate cell adhesion and migration by linking the cell’s cytoskeleton to adhesion receptor complexes via a process known as dimerization—the joining of two similar subunits. Control of the dimerization process is crucial for normal protein function in cell adhesion sites.

But mutations in the variant metavinculin, either inherited or spontaneous, corrupt this process, altering dimerization and, the study suggests, producing a decreased ability to stabilize critical cell adhesions, weakening the heart muscle over time.

The researchers found that these mutations—specifically, a mutation known as R975W in metavinculin—dictate the type of interaction during dimerization and can actually block the process. That, in turn, results in heart muscles that are far more susceptible to stress-induced heart disease.

The Scripps Research Institute www.scripps.edu/news/press/2016/20160811izard.html

An international research team has linked rare variations in a cell membrane protein to the wide variation in symptom severity that is a hallmark of porphyria, a rare disorder that often affects the skin, liver and nervous system. St. Jude Children’s Research Hospital helped to lead the research.

Porphyrias are a family of diseases usually caused by inherited mutations in one of the eight enzymes involved in assembling heme. Heme is a molecule that plays a critical role in oxygen transport, drug metabolism and other vital physiological processes. 

In this study, researchers discovered rare variations in the ABCB6 gene, also called Lan. The variations were associated with the toxic build-up in cells of chemicals produced during heme assembly. Investigators reported that the variants were more common in patients with severe porphyria than in those with less severe symptoms.

“One of the mysteries of this disease has been why some individuals with the same genetic defect have mild symptoms while others have severe symptoms and require hospitalization in the intensive care unit,” said corresponding author John Schuetz, Ph.D., a member of the St. Jude Department of Pharmaceutical Sciences. “Using gene sequencing, biochemical analysis and a new mouse model of the disease, we have identified variations in ABCB6 as an unexpected genetic modifier of porphyria severity.”

The discovery followed DNA sequencing of the protein-coding regions, or exomes, of seven porphyria patients with a history of life-threatening symptoms and hospitalization in the intensive care unit. They were among the 36 porphyria patients treated at the Royal Prince Alfred Hospital in Sydney, Australia, included in the study.

Researchers found that five of the seven patients carried rare versions of ABCB6 and made little or no functional ABCB6 protein. Sixty-two percent of patients with the rare ABCB6 variants were admitted to the intensive care unit compared to about 7 percent of other patients.

ABCB6 is carried on the surface of red blood cells, where 85 percent of heme is produced. The protein is one of several proteins that export porphyrins and related molecules from liver, blood and other cells.

Jann Ingmire
St. Jude Children’s Research Hospital www.stjude.org/media-resources/news-releases/2016-medicine-science-news/rare-genetic-variations-may-solve-mystery-of-porphyria-severity-in-some-patients.html

The International Congress on Quality in Laboratory Medicine will be held at Messukeskus, Expo and Convention Centre Helsinki on 9th-10th of February 2017. The annual congress is one of the largest events in Scandinavia focused on quality and laboratory medicine.

The congress inspires medical doctors, pathologists, clinical chemists, biomedical laboratory scientists, medical laboratory experts, managers, quality managers and point-of-care supervisors from the healthcare sector.

The 2017 Congress themes are Impact of Total Quality Management (TQM) and Evidence-Based Laboratory Medicine (EBLM).

Total Quality Management (TQM) is an already more than 60-year old concept that has steadily become more popular in healthcare settings. The idea is to develop a culture which aims at providing patients and customers with products and services that satisfy their needs. In Total Quality Management both management and employees are involved in the continuous improvement of services. It is a combination of quality and management tools to reduce wasteful processes and to avoid errors. In healthcare TQM outcomes are measured by patient health and customer satisfaction.
For healthcare organizations TQM means also a continuous learning process and its base is quantitative, thus being closely related to evidence-based medicine.
Labquality Days 2017 will bring distinguished international speakers together who will highlight the importance of management’s involvement in continuous process improvement. The speakers will also show some concrete examples and tools of TQM in smaller healthcare organizations and in large enterprises.

Evidence-Based Laboratory Medicine (EBLM) is the second theme of the 2017 Congress.
How important are laboratory results in clinical decision making? Are they as valuable in acute myocardial infarction as for a patient suffering from a common cold? Where is the evidence – and do we have enough data to support better patient outcomes?
Choosing the right laboratory test at the right time has become increasingly important particularly in improving and speeding up the diagnostic process and reducing diagnostic errors and costs. The speakers will discuss whether we have enough up-to-date evidence to evaluate the importance of laboratory results, though more controlled well-designed studies are needed.

