Obese patients at greater risk for surgical site infections

Obese patients undergoing colon surgery are 60% more likely to develop dangerous and costly surgical-site infections than their normal-weight counterparts, new Johns Hopkins research suggests. These infections, according to findings published in the journal Archives of Surgery, cost an average of US$17,000 more per patient, extend hospital stays and leave patients at a three times greater risk of hospital readmission.

“Obesity is a leading risk factor for surgical-site infections, and those infections truly tax the health care system,” says Elizabeth C. Wick, M.D., an assistant professor of surgery at the Johns Hopkins University School of Medicine and the lead author of the study. “The burdens of caring for obese patients need to be better recognised.”

Colon surgery – performed to treat colon cancer, diverticulitis and inflammatory bowel disease – costs roughly $300 more per obese patient, whether an infection occurred or not. Obese patients also had slightly longer hospital stays, regardless of infection.

The average cost of caring for a patient with a surgical-site infection was $32,182 compared to $15,131 for each patient who didn’t get infected. Those with infections stayed in the hospital for an average of 9.5 days compared to 8.1 days for those who did not contract one. The probability of hospital readmission in infected patients was 27.8% versus 6.8% in non-infected patients. When they had to be readmitted, those who had surgical-site infections stayed an average of two days longer than those without.

Not only are these findings relevant to physicians who need to pay special heed to infections in heavier patients but, the authors argue, to policymakers who plan to mandate public reporting of hospitals’ surgical-site infection rates. None of these plans take into account the higher infection rates found in obese surgical patients, Wick says.

Wick and her colleagues worry that punishing hospitals for surgical-site infections in obese patients could lead to discrimination, with surgeons shying away from operating on the heaviest patients for fear of financial loss and public shaming. If a hospital treated fewer obese patients, she notes, it would likely have fewer reportable infections. doi:10.1001/archsurg.2011.117

New compounds suppress progression of multiple sclerosis

Scientists from the Florida campus of The Scripps Research Institute have developed the first of a new class of highly selective compounds that effectively suppresses the severity of multiple sclerosis in animal models. The new compound could provide new and potentially more effective therapeutic approaches to multiple sclerosis and other autoimmune diseases that affect patients worldwide. Current treatments for autoimmunity suppress the patient’s entire immune system, leaving patients vulnerable to a range of adverse side effects. Because the new compound, known as SR1001, only blocks the actions of a specific cell type playing a significant role in autoimmunity, it appears to avoid many of the widespread side effects of current therapies.

“This is a novel drug that works effectively in animal models with few side effects,” said Tom Burris, Ph.D., a professor in the Department of Molecular Therapeutics at Scripps Florida who led the study, “We have been involved in several discussions with both pharmaceutical and biotechnology firms who are very interested in developing it further.” For the past several years, Burris and his colleagues have been investigating small-molecule compounds that affect particular diseaserelated receptors (structures that bind other molecules, triggering some effect on the cell). In particular, the scientists have been interested in a pair of “orphan nuclear receptors” (receptors with no known natural binding partner) called ROR and ROR involved in both autoimmune and metabolic diseases.

These particular receptors play a critical role in the development of TH17 cells, a form of T helper cells that make up part of the immune system. A relatively new discovery, TH17 cells have been implicated in the pathology of numerous autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and lupus. TH17 cells produce Interleukin-17, a natural molecule that can induce inflammation, a characteristic of autoimmunity. “If you eliminate TH17 cell signals, you basically eliminate the disease in animal models,” Burris said. “Our compound is the first smallmolecule orally active drug that targets this specific cell type and shuts it down. Once SR1001 is optimised, chances are it will be far more potent and effective.” doi: 10.1038/nature10075

Autism blurs distinctions between brain regions

Autism blurs the molecular differences that normally distinguish different brain regions, a new study suggests. Among more than 500 genes that are normally expressed at significantly different levels in the front versus the lower middle part of the brain's outer mantle, or cortex, only eight showed such differences in brains of people with autism, say researchers.

The study was published online 26 May 2011 in the journal Nature. The research was based on post-mortem comparisons of brains of people with the disorder and healthy controls.

In foetal development, different mixes of genes turn on in different parts of the brain to create distinct tissues that perform specialised functions. The new study suggests that the pattern regulating this gene expression goes awry in the cortex in autism, impairing key brain functions.

In an earlier study, the researchers showed that genes that turn on and off together at the same time hold clues to the brain’s molecular instructions. These modules of co-expressed genes can reveal genetic co-conspirators in human illness, through what researchers call “guilt by association.” A gene is suspect if its expression waxes and wanes in sync with others in an illness-linked module. Using this strategy, the researchers first looked for gene expression abnormalities in brain areas implicated in autism – genes expressed at levels different than in brains of healthy people. They found 444 such differently expressed genes in the cortexes of post-mortem brains of people with autism.

