intellectual vanities… about close to everything

Smokers are often more prone to bacterial infections and inflammatory diseases than the rest of us, thanks to hundreds of toxic components in their cigarettes. Next to dry and irritated mucosal linings in mouth and respiratory system due to smoke and nicotine, now new research shows that nicotine affects neutrophils, the short-lived white blood cells that defend against infection, by reducing their ability to seek and destroy bacteria.

Neutrophils are generated by our bone marrow, which they leave as terminally differentiated cells. Although nicotine is known to affect neutrophils, there has been no study until now of the mechanisms at work when nicotine is present during neutrophil differentiation. David Scott from the Oral Health and Systemic Disease Research Group at the University of Louisville School of Dentistry, Kentucky, USA, along with a team of international colleagues decided to investigate how nicotine influenced the differentiation process.

The authors suggest the processes they observed as contributing to impaired neutrophil function partially explain chronic tobacco users’ increased susceptibility to bacterial infection and inflammatory diseases. A better understanding of this relationship could pave the way for specific therapeutic strategies to treat a number of important tobacco-associated inflammatory diseases and conditions.

The team modeled the neutrophil differentiation process beginning with promyelocytic HL-60 cells, which differentiated into neutrophils following dimethylsulfoxide (DMSO) treatment both with and without nicotine. The researchers found that nicotine increased the percentage of cells in late differentiation phases (metamyelocytes, banded neutrophils and segmented neutrophils) compared to DMSO alone, but did not affect other neutrophil differentiation markers that they examined.

However, the nicotine treated neutrophils were less able to seek and destroy bacteria than nicotine-free neutrophils. The nicotine suppressed the oxidative burst in HL-60 cells, a function that helps kill invading bacteria. Nicotine also increased MMP-9 release, a factor involved in tissue degradation.

BMC Cell Biol. 2008 Apr 15;9(1):19 [Epub ahead of print]

The influence of nicotine on granulocytic differentiation - inhibition of the oxidative burst and bacterial killing and increased matrix metalloproteinase-9 release.

Xu M, Scott JE, Liu KZ, Bishop HR, Renaud DE, Palmer RM, Soussi-Gounni A, Scott DA.

ABSTRACT: BACKGROUND: Neutrophils leave the bone marrow as terminally differentiated cells, yet little is known of the influence of nicotine or other tobacco smoke components on neutrophil differentiation. Therefore, promyelocytic HL-60 cells were differentiated into neutrophils using dimethylsulfoxide in the presence and absence of nicotine (3-(1-methyl-2-pyrrolidinyl) pyridine). Differentiation was evaluated over 5 days by monitoring terminal differentiation markers (CD11b expression and formazan deposition); cell viability, growth phase, kinetics, and apoptosis; assessing cellular morphology and ultrastructure; and conformational changes to major cellular components. Key neutrophil effector functions (oxidative burst, bacterial killing, matrix metalloproteinase release) were also examined. Results: Nicotine increased the percentage of cells in late differentiation phases (metamyelocytes, banded neutrophils and segmented neutrophils) compared to DMSO alone (p < 0.05), but did not affect any other marker of neutrophil differentiation examined. However, nicotine exposure during differentiation suppressed the oxidative burst in HL-60 cells (p < 0.001); inhibited bacterial killing (p < 0.01); and increased the LPS-induced release of MMP-9, but not MMP-2 (p < 0.05). These phenomena may be alpha-7-acetylcholine nicotinic receptor-dependent. Furthermore, smokers exhibited an increased MMP-9 burden compared to non-smokers in vivo (p < 0.05). Conclusions: These findings may partially explain the known increase in susceptibility to bacterial infection and neutrophil-associated destructive inflammatory diseases in individuals chronically exposed to nicotine.

Scientists in the Laboratoire Hépatite C of the Institut de Biologie de Lille in collaboration with INSERM Unit 602 and a laboratory at Stanford University have provided evidence of a protein, called EWI-2wint, that inhibits the hepatitis C virus at an early stage of its infective cycle. This research suggests possible new perspectives for the development of therapies to block the virus before it enters a cell.

The EWI-2wint protein is not present in hepatocytes (liver cells). When it comes into contact with the hepatocyte, the hepatitis C virus can thus bind to the CD81 protein, which will allow it to enter the cell and pursue its infective cycle. In other types of cells in the body, the EWI-2wint protein is present and interacts with CD81, thus preventing the hepatitis C virus from entering these cells. (Credit: Copyright CNRS 2008 Sophana Ung)

Hepatitis C is a major public health problem that affects some 130 million people throughout the world. In France , where there are about 5000 new cases each year, it is estimated that half a million people could be affected by this disease. The causal agent is the hepatitis C virus (HCV) which targets cells in the liver called hepatocytes. HCV infection is usually chronic (60% to 80% of cases) and in the long term can lead to the development of cirrhosis and liver cancer.

