This longitudinal study was conducted with a group of mothers living in Vancouver and Winnipeg, Canada. Mothers of high risk children were recruited in their third trimester and ‘high risk’ was defined as having at least one parent with asthma or two parents with other IgE allergic diseases. Then house dust samples were collected and a questionnaire regarding health and exposures were completed before birth and at ages 1, 2 and 7. Additionally at years 2 and 7 allergy skin tests were performed on the following allergens: house dust mite, cat and dog dander, peanuts, eggs, cow’s milk, wheat and soy. Atopy was defined as one or more positive skin tests for any allergen. Also, cord blood IgE (CD-IgE) levels were collected at birth.
CD-IgE was detectable (≥0.5 KU/l) in 19.3% of the 285 children. A high percentage of children with detectable CD-IgE had a maternal history of asthma (p-value of 0.001), maternal atopy [adjusted OR 2.21 (1.01-4.84)], and were born in the winter months [adjusted OR 4.07 (1.68-9.83)]. Additionally at 7 years, detectable CD-IgE was associated with increased risks for atopy [OR 2.22 (1.11-4.41)], positive skin test reactions against any aeroallergen [OR 2.25 (1.13-4.47)] and recurrent wheeze [OR 2.51 (1.09-5.76)].
The data that they collected looks really interesting so make sure to look at the two tables they provided. Although this was a small study, the authors noted that this information can lead to targeted prevention efforts for infants who may be at higher risk for developing asthma. I think it’s most interesting that being born in the winter months was found to have a significant association with detectable CD-IgE. This is probably due to the increased exposure to inhalant allergens after birth but who knew the season you were born in may have that effect!
You can find the article at:
http://0-www3.interscience.wiley.com.impulse.ucdenver.edu/journal/123193720/issue
Elevated cord blood IgE is associated with recurrent wheeze and atopy at 7 yrs in a high risk cohort
Ferguson, Alexander A (12/2009). "Elevated cord blood IgE is associated with recurrent wheeze and atopy at 7 yrs in a high risk cohort". Pediatric allergy and immunology (0905-6157), 20 (8), p. 710.
14 December 2009
RXR Activation: Hope for New Parkinson's Disease Treatment
Parkinson’s disease is a neurodegenerative disease, which effects the dopamine-releasing cells in the brain. There has been a few experiments run attempting to rescue the dopamine neurons. This is done using chemicals that interact with the retinoid X receptor (RXR). The chemicals that will be investigated to interact with these receptors are known as RXR ligands. The article, which was published in journal BMC Neuroscience, describes the use of two cellular events which lead to the neuronal damage due to Parkinson’s disease. The two ligands examined in the experiment were the two RXR ligands LG268 and XCT. Specifically, they were studied to determine the neuroprotective function of the two.
Susanna Kjellander worked with a team of researchers from the Ludwig Institute for Cancer Research, Sweden, to test both the ligands and the two destructive Parkinson’s pathways. As a result she was able to make the following conclusion; "Nuclear hormone receptors like RXR and the Nurr1-RXR receptor heterodimer are emerging as interesting factors in Parkinson's research. It is unclear exactly how neurons are damaged in Parkinson's disease, but it is suggested that oxidative damage and energy depletion in the brain are involved. By activating RXR, neurons can be rescued from this degeneration."
In the study, there were two different dopaminergic cells (DA cells) to resemble the conditions present in persons with Parkinson’s. After studying these models, the researchers discovered the two RXR-activating ligands studied were able to selectively protect dopaminergic neurons from the stress induced in the model itself.
The results of this experiement were then confirmed to be accurate in a novel system in which dopaminergic neurons generated from mouse embryonic stem cells were treated with the neurotoxin. From this information they were able to theorize that "The regulation of RXR activity holds promise to contribute to a novel, alternative strategy to treat Parkinson's disease."
To reference the original article, it can be reached at http://www.sciencedaily.com/releases/2009/12/091210193158.htm. The article may also be searched by "RXR Activation: Hope for New Parkinson's Disease Treatment" ScienceDaily (Dec. 11, 2009).
13 December 2009
Thiamine Found Important for Diabetics
What was once termed “adult-onset diabetes” due to the fact that the vast majority of individuals with the disease were not in their youth, type 2 diabetes now effects people of all ages, and is one of the fastest growing health problems in the United States today. The most common procedure for treating an individual with type 2 diabetes is to simply limit the amount of sugars and refined carbohydrates in their diet. However, I came across an article, which proposed that a simple B vitamin referred to as Thiamine (B1) may play a key role in the treatment of the disease.
