Nature | doi:10.1038/news.2011.365
Scientists have for the first time created laser light using living biological material: a single human cell and some jellyfish protein.
"Lasers started from physics and are viewed as engineering devices," says Seok-Hyun Yun, an optical physicist at Harvard Medical School and Massachusetts General Hospital in Boston, who created the 'living laser' with his colleague Malte Gather. "This is the first time that we have used biological materials to build a laser and generate light from something that is living." The finding is reported today in Nature Photonics 1.
Building a laser requires two things: a lasing material that amplifies light from an external source (a 'gain medium') and an arrangement of mirrors (an 'optical cavity'), which concentrates and aligns the light waves into a tight beam. Until now, the gain medium has only been made from non-biological substances such as doped crystals, semiconductors or gases, but in this case the researchers used enhanced green fluorescent protein (GFP) — the substance that makes jellyfish bioluminescent, which is used extensively in cell biology to label cells.
The team engineered human embryonic kidney cells to produce GFP, then placed a single cell between two mirrors to make an optical cavity just 20 micrometres across. When they fed the cell pulses of blue light, it emitted a directional laser beam visible with the naked eye — and the cell wasn't harmed.
The width of the laser beam is "tiny" and "fairly weak" in its brightness compared to traditional lasers, says Yun, but "an order of magnitude" brighter than natural jellyfish fluorescence, with a "beautiful green" colour.
Illuminating biology
Yun and Gather have some broad and speculative ideas about how the technology might be used.
They suggest that biologists could turn cells of interest into lasers to study them. The light produced has a unique emission spectrum related to both the structure of the cell and the proteins inside it. "By analysing the pattern you can get some idea of what is happening inside the cell," says Yun.
The researchers also suggest possible medical applications. Doctors today shine lasers into the body to gather images or to treat disease by attacking cells. Yun thinks that lasers could instead be generated or amplified inside the body, where they could penetrate the relevant tissues more deeply.
But more work is needed first — including developing the laser so that it works inside an actual living organism. To achieve this, Yun envisages integrating a nano-scale optical cavity into the laser cell itself. Technologies to make such cavities are emerging, he says, and once they are available they could be used to create a cell that could "self lase" from inside tissue.
Experts praise the work as interesting and creative. "It is kind of neat," says Michael Berns, a biomedical engineer at the University of California, Irvine. "I have been working on cells and lasers for 40 years, and I don't think I would have thought of this."
But he says that the technique might more feasibly be used to study individual cells than for medical applications. He points out that external light is needed to stimulate the laser action, which would be difficult in the body, potentially limiting the technique to thin-tissue systems or cells in culture or suspension.
Thursday, June 16, 2011
Species spellchecker fixes plant glitches
Nature 474, 263 (2011) | doi:10.1038/474263a
Brian Enquist and his collaborators were delighted with their freshly compiled data set of 22.5 million records on the distribution and traits of plants in the Americas. But their delight turned to horror when they realized that the data set contained 611,728 names: nearly twice as many as there are thought to be plant species on Earth.
Completed in December 2010, the records were intended to help Enquist and his colleagues to discern trends in how forest trees in a wide variety of environments respond to climate change. But the data were clearly full of bogus names, making it impossible to count the species in a particular area, or their relative abundance. "I started to question our ability even to compare something as basic as species diversity at two sites," says Enquist, a plant ecologist at the University of Arizona in Tucson.
This month, Enquist's team will unveil a solution that could help botanists and ecologists worldwide. The Taxonomic Names Resolution Service (TNRS) aims to find and fix the incorrect plant names that plague scientists' records.
"It looks really good," says Gabriela Lopez-Gonzalez, a plant ecologist at the University of Leeds, UK, who curates a database of forest plots. Fixing species lists by hand is arduous, she says. "This should save us a lot of time".
She and others agree that the problem is widespread in botanical databases. "Digitization has made the problem worse," says TNRS co-leader, botanist Brad Boyle, also at the University of Arizona. Boyle explains that as more data are added to digital records, the chance of introducing errors also increases. Even in herbarium specimens, which ought to be the gold standard for plant identification, about 15% of the names are misspelt, he says.
Many of the errors seem to arise because biologists are not as careful as they should be when entering data into digital records. The TNRS team estimates that about one-third of the names entered into online repositories — such as GenBank, the US National Institutes of Health collection of DNA-sequence data, or the Ecological Society of America's VegBank database of plant-plot data — are incorrect.
The other problem is that names change. Old names can be abolished when experts reclassify plants as ideas about evolutionary relationships change, or when they realize the species already had a name — an occurrence almost as old as taxonomy itself. The result is that the same plant can have many names, and not everyone knows which one to use. Such synonyms are a particular problem in the study of medicinal plants, says Alan Paton, a plant taxonomist and bioinformatician at Kew Gardens in London.
