Research Round Up

Ronny P. Bartsch, PhD

Phase Synchronization: A New Form of Cardio-Respiratory Coupling

An international research team from the USA, Germany and Canada led by Ronny P. Bartsch, PhD and Plamen Ch. Ivanov, PhD, DSc, both of the BWH Sleep Medicine Division, developed a method based on the concept of phase synchronization to identify and quantify a new form of coupling between the cardiac and the respiratory system.

Plamen Ch. Ivanov, PhD,  DSc

The researchers found that the traditionally studied form of cardio-respiratory coupling, called respiratory sinus arrhythmia, defined as modulation of the average heart rate within the breathing cycle, does not fully represent the complex nature of cardio-respiratory interaction, and that this interaction is also characterized by stable phase synchronization between heartbeats and respiratory cycles.

The team discovered that the degree of cardio-respiratory phase synchronization is influenced by neuroautonomic function and dramatically changes with transitions from one physiologic state to another. They observed a 400% change of cardio-respiratory phase synchronization across sleep stages, a factor of 10 higher than the corresponding change in respiratory sinus arrhythmia, and that key physiologic variables, related to regulatory mechanisms of the cardiac and respiratory systems, which influence respiratory sinus arrhythmia do not affect cardio-respiratory phase synchronization.

The researchers also are the first to demonstrate the physiologic relevance of phase synchronization as it relates to mechanisms of sleep regulation and healthy aging. Cardio-respiratory phase synchronization significantly decreased by nearly 50% with aging. The researchers note that the strength of synchronization gradually increased from REM sleep and wake, to light sleep and deep sleep, and that this sleep-stage stratification pattern is consistently present across subjects from all age groups between 20 and 95 years old, despite the general decrease of synchronization with aging.

Given that sleep regulation has a stronger impact on cardio-respiratory coupling compared to aging, such effects need to be taken into consideration when assessing cardiovascular risk.

The study was published in the June 26, 2012 issue of Proceedings of the National Academy of Sciences.

Richard S. Blumberg, MD

Natural Killer T Cells May Play Role in Controlling Hepatitis B

According to the United States Centers for Disease Control and Prevention, approximately 800,000 to 1.4 million people in the country have chronic hepatitis B virus (HBV) infection. Globally, the virus affects approximately 350 million people.  A research team led by Richard S. Blumberg, MD, chief of the BWH Division of Gastroenterology, Hepatology and Endoscopy, is working toward better understanding how to curb infection. In their latest study, the team discovered that natural killer T cells may play a critical role in HBV control.

The researchers found that HBV-expressing hepatocytes generated endoplasmic reticulum-associated self-antigenic lipids. These lipids were sensed by natural killer T cells, thereby activating these cells. Absence of natural killer T cells or defects in the transfer process of these self-lipids, resulted in diminished HBV-specific immune responses and delayed viral control occurred.

"Previously, HBV was considered to be a ‘stealth virus' which evades early components of the normal immune response," said Blumberg. "These studies demonstrate this is not the case and open up potential avenues for novel interventions directed at early viral control."

The study was published in the June 17, 2012 online issue of Nature Medicine.

Stephen J. Elledge, PhD

Missing Pieces: Scientists Propose Cancer Gene Model

A study led by Stephen J. Elledge, PhD, professor of Genetics, Department of Genetics, Harvard Medical School and BWH, results in a hypothesis that may help explain the driving force behind tumorigenesis (the formation of tumors) across many cancer types. The researchers studied genes located within hemizygous deletions in search for those with cancer-relevant properties. A hemizygous deletion is loss of DNA in only one of the two-paired chromosomes.

The researchers found that recurring deletions preferentially over-represented STOP genes and under-represented GO genes. STOP genes restrain cell proliferation and include many known tumor suppressors, while GO genes are enriched for essential genes. 

From this observation, they proposed the Cancer Gene Island model showing that gene islands encompassing high densities of STOP genes and low densities of GO genes are hemizygously deleted.

"We think these findings suggest that many genes behave in a haploinsufficient manner to restrain tumorigenesis and that deletion of clusters of these genes act to spur proliferation without the need for a classical second hit in that region," said Elledge. "This gives us a new way to view tumor evolution."