The complications that often accompany the disease are devastating to the effected individual, as they might include nerve damage, eye problems, cardiovascular disease, and kidney damage. Also, kidney failure usually occurs 15 to 20 years following the onset of the disease.
A major contributing factor to this grim prognosis lies in the fact that most people are under the influence that by tightly regulating blood glucose levels with diet, oral medication, or insulin, one would likely avoid any complications. However, recent studies have shown that while these things may in fact delay complications, it often does not prevent their onset. This was found to be especially true with diabetic nephropathy, which occurs when the capillaries inside the glomerulus are destroyed. This leads to thickening and scarring of the glomerulus, resulting in the drastic decrease in normal renal function. The first detectable symptoms of diabetic nephropathy are an increased level of albumin in the urine, known as microalbuminuria. Research led by Dr. Naila Rabbani and Professor Paul J Thornalley at Warwick Medical School, University of Warwick, in collaboration with researchers at the University of Punjab and Sheik Zaid Hospital, Lahore, Pakistan, discovered that high doses of Thiamine administered orally can significantly decrease the secretion of albumin, and reverse the progression of early kidney disease in type 2 diabetics.
The subjects (40) for the study were type 2 diabetics between the ages of 35 and 65, and administered 100mg of thiamine three times a day for three months. The control group was administered a placebo. Of those given thiamine, there was a 41% decrease in albumin excretion, and 35% of the subjects given thiamine returned to their normal levels after the thiamine treatment.
Another study led by Professor Paul Thornalley was able to prove that thiamine deficiency plays a significant role in a vast array of vascular complications, and even diabetic neuropathy, as a result of diabetes. They also discovered that thiamine levels in type 1 and type 2 diabetes were 76% and 75% lower than the control, respectively. This drastic decrease in thiamine levels is not due to a low dietary intake of thiamine, but a significant increase in urinary output, therefore supplemental thiamine for diabetics may prove essential.
Possibly one of the most beneficial thiamine treatments, although synthetic, is Benfotiamine, which is chemically similar to the allithiamines one would find in garlic. One of the reasons Benfotiamine is so effective is its ability to readily cross lipid bilayers. This allows the compound to reach relatively high levels in the tissues, while avoiding being excreted rapidly. Benfotiamine has been shown to block three of the four metabolic pathways responsible for the progression of vascular disease in diabetics, and also demonstrated an ability to reduce Advanced Glycation Endproducts (AGEs).
For more information, the article can be found at http://www.NaturalNews.com/025136_thiamine_diabetic_diabetics.html or search “Thiamine Found Important for Diabetics”; by: Patty Donovan, citizen journalist.
Transmissible cancers
Came across a paper in Cell published in 2006 about the clonal origin of a transmissible cancer (CTVT) found in dogs. This was the first time I have heard about a tumor cell itself acting as the transmissible agent. The tumor cell itself was shown to be transferred as an allograft came from three different experiments: 1. CTVT can only be experimentally induced by transplanting living tumor cells, and not by lysates or killed cells. 2. The karyotype of the of the tumor cells is aneuploid but striking similar in tumors collected from various regions of unrelated dogs. And 3. A LINE-1 element upstream of c-myc was found in every tumor line examined. This tumor is passed from dog to dog usually by coitus but also can occur from licking and biting. This tumor is not fatal and usually is treatable. This cell has evolved into a parasite which represents the oldest somatic mammalian cell in continuous propagation.
For obvious reasons, Immunologists had a very hard time believing that the transmissible agent was the cell itself. The immune system is built to kill anything that is not recognized as self. So how did this cell evolve in such a way as to evade the hosts immune system? This was one of the questions that this paper sought to answer. As it turns out, MHC class I are downregulated in each of these tumors and class II are absent. Vertebrates has evolved NK cells to detect cells (typically tumors) that do not express MHC I and II and kill them because the normal acquired immune system would not be able to pick up these cells. These CTVT cells seemed to have evolved an expression level of MHC I that is high enough to keep the hosts NK cells at bay but low enough as to not illicit an immune response.
I found this paper really interesting and the authors and myself wonder why this isnt something that has occurred more often. At any rate, its amazing to see evolution in action, even at the cellular level. And we as researchers should look closely at this because it seems not a matter of 'if' but 'when' something like this will be seen in humans.