Most of the same genes turned out to be abnormally expressed in the frontal cortex as in the temporal cortex of autistic brains. Of these genes involved in synapses, the connections between neurons tended to be under-expressed when compared with healthy brains. Genes involved in immune and inflammatory responses tended to be over-expressed. Significantly, the same pattern held in a separate sample of autistic and control brains examined as part of the study. Yet normal differences in gene expression levels between the frontal and temporal cortex were missing in the modules of autistic brains. This suggests that the normal molecular distinctions - the tissue differences - between these regions are nearly erased in autism, likely affecting how the brain works. Strikingly, among 174 genes expressed at different levels between the two regions in two healthy control brains, none were expressed at different levels in brains of people with autism.

An analysis of gene networks revealed two key modules of co-expressed genes highly correlated with autism. One module was made up of genes in a brain pathway involved in neuron and synapse development, which were under-expressed in autism. Many of these genes were also implicated in autism in previous, genomewide studies. So, several different lines of evidence now converge, pointing to genes in this M12 module as genetic causes of autism. A second module of co-expressed genes, involved in development of other types of brain cells, was over-expressed in autism. These were determined not to be genetic causes of the illness, but likely gene expression changes related to secondary inflammatory, immune, or possible environmental factors involved in autism.

This newfound ability to see genes in the context of their positions in these modules, or pathways, provides hints about how they might work to produce illness. For example, from its prominent position in the M12 module, the researchers traced a potential role in creating defective synapses to a gene previously implicated in autism. Follow-up studies should explore whether the observed abnormalities in the patterning of gene expression might also extend to other parts of the brain in autism and could give a good pathway-based framework for understanding causes of other brain disorders stemming from similar molecular roots, such as schizophrenia and ADHD.

- Reference: Voineagu I, et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 25 May 2011. PMID:21614001

Researchers discover 25-year-old secret behind immune system’s success

After eight years of work, researchers have unearthed what has been a well-kept secret of our immune system’s success. The findings published online 9 June in Immunity, offer an explanation for how specialised immune cells are able to kill infected or cancerous cells without killing themselves in the process.

The focus of the study is a molecule known as perforin, whose job it is to open up a pore in cells targeted for destruction. With that pore in place, proteases known as granzymes can enter target cells and destroy them.

Perforin is one of the most critical ingredients for a functional immune system. Without it, mice succumb to viral illness and lymphoma. Humans born without a working perforin gene develop an aggressive immunoregulatory disorder in the first few months of life and usually die unless treated with cytoxic drugs or a bone marrow transplant.

But perforin itself is an incredibly destructive molecule. “Perforin forms a massive pore,” said Ilia Voskoboinik of the Peter MacCallum Cancer Centre in Australia. “It allows almost any protein to diffuse into a target cell. A few hundred molecules of perforin is sufficient to obliterate any cell.”

When the immune cells known as cytotoxic lymphocytes (including cytotoxic T lymphocytes and natural killer cells) are activated, “they produce a massive amount of perforin, yet the cells are fine,” Voskoboinik said. The question was: how do our immune cells manage such toxic cargo without endangering themselves?

Before perforin is released, the cells that produce it have to transport it from one part of the cell to another. That transport chain starts in a component of the cell known as the endoplasmic reticulum (ER). From there, it moves to the Golgi and into secretory granules where it is packaged together with granzymes. It is those secretory granules that ultimately fuse with the plasma membrane of the cytotoxic cell and allow its release into the junctions between the immune cell and the cell it aims to kill.

Scientists used to think perforin had an inhibitory domain within its structure that was only removed once they were safely stored in the secretory granules. (The acidic environment within secretory granules keeps perforin inactive until its release.) But Voskoboinik’s team purified perforin and found that the protein was always active regardless of whether they had removed the supposed inhibitory domain or not.

“It seeded doubt about how perforin is inhibited,” he says. “It was a puzzle. Perforin was fully functional but for some reason it couldn’t kill the cell [in which it was synthesised].”

The real danger zone for the cell when it comes to perforin is the ER, Voskoboinik explained. Conditions there should be ideal for perforin to work, but something keeps it from doing so. The new study links that protection to a single amino acid at one end of the perforin protein. When that amino acid is substituted with another, perforin doesn’t make it to the Golgi compartment, it builds up in the ER, and the cell dies.

“Perforin goes from zero to extremely high levels within 24 hours and it has everything it needs to be functional,” Voskoboinik said. “The cell relies on a really efficient transport system to move perforin away from the danger zone and as a result the cell is absolutely protected.”

The findings “close a chapter” in our understanding of the immune system that has existed in the field since perforin was discovered almost 25 years ago, Voskoboinik says. “It was one of those things that was out there on Olympus untouched. Everyone would just stare at it. That’s what got us interested.”

Memories change structure of brain

European researchers say they’ve recorded changes in the brain as it sorts what it has learned in a “clearing house” of memories. By analysing the brains of mice at various stages of learning, Italian, Swiss and German scientists observed the brain modifying its structure and organisation, making new connections while cancelling some others out, Italian news agency ANSA reported 2 May 2011.

“When we have to memorise something, in a structure called the hippocampus or the cerebellum,” Piergiorgio Strata, head of Italys National Neuroscience Institute, said, “the things to be remembered are selected. “Some of them are sent to permanent storage areas located in various parts of the brain’s cortex, while others are organised differently, with inhibitory synapses coming into play.”