Unlike the hepatitis A and B viruses, there is no vaccine to combat this virus. Furthermore, the treatments employed are only of limited efficacy (the failure rate reaches around 40%), and they involve considerable side effects. It is therefore crucial to develop new antiviral compounds to control this infection.

HCV uses at least three receptors to enter and infect a hepatocyte. One of these receptors is the CD81 protein, which has the particular characteristic of associating with numerous other proteins. It was by studying these CD81 partner proteins that the researchers identified the EWI-2wint protein, which prevents the recognition of CD81 by the hepatitis C virus and inhibits it at a very early stage in its infective cycle. This protein is present in other types of cells, which could explain why they are not infected by HCV. Discovery of the role of EWI-2wint in hepatocytes has demonstrated the complexity of the mechanisms of entry of HCV into its target cells, and opens the way to new therapeutic approaches.

PLoS ONE. 2008 Apr 2;3(4):e1866.

The CD81 partner EWI-2wint inhibits hepatitis C virus entry.

Rocha-Perugini V, Montpellier C, Delgrange D, Wychowski C, Helle F, Pillez A, Drobecq H, Le Naour F, Charrin S, Levy S, Rubinstein E, Dubuisson J, Cocquerel L.

Institut de Biologie de Lille (UMR8161), CNRS, Universités de Lille I et Lille II, Institut Pasteur de Lille, Lille, France.

Two to three percent of the world’s population is chronically infected with hepatitis C virus (HCV) and thus at risk of developing liver cancer. Although precise mechanisms regulating HCV entry into hepatic cells are still unknown, several cell surface proteins have been identified as entry factors for this virus. Among these molecules, the tetraspanin CD81 is essential for HCV entry. Here, we have identified a partner of CD81, EWI-2wint, which is expressed in several cell lines but not in hepatocytes. Ectopic expression of EWI-2wint in a hepatoma cell line susceptible to HCV infection blocked viral entry by inhibiting the interaction between the HCV envelope glycoproteins and CD81. This finding suggests that, in addition to the presence of specific entry factors in the hepatocytes, the lack of a specific inhibitor can contribute to the hepatotropism of HCV. This is the first example of a pathogen gaining entry into host cells that lack a specific inhibitory factor.

Inherited variations in the amount of an innate anxiety-reducing molecule help explain why some people can withstand stress better than others, according to a new study led by researchers at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health (NIH).

“Stress response is an important variable in vulnerability to alcohol dependence and other addictions, as well as other psychiatric disorders,” noted NIAAA Director Ting-Kai Li, M.D. “This finding could help us understand individuals’ initial vulnerability to these disorders.”

Scientists led by David Goldman, M. D., chief of the NIAAA Laboratory of Neurogenetics, identified gene variants that affect the expression of a signaling molecule called neuropeptide Y (NPY). Found in brain and many other tissues, NPY regulates diverse functions, including appetite, weight, and emotional responses.

“NPY is induced by stress and its release reduces anxiety,” said Dr. Goldman. “Previous studies have shown that genetic factors play an important role in mood and anxiety disorders. In this study, we sought to determine if genetic variants of NPY might contribute to the maladaptive stress responses that often underlie these disorders.” A report of the findings appears online today in Nature.

Analyses of human tissue samples led by researchers at NIAAA identified several NPY gene variants. Collaborations with NIH-supported scientists at the University of Michigan, University of Pittsburgh, University of Helsinki, University of Miami, University of Maryland, the University of California at San Diego, and Yale University, showed that these variants result in a range of different effects including altered levels of NPY in brain and other tissues, and differences in emotion and emotion-induced responses of the brain.

The researchers evaluated the NPY gene variants’ effects on brain responses to stress and emotion. Using functional brain imaging, they found that individuals with the variant that yielded the lowest level of NPY reacted with heightened emotionality to images of threatening facial expressions. “Metabolic activity in brain regions involved in emotional processing increased when these individuals were presented with the threatening images,” explained Dr. Goldman.

In another brain imaging experiment, people with the low level NPY variant were found to have a diminished ability to tolerate moderate levels of sustained muscular pain. Previous studies had shown that NPY’s behavioral effects are mediated through interactions with opioid compounds produced by the body to help suppress pain, stress, and anxiety. “As shown by brain imaging of opioid function, these individuals released less opioid neurotransmitter in response to muscle discomfort than did individuals with higher levels of NPY,” said Dr. Goldman. “Their emotional response to pain was also higher, showing the close tie between emotionality and resilience to pain and other negative stimuli.”