Murgia, C., Pritchard, JK., Kim, SY., Fassati, A., and Weiss, RA. Clonal Origin and Evolution of Transmissible Cancer. (2006) Cell 126, 477-487
10 December 2009
Inflammation and the Host Response to Injury
As we all learnt in this class inflammation is one of fundamental protection mechanisms in human biology. This is how we protect ourselves from foreign invaders as well as abnormal cell inside of our body. But gone awry inflammation that spreads beyond the primary locus or fails to subside poses serious chronic and acute health risks for millions of people.
Each year about 60 million Americans sustain injuries. Trauma accounts for more than 12% of all medical spending in America. After the first 24 hours following the injury the primary cause of death is Multiple Organ Failure (MOF). It presents as an excessive inflammatory response directed towards patient’s own tissues. It is closely related to Systemic Inflammatory Response Syndrome (SIRS) and Sepsis. Sepsis alone accounts for up to 215,000 American’s lifes every year, according to the National Institute of General Medical Sciences. We referred to SIRS in Immu 7630 course as cytokine storm.
Growing evidence suggests that genetic factors drive key aspects of an individual’s inflammatory outcome. Scientists studying inflammation are trying to identify the genes that drive inflammation as well as biomarkers from throughout the course of inflammation. Genomic studies, in addition to their proteomic and metabolomic cousins, aim to resolve an age-old mystery: namely, why some patients recover readily from inflammation while others suffer and die from it. Ideally, new gene based discoveries will provide diagnostic biomarkers to predict who among these patients will react poorly to inflammation and why. If doctors could reliably predict this outcome in advance, they might tailor antibiotics and other treatment options to a patient’s own inflammatory system, potentially saving lives.
Among the numerous programs moving inflammation research forward is an effort funded by a National Institute of General Medical Sciences “glue grant,” so named because it “glues together” multidisciplinary efforts to tackle biomedical questions beyond the means of any one research group. This program, called Inflammation and the Host Response to Injury, strives to determine why patients can have dramatically different outcomes after traumatic injuries and burns.
UCD and Denver Health Medical Center are part of this multicenter research study.
In order to find immuno-inflammatory biomarkers for developing MOF Glue Grant is using genomic and proteomic analyses:
mRNA Isolation for Protein Coding
The Glue Grant investigators nationwide are isolating messenger RNA (mRNA) from blood and other available tissues. Isolation of the mRNA molecule is key to finding expressed genes in the vast expanse of the human genome. Since mRNA is very unstable outside of a cell, we are using a special enzyme called reverse transcriptase to convert it to complementary DNA (cDNA) which is a much more stable compound than mRNA and is presumed to represent the sequences of the genes being expressed. Sequences contained in the cDNA are used to generate expressed sequence tags (ESTs) that code for the protein in question or represent non-translated regions. ESTs are powerful tools for gene mapping and gene discovery. In the search for known genes, they greatly reduce the time needed to locate a gene. ESTs provide sequences that can be generated rapidly and inexpensively, in that only one sequencing experiment is needed per each cDNA generated and ESTs do not have to be confirmed for sequencing errors.
Only a fraction of genes are turned on, and it is the subset that is "expressed" that confers the unique properties to each cell type. Gene expression is the term used to describe the transcription of the information contained within the DNA into mRNA molecules that are then translated into the proteins that perform most of the critical functions of cells. Gene expression is a highly complex and tightly regulated process that allows a cell to respond dynamically both to environmental stimuli and its own changing needs. This mechanism acts as both an "on/off" switch to control which genes are expressed in a cell as well as a "volume control" that increases or decreases the level of expression of particular genes as necessary.
Microarray technology is applied to the samples to collect gene expression data. This technology works through the ability of a given mRNA molecule to bind specifically to, or hybridize to, the DNA template from which it originated. By using an array that contains many DNA samples, we can determine - in a single experiment - the expression levels of thousands of genes within a cell by measuring the amount of mRNA bound to each site on the array. The amount of mRNA bound to the spots on the microarray is precisely measured, thus generating a profile of gene expression in the cell. Microarray expression analysis are performed on the samples to determine the level, or volume, at which a certain gene is expressed. The arrays used in this analysis are called expression chips or "Gene Chips". We use the expression chips to detect expression patterns, that is, whether or not a particular gene is being expressed more or less under certain circumstances, and to examine changes in gene expression over a given period of time.