The TNRS was built with financial and technical support from iPlant, a project run by the US National Science Foundation to fund cyberinfrastructure for plant science. It corrects names by comparing lists that users feed into it with the 1.2 million names in the Missouri Botanical Garden's Tropicos database, one of the most authoritative botanical databases. If the TNRS cannot find a name in Tropicos, it uses a fuzzy-matching algorithm, similar to a word-processor's spellchecker, to find and correct misspellings. It also hunts through Tropicos's lists of alternative names and supplies the one that is most up to date. When Enquist ran the 611,728 names through the system, just 202,252 came back, showing that two-thirds of them were invalid.
Because Tropicos is less comprehensive for plants outside the Americas, the team hopes to link the TNRS with The Plant List (www.theplantlist.org), a collaborative compilation of databases from Kew and other sources. Launched online in December 2010, it aims to become a global record of plants. The scientists are also working on a tool to correct geographical data — one that knows, for example, that Brazil, Brasil and Brésil are the same place, and can recognize when someone has muddled up longitude and latitude.
Brian Enquist and his collaborators were delighted with their freshly compiled data set of 22.5 million records on the distribution and traits of plants in the Americas. But their delight turned to horror when they realized that the data set contained 611,728 names: nearly twice as many as there are thought to be plant species on Earth.
Completed in December 2010, the records were intended to help Enquist and his colleagues to discern trends in how forest trees in a wide variety of environments respond to climate change. But the data were clearly full of bogus names, making it impossible to count the species in a particular area, or their relative abundance. "I started to question our ability even to compare something as basic as species diversity at two sites," says Enquist, a plant ecologist at the University of Arizona in Tucson.
This month, Enquist's team will unveil a solution that could help botanists and ecologists worldwide. The Taxonomic Names Resolution Service (TNRS) aims to find and fix the incorrect plant names that plague scientists' records.
"It looks really good," says Gabriela Lopez-Gonzalez, a plant ecologist at the University of Leeds, UK, who curates a database of forest plots. Fixing species lists by hand is arduous, she says. "This should save us a lot of time".
She and others agree that the problem is widespread in botanical databases. "Digitization has made the problem worse," says TNRS co-leader, botanist Brad Boyle, also at the University of Arizona. Boyle explains that as more data are added to digital records, the chance of introducing errors also increases. Even in herbarium specimens, which ought to be the gold standard for plant identification, about 15% of the names are misspelt, he says.
Many of the errors seem to arise because biologists are not as careful as they should be when entering data into digital records. The TNRS team estimates that about one-third of the names entered into online repositories — such as GenBank, the US National Institutes of Health collection of DNA-sequence data, or the Ecological Society of America's VegBank database of plant-plot data — are incorrect.
The other problem is that names change. Old names can be abolished when experts reclassify plants as ideas about evolutionary relationships change, or when they realize the species already had a name — an occurrence almost as old as taxonomy itself. The result is that the same plant can have many names, and not everyone knows which one to use. Such synonyms are a particular problem in the study of medicinal plants, says Alan Paton, a plant taxonomist and bioinformatician at Kew Gardens in London.
The TNRS was built with financial and technical support from iPlant, a project run by the US National Science Foundation to fund cyberinfrastructure for plant science. It corrects names by comparing lists that users feed into it with the 1.2 million names in the Missouri Botanical Garden's Tropicos database, one of the most authoritative botanical databases. If the TNRS cannot find a name in Tropicos, it uses a fuzzy-matching algorithm, similar to a word-processor's spellchecker, to find and correct misspellings. It also hunts through Tropicos's lists of alternative names and supplies the one that is most up to date. When Enquist ran the 611,728 names through the system, just 202,252 came back, showing that two-thirds of them were invalid.
Because Tropicos is less comprehensive for plants outside the Americas, the team hopes to link the TNRS with The Plant List (www.theplantlist.org), a collaborative compilation of databases from Kew and other sources. Launched online in December 2010, it aims to become a global record of plants. The scientists are also working on a tool to correct geographical data — one that knows, for example, that Brazil, Brasil and Brésil are the same place, and can recognize when someone has muddled up longitude and latitude.
Phage on the rampage
9 June 2011 | Nature | doi:10.1038/news.2011.360
Antibiotic use may have driven the development of Europe's deadly E. coli.
Women, beansprouts, cucumbers, bacteria, cows: the cast of the current European Escherichia coli outbreak is already a crowd. Enter the phage. Bacteriophages are viruses that infect bacteria, and they are star players in the chain of events that led to this outbreak.
Bacterial infections often originate from contaminated food, but it is now about six weeks since the start of this outbreak and the trail is going cold. It's hard to be sure of the culprit — but this simply serves to highlight the importance of understanding how infectious bacteria get into the food chain in the first place.