In a preliminary finding, the low level NPY gene variant was found to be more common than other variants among a small sample of individuals with anxiety disorders. The researchers also found that low level NPY expression was linked to high levels of trait anxiety. “Trait anxiety is an indication of an individual’s level of emotionality or worry under ordinary circumstances,” explained Dr. Goldman.

The researchers conclude that these converging findings are consistent with NPY’s role as an anxiety-reducing peptide and help explain inter-individual variation in resiliency to stress. “This inherited functional variation could also open up new avenues of research for other human characteristics, such as appetite and metabolism, which are also modulated by NPY,” said Dr. Goldman.

Nature. 2008 Apr 2 [Epub ahead of print]

Genetic variation in human NPY expression affects stress response and emotion.

Zhou Z, Zhu G, Hariri AR, Enoch MA, Scott D, Sinha R, Virkkunen M, Mash DC, Lipsky RH, Hu XZ, Hodgkinson CA, Xu K, Buzas B, Yuan Q, Shen PH, Ferrell RE, Manuck SB, Brown SM, Hauger RL, Stohler CS, Zubieta JK, Goldman D.

[1] Laboratory of Neurogenetics, NIAAA, NIH, Bethesda, Maryland 20892, USA [2] These authors contributed equally to this work.

Understanding inter-individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y (NPY) is anxiolytic and its release is induced by stress. NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories. Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in post-mortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases.

Scientists in the Laboratoire de Neurobiologie des Processus Adaptatifs (CNRS/Université Pierre et Marie Curie) have shown that it is possible to repair an injured brain by creating a small number of new, specifically-targeted innervations, rather than a larger number of non-specific connections. Behavioral tests have demonstrated that such reinnervation can thus restore damaged cerebral functions.

Researchers studying deer mice have discovered evidence to support what mothers everywhere have long suspected: the immune system needs food to function properly. In a new study Lynn Martin and coauthors find that reduced food intake leads to a decline in immune function in their subjects. The findings could have profound implications for human health.

Immune System Overview

Why immune activity is variable in many wild animals is a question that has long puzzled researchers. “Animals live different lifestyles, so they may use different types of defenses against infection depending on the situation. Perhaps this is why immune defenses vary seasonally in most species; some may be too expensive to use all the time,” Martin said, referring to previous work on Peromyscus and other small mammals and birds.

While it is known that the immune system expends energy when it gears up to fight a virus or an infection–a fever, for example–the researchers found that restricting their subjects’ diet by 30% significantly decreased the amount of available B cells, which produce antibodies and maintain immune memory. Without these cells, the immune system must relearn how to fight a threat if it reappears.

Research on the relationship between food and the immune system could have profound implications for humans. Martin and fellow researchers cite previous studies that have found that infections are “more frequent and tend to be chronic in malnourished children.” Vaccines, in order to work effectively, must provoke B cells to produce sufficient antibodies for immune memory.

Previous studies have found that vaccines such as those for measles have a significantly lower rate of efficacy among the malnourished. “A 30% restriction in food intake doesn’t affect body mass and only minimally reduces activity in deer mice, but it eliminates the long-term immune protection provided by antibodies. One wonders whether similar moderate food restriction has comparable immune effects in humans,” Martin asked. Although other variables may be at work, the authors propose that for both wild animals and humans, food availability impinges on immunity and future research should determine what specific components of a diet (calories, protein, micronutrients) are responsible.

Physiological and Biochemical Zoology. Volume 81, Issue 3, Page 366–372, May 2008

Food Restriction Compromises Immune Memory in Deer Mice (Peromyscus maniculatus) by Reducing Spleen‐Derived Antibody‐Producing B Cell Numbers

Lynn B. Martin II, Kristen J. Navara, Michael T. Bailey, Chelsea R. Hutch, Nicole D. Powell, John F. Sheridan, and Randy J. Nelson

Abstract

Immune activity is variable in many wild animals, despite presumed strong selection against immune incompetence. Much variation may be due to changes in prevalence and abundance of pathogens (and/or their vectors) in time and space, but the costs of immune defenses themselves may also be important. Induction of immune activity often increases energy and protein expenditure, sometimes to the point of compromising fitness. Whether immune defenses are expensive to maintain once they are generated, however, is less well appreciated. If so, organisms would face persistent challenges of allocating resources between immunity and other expensive physiological processes, which would mandate trade-offs. Mild food restriction (70% ad lib. diet) reduces secondary antibody responses in deer mice (Peromyscus maniculatus), functionally representing a cost of immune memory. In this study, we asked whether compromised immune memory was mediated by a decrease in size of the B cell population responsible for producing antibodies (i.e., spleen-derived B lymphocytes producing immunoglobulin G [IgG]). Two weeks of food restriction reduced total splenocytes, total splenic B lymphocytes (B220+ cells), and splenic B lymphocytes producing IgG (B220+/IgG+ cells) but did not affect body mass or two circulating antibody subclasses (IgG1 and IgG2a) in deer mice. These results further indicate that maintenance of immune memory is expensive and may be subject to trade-offs with other physiological processes.

