Identifying and treating metabolic deficiencies in patients with treatment-resistant depression can improve symptoms and in some cases even lead to remission, according to new research from the University of Pittsburgh School of Medicine.

“What’s really promising about these new findings is that they indicate that there may be physiological mechanisms underlying depression that we can use to improve the quality of life in patients with this disabling illness,” said David Lewis, M.D., Thomas Detre Professor and Chair of Pitt’s Department of Psychiatry.

Major depressive disorder, also referred to simply as depression, affects nearly 15 million American adults and is one of the most common mental disorders. Unfortunately, at least 15 percent of patients don’t find relief from conventional treatments such as antidepressant medications and psychotherapy, explained lead study investigator Lisa Pan, M.D., professor of psychiatry, and clinical and translational science, Pitt School of Medicine. Depression also is the cause of more than two-thirds of suicides that occur annually.

The groundwork for the current study was laid five years ago when Dr. Pan and David Brent, M.D., Endowed Chair in suicide studies at Pitt, treated a teen with a history of suicide attempts and long-standing depression. “Over a period of years, we tried every treatment available to help this patient, and yet he still found no relief from his depression symptoms,” she explained.

Searching for answers, Dr. Pan contacted Jerry Vockley, M.D., Ph.D., chair of genetics, Children’s Hospital of Pittsburgh of UPMC, and David Finegold, M.D., professor of human genetics at Pitt’s Graduate School of Public Health, and through a series of biochemical tests, the three discovered that the patient had a cerebrospinal fluid deficiency in biopterin, a protein involved in the synthesis of several brain signalling chemicals called neurotransmitters.

After receiving an analogue of biopterin to correct the deficiency, the patient’s depression symptoms largely disappeared and today he is a thriving college student.

The success prompted the researchers to examine other young adults with depression who were not responding to treatment, explained Dr. Pan.

In the published trial, the researchers looked for metabolic abnormalities in 33 adolescents and young adults with treatment-resistant depression and 16 controls. Although the specific metabolites affected differed among patients, the researchers found that 64 percent of the patients had a deficiency in neurotransmitter metabolism, compared with none of the controls.

In almost all of these patients, treating the underlying deficiency improved their depression symptoms, and some patients even experienced complete remission. In addition, the further along the patients progress in the treatment, the better they are getting, Dr. Pan added.

University of Pittsburgh School of Medicine www.upmc.com/media/NewsReleases/2016/Pages/l-pan.aspx

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