Detection and Analyses of SNPs
A single nucleotide polymorphism (SNP) is a small genetic alteration that can occur in a patient's DNA sequence. An SNP variation occurs when a single nucleotide (adenine, cytosine, thymine, or guanine) is replaced by one of the other three nucleotides. Each patient's genetic material contains a unique genetic pattern that is composed of several different genetic variations, including SNPs. It is believed that SNPs can serve both as a biological marker for pinpointing a disease or condition and may be directly associated with or causative of a certain disease or condition.
Proteomic Analyses
Cytokine mediators, leukocyte phenotypes, and cell signaling intermediates (e.g., protein kinases, NF-ê B family) will be analyzed from blood and plasma of trauma patients. Of particular interest are investigations of changes in pro-inflammatory and anti-inflammatory cytokines in isolated populations of cells from these patients. There are several cytokines of interest that include TNF, IL-1, IL-6, IL-8, IL-10, IL-12, IL-18, IL-1ra, p55, and p75.
Glue Grant study is still underway and the final results are yet to be analyzed…
For more information please visit www.gluegrant.org or search PubMed for “Inflammation and the host response to injury: a Large-Scale Collaborative Project”.
Each year about 60 million Americans sustain injuries. Trauma accounts for more than 12% of all medical spending in America. After the first 24 hours following the injury the primary cause of death is Multiple Organ Failure (MOF). It presents as an excessive inflammatory response directed towards patient’s own tissues. It is closely related to Systemic Inflammatory Response Syndrome (SIRS) and Sepsis. Sepsis alone accounts for up to 215,000 American’s lifes every year, according to the National Institute of General Medical Sciences. We referred to SIRS in Immu 7630 course as cytokine storm.
Growing evidence suggests that genetic factors drive key aspects of an individual’s inflammatory outcome. Scientists studying inflammation are trying to identify the genes that drive inflammation as well as biomarkers from throughout the course of inflammation. Genomic studies, in addition to their proteomic and metabolomic cousins, aim to resolve an age-old mystery: namely, why some patients recover readily from inflammation while others suffer and die from it. Ideally, new gene based discoveries will provide diagnostic biomarkers to predict who among these patients will react poorly to inflammation and why. If doctors could reliably predict this outcome in advance, they might tailor antibiotics and other treatment options to a patient’s own inflammatory system, potentially saving lives.
Among the numerous programs moving inflammation research forward is an effort funded by a National Institute of General Medical Sciences “glue grant,” so named because it “glues together” multidisciplinary efforts to tackle biomedical questions beyond the means of any one research group. This program, called Inflammation and the Host Response to Injury, strives to determine why patients can have dramatically different outcomes after traumatic injuries and burns.
UCD and Denver Health Medical Center are part of this multicenter research study.
In order to find immuno-inflammatory biomarkers for developing MOF Glue Grant is using genomic and proteomic analyses:
mRNA Isolation for Protein Coding
The Glue Grant investigators nationwide are isolating messenger RNA (mRNA) from blood and other available tissues. Isolation of the mRNA molecule is key to finding expressed genes in the vast expanse of the human genome. Since mRNA is very unstable outside of a cell, we are using a special enzyme called reverse transcriptase to convert it to complementary DNA (cDNA) which is a much more stable compound than mRNA and is presumed to represent the sequences of the genes being expressed. Sequences contained in the cDNA are used to generate expressed sequence tags (ESTs) that code for the protein in question or represent non-translated regions. ESTs are powerful tools for gene mapping and gene discovery. In the search for known genes, they greatly reduce the time needed to locate a gene. ESTs provide sequences that can be generated rapidly and inexpensively, in that only one sequencing experiment is needed per each cDNA generated and ESTs do not have to be confirmed for sequencing errors.
Only a fraction of genes are turned on, and it is the subset that is "expressed" that confers the unique properties to each cell type. Gene expression is the term used to describe the transcription of the information contained within the DNA into mRNA molecules that are then translated into the proteins that perform most of the critical functions of cells. Gene expression is a highly complex and tightly regulated process that allows a cell to respond dynamically both to environmental stimuli and its own changing needs. This mechanism acts as both an "on/off" switch to control which genes are expressed in a cell as well as a "volume control" that increases or decreases the level of expression of particular genes as necessary.