A team led by a Purdue University researcher has achieved images of a virus in detail two times greater than had previously been achieved.

Shown is an image of bacteriophage Epsilon15 studied by Wen Jiang, an assistant professor of biological sciences at Purdue. The bacteriophage is shown at a resolution of 4.5 angstrom - the highest resolution achieved for a living organism of this size. (Credit: Graphic/Wen Jiang lab)

Wen Jiang, an assistant professor of biological sciences at Purdue, has published for several years results of single-particle electron cryomicroscopy, and now led a research team that used this emerging technique to capture a three-dimensional image of a virus at a resolution of 4.5 angstroms. Approximately 1 million angstroms would equal the diameter of a human hair.

“This is one of the first projects to refine the technique to the point of near atomic-level resolution,” said Jiang, who also is a member of Purdue’s structural biology group. “This breaks a threshold and allows us to now see a whole new level of detail in the structure. This is the highest resolution ever achieved for a living organism of this size.”

Details of the structure of a virus provide valuable information for development of disease treatments, he said.

“If we understand the system - how the virus particles assemble and how they infect a host cell - it will greatly improve our ability to design a treatment,” Jiang said. “Structural biologists perform the basic science and provide information to help those working on the clinical aspects.”

Roger Hendrix, a professor of biological sciences at the University of Pittsburgh, said what is learned about viruses can be applied to many other biological systems.

“Understanding the proteins that create the structure of a virus gives us insight into the tiny biological machines found throughout our bodies,” he said. “Getting to 4.5 angstrom using this technique is a watershed of sorts because it is the first time we can actually trace the polypeptide chain - the backbone of proteins. Now we can see the tiny gears and levers that allow the proteins to move and interact as they carry out their intricate biological roles.”

The imaging technique, called cryo-EM, has the added benefit of maintaining the sample being studied in a state very similar to its natural environment. Other imaging techniques used regularly, such as X-ray crystallography, require the sample be manipulated.

“This method offers a new approach for modeling the structure of proteins in other macromolecular assemblies, such as DNA, at near-native states,” Jiang said. “The sample is purified in a solution that is very similar to the environment that would be found in a host cell. It is as if the virus is frozen in glass and it is alive and infectious while we examine it.”

In addition to Jiang, Matthew L. Baker, Joanita Jakana and Wah Chiu from Baylor College of Medicine, and Peter R. Weigele and Jonathan King from Massachusetts Institute of Technology worked on the project, which was funded by the National Institutes of Health and the National Science Foundation.

The team obtained a three-dimensional map of the capsid, or protein shell, of the epsilon15 bacteriophage, a virus that infects bacteria and is a member of a family of viruses that are the most abundant life forms on Earth, Jiang said.

Other methods of determining the structure could not be used for this family of virus. None had been successfully crystallized, and the complexity of members of this family had prevented evaluation through the genome sequence alone.

“This demonstration shows that cryo-EM is doable and is a major step in reaching the full potential of this technique,” he said. “The goal is to have it reach a 3 to 4 angstrom resolution, which would allow us to clearly see the amino acids that make up a protein.”

In electron microscopy, a beam of electrons takes the place of the light beam used in a conventional microscope. The use of electrons instead of light allows the microscope to “see” in much greater detail.

Cryo-EM cools specimens to temperatures well below the freezing point of water. This decreases damage from the electron beam and allows the specimens to be examined for a longer period of time. Longer exposure time allows for sharper, more detailed images.

Researchers using cryo-EM had obtained images at a resolution of 6-9 angstroms but could not differentiate between smaller elements of the structure spaced only 4.5 angstroms apart.

“There are different elements that make up the protein building blocks of the virus,” Jiang said. “It is like examining a striped blanket. From a distance, the stripes blur together and the blanket appears to be one solid color. As you get closer you can see the different stripes, and if you use a magnifying glass you can see the strands of string that make up the material. The resolution needs to be smaller than the distance between the strands of thread in order to see two separate strands.