The study was published in the May 24, 2012 online issue of Science.

Blanca Himes, PhD

Breathe Easy: Researchers Identify New Bronchodilator Response Gene

A new study from researchers in the BWH Channing Division of Network Medicine has found that the SPATS2L gene may be a regulator of bronchodilator response (BDR), an important asthma phenotype. BDR is a measurement of airway blockage reversibility taken by assessing the effect of short-acting ß₂-agonists (a common type of asthma medication) on lung function.

The researchers performed a genome-wide association study of BDR in 1,644 people with asthma from six clinical trials and attempted to validate the findings in two cohort studies with 1,051 participants with asthma.

After observing that variants near the SPATS2L gene were associated with BDR, the researchers knocked down SPATS2L mRNA in human airway smooth muscle cells. They found that ß₂-adrenergic receptor levels increased, leading to the conclusion that SPATS2L may be a BDR regulator.

"Our results may lead to a better understanding of asthma and ß₂-agonist treatment response." said Blanca Himes, PhD, BWH Channing Division of Network Medicine, and study first author.

The study was published online in PLoS Genetics on July 5, 2012.

Jeffrey Linder, MD

To Dictate or Not to Dictate?

According to a new study, doctors who dictated their patient notes appeared to have worse quality of care than those who used structured documentation.

The researchers evaluated 18,569 visits by 7,000 patients with coronary artery disease and diabetes to participating physicians in a regional healthcare delivery network in eastern Massachusetts.

Of these 234 doctors in the study, 20 (9 percent) dictated their notes, 68 (29 percent) used structured documentation, and146 (62 percent) typed free-text notes.

The main outcome measures were 15 coronary artery disease and diabetes measures assessed 30 days after primary care visits.

Compared to the other two documentation styles, quality of care was significantly worse on three outcome measures for dictators. These measures were antiplatelet medication, tobacco use documentation and diabetic eye exam.

Quality of care was better on three measures for doctors who used structured documentation. These measures were blood pressure documentation, body mass index documentation and diabetic foot exam. Doctors who used free-text notes had better quality of care in providing influenza vaccinations.

There was no measure associated with higher quality of care for doctors who dictated their notes.

"Doctors who dictate may not be paying as close attention to information and alerts in the electronic health record that are important for patient health," said Jeffrey Linder, MD, associate professor of medicine at BWH and Harvard Medical School, and lead study author.

The study is published online in the Journal of the American Medical Informatics Association.

Jorge Plutzky, MD

"Browning" White Fat by Blocking Vitamin A Metabolism

Jorge Plutzky, MD, director of The Vascular Disease Prevention Program at BWH and his team have discovered a way to turn the more dangerous white fat, which stores energy, into more beneficial brown fat, which releases energy. The findings raise the prospects of novel approaches to treat obesity and its complications.

One of the functions of vitamin A metabolites, molecules known as retinoids, is to control fat cell development and function. A key step in retinoid metabolism occurs with help from an enzyme called retinaldehyde dehydrogenase 1, or Aldh1a1.

Plutzky and colleagues observed that in humans and mice, Aldh1a1 was abundant in white fat cells, especially in the more dangerous visceral fat. Indeed, in humans, levels of Aldh1a1 correlated with visceral obesity and body mass.

By manipulating Aldh1a1, a key player in converting vitamin A-or retinol-into retinoic acid, Plutzky and colleagues found that white fat cells took on characteristics of brown fat.

One of the defining characteristics of brown fat is its ability to release energy as heat. Mice with either deficiency or inhibition of Aldh1a1 become protected against exposure to cold. The researchers saw this classic indicator of brown fat and its ability to generate heat by oxidizing fat in their research.

The researchers, including first author and BWH post-doctoral fellow Florian Kiefer, MD, PhD, also found that knocking down expression of the Aldh1a1 gene by injecting antisense molecules into mice made fat by diet resulted in less visceral fat, less weight gain, lower glucose levels and protection against cold exposure as compared to control mice.

The study was published online on May 6, 2012 in Nature Medicine.