Microarray technology is applied to the samples to collect gene expression data. This technology works through the ability of a given mRNA molecule to bind specifically to, or hybridize to, the DNA template from which it originated. By using an array that contains many DNA samples, we can determine - in a single experiment - the expression levels of thousands of genes within a cell by measuring the amount of mRNA bound to each site on the array. The amount of mRNA bound to the spots on the microarray is precisely measured, thus generating a profile of gene expression in the cell. Microarray expression analysis are performed on the samples to determine the level, or volume, at which a certain gene is expressed. The arrays used in this analysis are called expression chips or "Gene Chips". We use the expression chips to detect expression patterns, that is, whether or not a particular gene is being expressed more or less under certain circumstances, and to examine changes in gene expression over a given period of time.
Detection and Analyses of SNPs
A single nucleotide polymorphism (SNP) is a small genetic alteration that can occur in a patient's DNA sequence. An SNP variation occurs when a single nucleotide (adenine, cytosine, thymine, or guanine) is replaced by one of the other three nucleotides. Each patient's genetic material contains a unique genetic pattern that is composed of several different genetic variations, including SNPs. It is believed that SNPs can serve both as a biological marker for pinpointing a disease or condition and may be directly associated with or causative of a certain disease or condition.
Proteomic Analyses
Cytokine mediators, leukocyte phenotypes, and cell signaling intermediates (e.g., protein kinases, NF-ê B family) will be analyzed from blood and plasma of trauma patients. Of particular interest are investigations of changes in pro-inflammatory and anti-inflammatory cytokines in isolated populations of cells from these patients. There are several cytokines of interest that include TNF, IL-1, IL-6, IL-8, IL-10, IL-12, IL-18, IL-1ra, p55, and p75.
Glue Grant study is still underway and the final results are yet to be analyzed…
For more information please visit www.gluegrant.org or search PubMed for “Inflammation and the host response to injury: a Large-Scale Collaborative Project”.
09 December 2009
More news on my new favorite spice, tumeric! In a recent report researchers at the Univ. of Michigan found that the active ingredient in tumeric, curcumin, when applied to breast cancer cells in culture, was able to repress the growth of cancer stem cells, while not affecting the growth on non-stem cells. The same activity was seen with the active ingredient from black pepper, piperinem and was greatest when the two compounds were used together. Is this anti-stem cell activity a component in the anti-inflammatory mechanism used by curcumin, or perhaps an entirely separate effect?
This stem-cell specific growth inhibition may provide a better approach to limiting the growth of tumor cells in situ. Current treatments, such as standard chemotherapy or radiation, are thought to indiscriminately inhibit the growth of all cancer cells. But research has shown that many cancers are the result of cancerous stem cells driving the growth of tumors. And treatments that can specifically target these stem cells may provide better eradication than current treatments which are thought to often miss total irradication of the cancer stem cells.
Of note, the concentration of curcumin applied in culture is far greater (some 20 fold greater) than what could be obtained in the diet - supplementation would be required. Also, the study was an in vitro cell culture study, with all of the limitations inherent to cell culture models. But, the authors report that they hope to conduct Phase I safety trials as soon as next year.
1. Madhuri Kakarala, Dean E. Brenner, Hasan Korkaya, Connie Cheng, Karim Tazi, Christophe Ginestier, Suling Liu, Gabriela Dontu and Max S. Wicha. (2009) Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Research and Treatment, Vol 66(3), p123-133
This stem-cell specific growth inhibition may provide a better approach to limiting the growth of tumor cells in situ. Current treatments, such as standard chemotherapy or radiation, are thought to indiscriminately inhibit the growth of all cancer cells. But research has shown that many cancers are the result of cancerous stem cells driving the growth of tumors. And treatments that can specifically target these stem cells may provide better eradication than current treatments which are thought to often miss total irradication of the cancer stem cells.
Of note, the concentration of curcumin applied in culture is far greater (some 20 fold greater) than what could be obtained in the diet - supplementation would be required. Also, the study was an in vitro cell culture study, with all of the limitations inherent to cell culture models. But, the authors report that they hope to conduct Phase I safety trials as soon as next year.
1. Madhuri Kakarala, Dean E. Brenner, Hasan Korkaya, Connie Cheng, Karim Tazi, Christophe Ginestier, Suling Liu, Gabriela Dontu and Max S. Wicha. (2009) Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Research and Treatment, Vol 66(3), p123-133
08 December 2009
Hygiene Hypothesis goes in utero!
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