“By being able to zoom in, researchers were able to see components that blurred together at the earlier achieved resolution.”

Cryo-EM requires high-end electron microscopes and powerful computing resources. The research team used the Baylor College of Medicine’s cryoelectron microscope. It is expected that Purdue will install a state-of-the-art cryoelectron microscope in 2009.

In 2006 Purdue received a $2 million grant from the National Institute of Health to purchase the microscope. It will be installed in Hockmeyer Hall of Structural Biology, expected to open in 2009.

Computer programs are used to extract the signal from the microscope and to combine thousands of two-dimensional images into an accurate three-dimensional image that maps the structure of the virus. This requires use of a large data set and could not have been done without the resources of Purdue’s Office of Information Technology, or ItaP, Jiang said.

Jiang used Purdue’s Condor program - which links computers including desktop machines and large, powerful research computers - to create the largest distributed computing network at a university.

“ITaP provided us with computational power at the supercomputer scale that was necessary for this work,” he said. “Purdue’s Condor program allowed us to take advantage of the power of 7,000 computers. This was a critical element to our success.”

Jiang plans to continue to refine every step of the process to improve the capabilities of the technique and to examine more medically relevant virus species.

Purdue’s structural biology group studies a diverse group of problems, including cellular signaling pathways, RNA catalysis, bioremediation, molecular evolution, viral entry, viral replication and viral pathogenesis. Researchers use a combination of X-ray crystallography, electron cryomicroscopy, NMR spectroscopy, and advanced computational and modeling tools to study these problems.

Nature 451, 1130 - 1134 (28 Feb 2008), doi: 10.1038/nature06665, Letter

A half-century after the determination of the first three-dimensional crystal structure of a protein1, more than 40,000 structures ranging from single polypeptides to large assemblies have been reported2. The challenge for crystallographers, however, remains the growing of a diffracting crystal. Here we report the 4.5-Å resolution structure of a 22-MDa macromolecular assembly, the capsid of the infectious epsilon15 (epsilon15) particle, by single-particle electron cryomicroscopy. From this density map we constructed a complete backbone trace of its major capsid protein, gene product 7 (gp7). The structure reveals a similar protein architecture to that of other tailed double-stranded DNA viruses, even in the absence of detectable sequence similarity3, 4. However, the connectivity of the secondary structure elements (topology) in gp7 is unique. Protruding densities are observed around the two-fold axes that cannot be accounted for by gp7. A subsequent proteomic analysis of the whole virus identifies these densities as gp10, a 12-kDa protein. Its structure, location and high binding affinity to the capsid indicate that the gp10 dimer functions as a molecular staple between neighbouring capsomeres to ensure the particle’s stability. Beyond epsilon15, this method potentially offers a new approach for modelling the backbone conformations of the protein subunits in other macromolecular assemblies at near-native solution states.

Bach is better than sex - applies to the composer rather than the inventor of the same named flowers. One of the most comprehensive investigations done to date on aromatherapy failed to show any improvement in either immune status, wound healing or pain control among people exposed to two often-touted scents.

While one of two popular aromas touted by alternative medicine practitioners – lemon – did appear to enhance moods positively among study subjects, the other – lavender – had no effect on reported mood, based on three psychological tests.

Neither lemon nor lavender showed any enhancement of the subjects’ immune status, nor did the compounds mitigate either pain or stress, based on a host of biochemical markers. In some cases, even distilled water showed a more positive effect than lavender.

The study, published online in the journal Psychoneuroendocrinology, looked for evidence that such aromas go beyond increasing pleasure and actually have a positive medical impact on a person’s health.  While a massive commercial industry has embraced this notion in recent decades, little, if any, scientific proof has been offered supporting the products’ health claims.

“We all know that the placebo effect can have a very strong impact on a person’s health but beyond that, we wanted to see if these aromatic essential oils actually improved human health in some measurable way,” explained Janice Kiecolt-Glaser, professor of psychiatry and psychology at Ohio State University and lead author of the study.

The researchers chose lemon and lavender since they were two of the most popular scents tied to aromatherapy.  Recently, two other studies focused on these same two scents.

For the study, Kiecolt-Glaser; Ronald Glaser, a professor of molecular virology, immunology and medical genetics, and William Malarkey, professor of internal medicine, assembled a group of 56 healthy volunteers.  These men and women were screened beforehand to confirm their ability to detect standard odors.  Some were proponents of the merits of aromatherapy while others expressed no opinion on its use.

Each person took part in three half-day sessions where they were exposed to both scents.  Participants were monitored for blood pressure and heart rate during the experiments, and the researchers took regular blood samples from each volunteer.