Since some memories, such as fears, can leave a very intense permanent trace, the research could pave the way for discovering the molecular foundations of phobias and anxieties, the researchers said. The research, published in the journal Nature, shows that “short-term memory can become long-term via a process called consolidation, which is completed over several days,” Strata said. New treatment dissolves blood clots in brain tissue

A new treatment that treats a subset of stroke patients by combining minimally invasive surgery, an imaging technique likened to “GPS for the brain,” and the clot-busting drug t-PA appears to be safe and effective, according to a multicentre clinical trial led by Johns Hopkins researchers.

The novel treatment, detailed for the first time at last month’s European Stroke Conference in Hamburg, Germany, was developed for patients with intracerebral haemorrhage (ICH), a bleed in the brain that causes a clot to form within brain tissue. This clot builds up pressure and leaches inflammatory chemicals that can cause irreversible brain damage, often leading to death or extreme disability. The usual treatments for ICH – either general supportive care such as blood pressure control and ventilation, which is considered the current standard of care, or invasive surgeries that involve taking off portions of the skull to remove the clot – have similar mortality rates, ranging from 30% to 80% depending on the size of the clot.

Seeking to improve these mortality rates and surviving ICH patients’ quality of life, Daniel Hanley, M.D., professor of neurology at the Johns Hopkins University School of Medicine, and his colleagues developed and tested the new treatment on 60 patients at 12 hospitals in the United States, Canada, the United Kingdom and Germany. They compared their results to those of 11 patients who received only supportive care.

The researchers found that clot size in patients treated with t-PA shrunk by more than half, compared to only 1% in patients who received only supportive care. Comparison of daily CT scans showed that patients in the treatment group whose catheters were most accurately placed through the longest part of the clot had the most effective clot size reduction.

Those in the treatment group and the supportive care group had about a 10% mortality rate at 30 days after treatment, lower than the typically high mortality rates expected for this condition. After following the patients out for six months, the researchers found that the treated patients scored significantly higher on a test that measures the ability to function in daily life compared to those who received just supportive care.

Overall, Hanley says, the new treatment appears to be a viable and promising alternative to the current standard treatments of supportive care or invasive surgery. “We’re confirming that patients do recover better if we remove as much of the clot as we can, but gentle removal appears to be key,” he says. “Reducing the clot’s size with a minimally invasive method seems to be pivotal for optimising patient recovery.”

Concerns raised over using old blood for transfusions

New research provides evidence for significant differences between new and old red blood cells used for transfusions and could provide a cheap, rapid and effective way to monitor the quality of blood supplies. Even with preservatives, blood stored in banks continues to age, resulting in biomaterials leaking from the red blood cells and subsequent changes to cell properties and function. There have been concerns raised worldwide about using older stored blood because of questions about various changes believed to affect the quality of the red blood cells. Currently, blood stored in a special medium can be used for clinical transfusion for up to 42 days, but monitoring of the blood varies.

Dr Jay Mehrishi, PhD, FRCPath (a Fellow of the Royal College of Pathologists), formerly of the Department of Radiotherapeutics and Medicine (now called the Department of Haematology) at the University of Cambridge and one of the lead authors of the study, said: “Recent trials on cardiac surgery patients involving over 40,000 patients showed that transfused blood which was older than 14 days produced serious side effects.

“The side effects of transfusing old blood are thought to result in acute lung injury and possible adverse effects of the immune system. In severe trauma patients, transfusion of blood stored for more than 28 days doubled the incidence of deep vein thrombosis and increased death secondary to multiple organ failure. Our research will hopefully highlight the significant differences between old and new blood used in transfusions as well as the possibility of using our technique to quickly and cheaply monitor blood supply quality.”

The electrical properties approach has previously been used to distinguish between foetal and adult haemoglobin as well as the mutated form of haemoglobin found in sickle cells from normal haemoglobin. Now, using the unique electrical properties of red blood cells, Dr Mehrishi, working with Professor Yao-Xiong Huang from the Ji Nan University in China, used fluorescence from the positively charged quantum dots, which had been bound to electrical charges on the negatively charged cells to discriminate between old cells (which had diminished in quality) and young cells.

On young red blood cells the fluorescence was intense bright, indicating that the surface architecture was intact. Whereas on the older red blood cells, the fluorescence was almost zero and the cells shown significantly darker, indicating that there had been a substantial loss of the electrical charges and the cell membrane integrity had been compromised. It is recognised that such damaged cells are not useful for transfusions because the body eliminates them from circulation quite quickly.

In addition to its use as a monitoring technique for the quality of blood stored in blood banks, Dr Mehrishi believes that it could also be used to ensure a high quality of ‘cleaned up’ blood (older blood which has had the leaked biomaterials removed), which is of immense practical clinical importance worldwide. “Our novel approach is also likely to be of practical value in clinics before, during and after therapy, for such problems as circulatory disorders, abnormal red cells, macrophages – e.g.in Gaucher disease, hypoxia, for high-altitude mountaineers and residents at high altitudes, etc.”

The findings have been published in the Journal of Cellular and Molecular Medicine.

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