A simple sugar solution may lead to a therapy for acute respiratory distress syndrome, which can stem from several different conditions, including the SARS virus, sepsis, and trauma. The new research suggests a sucrose solution injected into the patient's bloodstream may be able to prevent the dangerous accumulation of fluid in the lung that interferes with gas exchange.
Acute respiratory distress syndrome (ARDS) arises after the lung's capillaries leak and let fluid into the air-filled alveoli, thereby preventing oxygen uptake. Cells that line capillaries are arranged like layers of bricks with mortar in between, forming a fluid barrier. When a layer leaks, fluid passes through the junctions between the cells.
A team at St. Luke's led by Dr. Jahar Bhattacharya, professor of clinical physiological medicine, looked to see if the sucrose solution could somehow dam up the cell junctions to reduce the layer's leakiness. The researchers found that, in isolated rat lungs, a 15-minute infusion of the solution strengthened the barrier against fluids and that the effect lasted for two hours. They also found that the solution could prevent leaks in the barrier when the layer was subjected to cytokines and chemicals known to injure the layer and induce leakiness. The research was published in the Nov. 14 issue of the Journal of Clinical Investigation.
The secret in the sucrose solution lies not in its sugar, but in its high concentration. The hyperosmolar solution initially makes the barrier more leaky by sucking water from the barrier's cells and shrinking them. But after the initial shrinking, the barrier unexpectedly strengthens and cuts off the passage of fluid. Dr. Bhattacharya also found that barrier strengthening is accompanied by an increase in actin filaments inside the cells and cadherin molecules between them, a response he believes may stem from signals generated by the initial cell shrinkage.
A new study published this year finds that ARDS causes more deaths in the United States than AIDS or emphysema. Mechanical ventilation can help but the syndrome still kills about 40 percent of patients. "If hyperosmolarity works, the therapy could start when the person is first diagnosed with the syndrome or as a preventive modality if the patient may develop ARDS," Dr. Bhattacharya says. "We still don't know if it will work, but we're quietly hopeful."
Studies by Columbia University researchers are adding to the growing evidence that the conventional way to measure cancer risk from low-dose radiation exposure, such as radon gas in homes, needs adjustment. The issue is particularly relevant for residents in the Northeast radon belt which includes the New York metropolitan area where radon levels in some homes could be higher than the Environmental Protection Agency limit.
Radiation cancer risk estimates are based primarily on cancer rates of atomic bomb survivors in Japan, who were subjected to high doses of radiation. For decades, researchers have extrapolated the cancer risk estimates for low-dose radiation from data on high doses using a linear model.
But studies by researchers in Columbia's Center for Radiological Research indicate that the effects of radiation are more variable. The researchers have published a series of papers in the Proceedings of the National Academy of Sciences over the past few years indicating that cells hit directly by radiation spread it to neighboring cells in a process known as the bystander effect. They were able to measure the genetic effects in human-hamster hybrid cells using a state-of-the-art charged-particle microbeam irradiator to target individual cells at specific intracellular locations.
In the latest study, Dr. Tom K. Hei, professor of radiation oncology at P&S and environmental health sciences at the Mailman School of Public Health, and colleagues found cells exposed to a low dose of X-rays four hours before receiving a second and higher dose of radon had a significantly decreased bystander response effect. In essence, the low dose of X-rays protect against radon-induced bystander damage in an effect known as adaptive response. However, when the researchers hit the bystander cells with another dose of radiation, they found these cells were more sensitive to the radiation and had higher mutation rates.
"The findings should help in developing more accurate radiation risk assessment models because they highlight the importance of actual target size, adaptive response and bystander effect at low-dose radiation," says Dr. Hongning Zhou, associate research scientist and first author of the paper, which was published in the November issue of Radiation Research.
Recent success in the use of gene therapy to cure sickle cell disease in mice has kindled hope that a similar cure for humans may be just around the corner. But several problems still remain in engineering a virus that can safely and efficiently introduce a new gene into the bone marrow cells of a sickle cell patient.
CUMC researchers have solved some of these problems and say they're now close to developing a system for human trials. Their research was published in the November issue of Molecular Therapy.
The idea behind sickle cell gene therapy is to take stem cells from the patient's blood, use a virus to insert a normal beta globin gene into the cells' DNA, and then inject the cells back into the patient.
Gene therapy researchers have recently turned to the HIV virus as a gene delivery device, using an engineered version of the virus incapable of causing AIDS, to cure the sickle cell mice. The engineered HIV virus transfers the globin gene into the blood cells more efficiently than viruses tried previously.
A remaining problem, according to Dr. Arthur Bank, professor of medicine and genetics & development, is that a protein added to the HIV vector, VSV-G, kills the cells used to produce the vast quantities of virus needed for gene therapy. Therefore, to make enough virions, gene therapists would have to grow the virus in thousands of different short-lived cell cultures. For Dr. Bank, this causes a safety problem, because the virus produced by each separate culture could be contaminated and the entire viral culture would have to be certified as safe before the virus could be used in a patient.
Instead, Dr. Bank favors using an engineered HIV virus that doesn't kill the culture in which the cells grow so that only one large stable culture is needed. To do that, he needed to find an alternative to VSV-G. An envelope of VSV-G or alternative envelope is required to make the virus enter the blood's stem cells, which it normally wouldn't do.
The new research, conducted by senior staff associate Maureen Ward, shows that another protein, RD114, is just as effective as VSV-G at getting the engineered virus into human stem cells and doesn't kill the cells used to produce the virus. Because she tested RD114 in a different type of retrovirus, Dr. Bank says the next step is to test the protein in an HIV vector and then see if the vector can insert a globin gene into human cells. "We're two steps away from doing good stuff," Dr. Bank says.