Researchers taped cotton balls laced with either lemon oil, lavender oil or distilled water below the volunteers’ noses for the duration of the tests.

The researchers tested volunteers’ ability to heal by using a standard test where tape is applied and removed repeatedly on a specific skin site.  The scientists also tested volunteers’ reaction to pain by immersing their feet in 32-degree F water.

Lastly, volunteers were asked to fill out three standard psychological tests to gauge mood and stress three times during each session.   They also were asked to record a two-minute reaction to the experience which was later analyzed to gauge positive or negative emotional-word use.

The blood samples were later analyzed for changes in several distinct biochemical markers that would signal affects on both the immune and endocrine system.  Levels of both Interleukin-6 and Interleukin-10 – two cytokines – were checked, as were stress hormones such as cortisol, norepinephrine and other catacholomines.

While lemon oil showed a clear mood enhancement, lavender oil did not, the researchers said.  Neither smell had any positive impact on any of the biochemical markers for stress, pain control or wound healing.

“This is probably the most comprehensive study ever done in this area, but the human body is infinitely complex,” explained Malarkey.  “If an individual patient uses these oils and feels better, there’s no way we can prove it doesn’t improve that person’s health.

“But we still failed to find any quantitative indication that these oils provide any physiological effect for people in general.”

The wound healing experiments measured how fast the skin could repair itself, Glaser said.  “Keep in mind that a lot of things have to take place for that healing process to succeed.  We measured a lot of complex physiological interactions instead of just a single marker, and still we saw no positive effect,” he said.

The project was supported in part by the National Center for Complementary and Alternative Medicine at the National Institutes of Health.  Kiecolt-Glaser, Glaser and Malarkey are all members of Ohio State’s Institute for Behavioral Medicine Research.

Psychoneuroendocrinology. 2008 Apr;33(3):328-39.

Olfactory influences on mood and autonomic, endocrine, and immune function.

Kiecolt-Glaser JK, Graham JE, Malarkey WB, Porter K, Lemeshow S, Glaser R.

Department of Psychiatry, The Ohio State University, 1670 Upham Drive, Columbus, OH 43210, USA; The Ohio State Institute for Behavioral Medicine Research, 2175 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, USA.

Despite aromatherapy’s popularity, efficacy data are scant, and potential mechanisms are controversial. This randomized controlled trial examined the psychological, autonomic, endocrine, and immune consequences of one purported relaxant odor (lavender), one stimulant odor (lemon), and a no-odor control (water), before and after a stressor (cold pressor); 56 healthy men and women were exposed to each of the odors during three separate visits. To assess the effects of expectancies, participants randomized to the “blind” condition were given no information about the odors they would smell; “primed” individuals were told what odors they would smell during the session, and what changes to expect. Experimenters were blind. Self-report and unobtrusive mood measures provided robust evidence that lemon oil reliably enhances positive mood compared to water and lavender regardless of expectancies or previous use of aromatherapy. Moreover, norepinephrine levels following the cold pressor remained elevated when subjects smelled lemon, compared to water or lavender. DTH responses to Candida were larger following inhalation of water than lemon or lavender. Odors did not reliably alter IL-6 and IL-10 production, salivary cortisol, heart rate or blood pressure, skin barrier repair following tape stripping, or pain ratings following the cold pressor.

In a study of 104 children under treatment for type 2 diabetes at the Vanderbilt Eskind Pediatric Diabetes Clinic, the children and their parents were surveyed about their perceptions of the child’s weight, dietary and exercise practices, as well as barriers to improving diet and exercise habits.

Quite often, both the children and their parents underestimated the child’s weight status.

“You could argue the first step for overcoming obesity is recognition,” said Russell Rothman, M.D., assistant professor of Internal Medicine and Pediatrics at the Vanderbilt Center for Health Services Research, and senior author on the study in February’s Diabetes Care.

“This is a group that is already getting treatment for type 2 diabetes, including education about exercise and nutrition. If anything, you might expect them to be more aware about weight issues. This should send up a red flag about how challenging it is to treat obesity in this population, if many of the parents and patients in this group don’t even recognize the problem.”

The parents and children were surveyed by telephone and were asked, among other things, “do you think your child’s/your weight is very overweight, slightly overweight, about right, slightly thin or very thin.”

While 87 percent of the children surveyed were obese by the most recent Centers for Disease Control and Prevention (CDC) standards, only 41 percent of parents, and 35 percent of the children reported themselves “very overweight.” Among parents who reported their child’s weight as “about right,” 40 percent had children who actually were at or over the 95th percentile for weight and were considered obese by government standards.