The International Congress on Quality in Laboratory Medicine will gather leading international speakers and opinion leaders together. The programme consists of scientific lectures and panel discussions. During the congress, participants have the opportunity to meet colleagues, share ideas and experience the extensive clinical laboratory exhibition.

www.labqualitydays.com

Nova Biomedical recently announced the opening of a new sales, service, manufacturing, and distribution subsidiary in Brazil. The new facility demonstrates Nova’s commitment to the Brazilian market and to supporting the strong growth of in vitro diagnostic testing in Brazil and Mercosur countries. Located in the town of Nova Lima, a suburb of the city of Belo Horizonte in the state of Minas Gerais, Nova’s new subsidiary is designed to fully support current business and to allow for anticipated future growth. The new subsidiary provides full sales and service support, inventory warehousing and distribution, and manufacturing for Nova customers in Brazil. With the new subsidiary, Nova brings the most advanced technology whole blood analysers for hospital and point-of-care (POC) use to Brazil. The Stat Profile Prime line of hospital analysers includes the Critical Care System (CCS), Electrolyte System (ES), and Prime Plus, which all feature Prime’s innovative, no-maintenance cartridge and reagent technology that saves time and space, and reduces costs. Prime CCS offers a comprehensive testing menu of pH, PCO2, PO2, Hct, Na, K, Cl, iCa, Glu, and Lac. Prime ES provides comprehensive electrolyte testing with Na, K, Cl, iCa, and iMg. Results are ready for both devices in only 60 seconds from 100 microliters of whole blood. Prime Plus combines blood gas, electrolyte, and metabolite testing with co-oximetry, for an extensive, 22-test menu that’s ready in only 60 seconds. The Stat Profile pHOx Ultra analyser provides up to 20 critical care tests from 210 microliters in only two minutes, with other partial test panels available in less than one minute. The StatStrip and StatSensor line of handheld, POC meter and test strip analysers provide rapid glucose/ketone, lactate, and creatinine results at the bedside to support clinical decision making. “We, at Nova Biomedical, are excited to welcome our new Brazilian subsidiary to our international team and for the opportunity to continue to bring Nova’s in vitro diagnostic testing technology to this important global market,” said Ken Lumm, Senior Director, International Sales at Nova.

http://www.novabio.us/

Scientists at Baylor College of Medicine, the National Institutes of Health and Virginia Tech Carilion Research Institute have discovered a new mechanism in the mouse brain that regulates obesity. The study shows that this new mechanism can potentially be targeted to treat obesity.

“It’s well known that the brain is involved in the development of obesity, but how a high-fat diet changes the brain so it triggers the accumulation of body fat is still unclear,” said senior author Dr. Makoto Fukuda, assistant professor of paediatrics at Baylor and the USDA/ARS Children’s Nutrition Research Center at Baylor and Texas Children’s Hospital.

Fukuda and colleagues studied the mouse Rap1 gene, which is expressed in a variety of tissues, including the brain where it is involved in functions such as memory and learning. Little was known, however, of the role brain Rap1 plays in energy balance.

To explore the role Rap1 plays in a mouse model, the scientists selectively deleted the Rap1 gene in a group of neurons in the hypothalamus, a region of the brain that is involved in regulating whole-body metabolism.

The scientists had two groups of mice. In one group, the mice were genetically engineered to lack the Rap1 gene, while the control group had a functional Rap 1 gene. Then, the scientists fed the mice in both groups a high-fat diet in which 60 percent of the calories came from fat. As expected, the control mice with a working Rap1 gene gained weight, but, in comparison, the mice that lacked Rap 1 had markedly reduced body weight and less body fat. Interestingly, when both groups of mice were fed a normal diet, both showed similar weights and body fat. 

The scientists then looked closer at why the mice lacking the Rap1 gene had not gained weight despite eating a high-fat diet.
“We observed that the mice lacking Rap1 were not more physically active. However, they ate less and burned more body fat than mice with Rap1,” said Fukuda. “These observations were associated with the hypothalamus producing more of a hormone that reduces appetite, called POMC, and less of hormones that stimulate appetite, called NPY and AgRP.” These mice also had lower levels of blood glucose and insulin than controls.
The scientists also were interested in studying whether leptin changed in mice lacking Rap1. Leptin, the ‘satiety hormone’ produced by fatty tissue, helps regulate body weight by inhibiting appetite. Obese people, however, do not respond to leptin’s signals of satiety, and the blood levels of leptin are higher than those in non-obese people. Leptin resistance is a hallmark of human obesity.

Mice that lacked Rap1 and ate a high-fat diet, on the other hand, did not develop leptin resistance; they were able to respond to leptin, and this was reflected in the hormone’s lower blood levels.

Fukuda and colleagues also tested the effect of inhibiting Rap1 with drugs instead of deleting the gene on mice on a high-fat diet. The scientists inhibited RAP1 action with inhibitor ESI-05.

“When we administered ESI-05 to obese mice, we restored their sensitivity to leptin to a level similar to that in mice eating a normal diet. The mice ate less and lost weight,” said Fukuda.

The scientists have shown a new mechanism by which the brain can affect the development of obesity triggered by consuming a high-fat diet. Consuming a high-fat diet results in changes in the brain that increase Rap1 activity, which in turn leads to a decreased sensitivity to leptin, and this sets the body on a path to obesity.
“This new mechanism involving Rap1 in the brain may represent a potential therapeutic target for treating human obesity in the future,” said Fukuda.

Baylor College of Medicine www.bcm.edu/news/nutrition/rap1-potential-new-target-to-treat-obesity