Girls were more likely than boys to underestimate their weight, and parents underestimated their children’s weight more often than the children did themselves. Additionally, those who underreported weight were more likely to report a poor diet and exercise than those who correctly reported their weight status. Those with misperceptions about weight also reported more barriers to better exercise and diet behaviors.

There have been other studies showing parents and children in the general population often don’t accurately perceive weight. However, Rothman said this is the first study to examine weight perception among children with type 2 diabetes — a population that should already have been informed of their weight status and its contribution to diabetes from their health care providers.

“As health care providers we need to take a step back and realize these families need better guidance about understanding their weight status before we can convince them to make lifestyle changes to improve their health,” said Rothman, who also serves as director of the Vanderbilt Program on Effective Health Communication. “We need to do a better job as providers to work on shared communication, using more clear language, goal setting with families about key behavior changes, identifying barriers and setting realistic goals.”

Diabetes Care. 2008 Feb;31(2):227-9. Epub 2007 Nov 13.

Accuracy of perceptions of overweight and relation to self-care behaviors among adolescents with type 2 diabetes and their parents.

Skinner AC, Weinberger M, Mulvaney S, Schlundt D, Rothman RL.

Health Policy and Administration, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7411, USA. asheley@unc.edu

OBJECTIVE: To examine how adolescents with type 2 diabetes and their parents/primary caregivers perceive the adolescents’ weight and the relationship of those perceptions to diet and exercise behaviors and perceived barriers to healthy behaviors. RESEARCH DESIGN AND METHODS: Interviews were conducted with adolescents and their parents about perceptions of the adolescents’ weight, diet, and exercise behaviors, as well as barriers to engaging in healthy diet and exercise behaviors. Interviews were linked with clinic records to provide BMI. RESULTS: A total of 104 parent-adolescent dyads participated. Parents and adolescents typically perceived the adolescents’ weight as less severe than it actually was. For parents and adolescents, underestimating the adolescents ‘ weight was associated with poorer diet behaviors and more perceived barriers to following healthy diet or exercise behaviors. CONCLUSIONS: Addressing misperceptions of weight by adolescents and their parents may be an important first step to improving weight in these patients.

for bodyweight perception in adults see:

Size Does Not Matter, Thinking Does…

 

Using artificial cell-like particles, Yale biomedical engineers have devised a rapid and efficient way to produce a 45-fold enhancement of T cell activation and expansion, an immune response important for a patient’s ability to fight cancer and infectious diseases, according to an advance on line report in Molecular Therapy.

Stimulatory particles (red) bound to activated T-cells (blue) as seen by fluorescence microscopy. Scale bar = 10 µm (Credit: Fahmy-Steenblock/Yale)

The artificial cells, developed by Tarek Fahmy, assistant professor of biomedical engineering at Yale and his graduate student Erin Steenblock, are made of a material commonly used for biodegradable sutures. The authors say that the new method is the first “off-the-shelf” antigen-presenting artificial cell that can be tuned to target a specific disease or infection.

“This procedure is likely to make it to the clinic rapidly,” said senior author Fahmy. “All of the materials we use are natural, biodegradable already have FDA approval.”

Cancer, viral infections and autoimmune diseases have responded to immunotherapy that boosts a patient’s own antigen-specific T cells. In those previous procedures, a patient’s immune cells were harvested and then exposed to cells that stimulate the activation and proliferation of antigen-specific T-cells. The “boosted” immune cells were then infused back into the patient to attack the disease.

Limitations of these procedures include costly and tedious custom isolation of cells for individual patients and the risk of adverse reaction to foreign cells, according to the Yale researchers. They also pointed to difficulty in obtaining and maintaining sufficient numbers of activated T-cells for effective therapeutic response.

In the new system, the outer surface of each particle is covered in universal adaptor molecules that serve as attachment points for antigens — molecules that activate the patient’s T-cells to recognize and fight off the targeted disease — and for stimulatory molecules. Inside of each particle, there are slowly released cytokines that further stimulate the activated T-cells to proliferate to as much as 45 times their original number.

“Our process introduces several important improvements,” said lead author Steenblock. “First, the universal surface adaptors allow us to add a span of targeting antigen and co-stimulatory molecules. We can also create a sustained release of encapsulated cytokines. These enhancements mimic the natural binding and signaling events that lead to T-cell proliferation in the body. It also causes a fast and effective stimulation of the patient’s T-cells — particularly T-cells of the cytotoxic type important for eradicating cancer.”

“Safe and efficient T-cell stimulation and proliferation in response to specific antigens is a goal of immunotherapy against infectious disease and cancer,” said Fahmy. “Our ability to manipulate this response so rapidly and naturally with an “off the shelf” reproducible biomaterial is a big step forward.”

Fahmy was recently awarded a five-year National Science Foundation (NSF) Career Award for work on this process and ways of engineering biomaterials to manipulate immune responses to fight cancer and other diseases. His approach incorporates signals important for T-cell stimulation in biocompatible polymer particulates, and integrates all the signals needed for efficient T-cell stimulation.

According to the NSF, devices as such these offer ease and flexibility in targeting different types of T-cells, and is expected to lead to state of the art improvements in the preparation of a new generation of therapeutic systems.

Molecular Therapy (2008); doi:10.1038/mt.2008.8

Mechanisms of Immunization Against Cancer Using Chimeric Antigens

Manuel E Engelhorn¹, José A Guevara-Patiño², Taha Merghoub¹, Cailian Liu¹, Cristina R Ferrone³, Gabriele A Rizzuto¹, Daniel H Cymerman¹, David N Posnett¹, Alan N Houghton¹ and Jedd D Wolchok¹

At the Institut Curie, Inserm researchers, in collaboration with collegues from Dynavax(1), have discovered a new mechanism controlling the choice in humans between two lines of defense in the event of attack. In the presence of viruses or bacteria, the immune system can trigger a response that is rapid but devoid of memory – innate immunity – or a response that takes longer to put in place but is more specifically targeted – adaptive immunity.

PI3-kinase, a protein essential to the activation of the innate response immune in this image, immune cells responding to attack: IRF-7 (red) is in the nucleus and so can trigger the innate immune response. (Credit: Copyright Cristiana Guiducci/Institut Curie)

The essential prerequisite to the proper functioning of innate immunity is the “turning on” of the protein PI3-kinase. Once PI3-kinase is activated, the immune response is triggered, leading to the production of type I interferons, the spearhead of innate immunity, which destroy the body’s invaders. This discovery opens up new therapeutic prospects since it may suggest ways of restoring the function of innate immunity, which is overactivated in autoimmune diseases and inhibited in certain cancers.

The body is often faced with attacks from outside (viral or bacterial infection) and sometimes from inside, because of the dysfunction of its own cells (cancer), and defends itself by activating its immune system. There are two types of defence. The first is innate immunity: this has no memory, and is permanently on guard to detect and destroy abnormal cells, tumor cells, or virus-infected cells. The second, which takes longer to initiate, is adaptive immunity, which specifically targets an invader. This response requires a education phase during which the cells of the immune system learn to recognize their enemy.

Dendritic cells, the body’s “sentinels”, are the first line of defence against invading pathogens: they recognize viruses and bacteria and then trigger an immune response, which, depending on the case, may be innate or adaptive. In response to an intruder, the so-called plasmacytoid dendritic cells can either produce large amounts of interferons, molecules that trigger a rapid response against viral infections, or “specialize” and become cells able to teach the immune system to recognize the pathogens.

At the Institut Curie, Vassili Soumelis(2) and his team (“Immunity and Cancer”, Inserm/Institut Curie Unit 653) have discovered how the dendritic cells choose between the two types of immune response. First, whatever the response, the presence of an intruder stimulates the TLR receptor inside the dendritic cells. Only then is the choice made between the two types of response. The PI3-kinase signaling pathway is activated, and the innate response is triggered. Kinase PI3 is the switch that turns on a whole cascade of proteins inside the cell. Information on the presence of an intruder in the body is thus transmitted to its final destination, in the cell’s nucleus, where the protein IRF-7 (transcription factor) modifies the expression of specific genes and so alters the cell’s behavior. In this specific case, IRF-7 induces the production of type 1 interferons (interferon-alpha, for example), which will bring about the destruction of the viruses and strongly activate various cells of the immune system.

Vassili Soumelis MD, PhD at the Institut Curie explains: “Activation of the protein PI3-kinase is one of the very first steps needed for the production of large quantities of type 1 interferons, leading to the triggering or strengthening of the innate immune response.”

In certain autoimmune diseases this innate response overstimulated, leading to an abnormal defense reaction of the immune system, which attacks its own cells, tissues, or organs. In some cancers, on the other hand, the innate response is virtually absent. It may be that the cancer cells are able to block the PI3-kinase signaling pathway. Through this discovery, Vassili Soumelis and his collaborators hope, in time, to develop new treatments for use in autoimmune diseases and oncology. By acting on PI3-kinase, it may be possible to adapt the innate response, so as to inhibit it in the treatment of autoimmune diseases and boost it in cancer treatment.