Case-control studies of patients in the German outbreak pointed to salad vegetables, and both cucumbers and beansprouts have been suspects. It is possible that the vegetables were contaminated with bacteria originally carried in soil or water; but the more likely source of the bacteria is animals. Pathogenic E. coli are typically passed to humans from ruminant animals (cows or sheep) via faecal contamination in the food chain or through consumption of raw milk or meat products.
But how do pathogenic E. coli arise in the first place? This is where bacteriophage come in. The bacterium in this outbreak, currently recognised as strain O104:H4, makes Shiga toxin, which is responsible for the severe diarrhoea and kidney damage in patients whose E. coli infections develop into haemolytic uremic syndrome (HUS). The genes for the Shiga toxin are not actually bacterial genes, but phage genes being expressed by infected bacteria. So when an E. coli bacterium gets infected with a Shiga-toxin-producing phage, it becomes pathogenic to humans.
Our use of antibiotics may be helping those viral genes to spread. If bacteria are exposed to some types of antibiotics they undergo what is called the SOS response, which induces the phage to start replicating. Active replication of the phage causes the bacterial cells to burst open, which releases the phage. It also releases the toxin, which is why antibiotics are not usually used to treat E. coli infections (see 'Europe's E. coli outbreak: time for the antibiotics?').
The cost of protection
One of the many unusual characteristics of strain O104:H4 is that it has resistance genes to multiple classes of antibiotics. This suggests that wherever the bacteria have come from, there has been selective pressure to resist antibiotics. Heather Allison, a microbiologist at the University of Liverpool, UK, and David Acheson, a managing director for food safety at consulting firm Leavitt Partners in Washington DC, agree it is plausible that exposure to antibiotics — in agricultural use or in the environment — might be enhancing the spread of Shiga-toxin-producing phage.
Acheson worked on this question when he led a research group at Tufts University in Medford, Massachusetts, studying the molecular pathogenesis of Shiga-toxin-producing E. coli in the 1990s. He says they saw Shiga-toxin-producing phage transfer between E. coli in response to sub-therapeutic levels of the antibiotic ciprofloxacin in vitro and in the intestines of mice.
"They do it in the laboratory," he says, "but it's hard to show it happens in the environment." He is convinced it does, though. "The potential for the creation of new pathogens via phage release is absolutely a factor in the broader environmental danger of overuse of antibiotics."
Agricultural use of antibiotics is a possible suspect. "Phage are particularly abundant in the guts of ruminants", says Alfredo Caprioli, from the European Reference Laboratory for verotoxin-producing E. coli in Rome, Italy (verotoxin is another name for Shiga toxin). And the gut is one place in which the phage move between different bacteria, and new pathogenic bacterial strains emerge.
Shiga toxins have been causing diarrhoeal disease in humans for centuries — the bacterial genus Shigella and the Shiga toxins were first named for Kiyoshi Shiga, a Japanese medical doctor who identified the bacterium during an outbreak of dysentery in Japan in 1897. According to Allison, Shiga-toxin producing phage probably picked up the genes encoding Shiga toxin from these bacteria, and since the 1980s have been spreading these virulent genes to other bacteria, including many strains of E. coli.
"We are seeing more and more Shiga-toxin-producing strains," says Alison Weiss, microbiologist at the University of Cincinnati in Ohio.
How have Shiga-toxin-producing phage spread so widely in just a few decades? Allison says they have unusual characteristics that make them very successful. They infect bacteria by binding to a protein called BamA on the surface of many bacterial cells, which gives them a broad range of hosts. Most phage can only infect a host cell once, but Shiga-toxin-producing phage can infect the same cell multiple times, giving them greater pathogenic potential. And they can survive outside their hosts, in water or soil, for example.
Weiss adds that carrying the phage also provides a survival advantage for the host bacteria. "Once the bacteria are out in the environment — say in manure — they are fed on by other microbes, such as protozoans. The toxins kill the other microbes, giving these bacteria an advantage."
Not only are more E. coli strains being infected with Shiga toxin, but it seems to be moving into different classes of bacteria. The genome of strain O104:H4 has been sequenced, and it shares many genes with enteroaggerative E. coli (EAEC) strains. "EAEC strains are not typically associated with zoonotic infections, and EAEC and Shiga toxin is a very unusual combination," says Caprioli.
This increased movement of Shiga-toxin-producing phage means that even more unusual and dangerous strains could be on the horizon.
Antibiotic use may have driven the development of Europe's deadly E. coli.
Women, beansprouts, cucumbers, bacteria, cows: the cast of the current European Escherichia coli outbreak is already a crowd. Enter the phage. Bacteriophages are viruses that infect bacteria, and they are star players in the chain of events that led to this outbreak.
Bacterial infections often originate from contaminated food, but it is now about six weeks since the start of this outbreak and the trail is going cold. It's hard to be sure of the culprit — but this simply serves to highlight the importance of understanding how infectious bacteria get into the food chain in the first place.
Case-control studies of patients in the German outbreak pointed to salad vegetables, and both cucumbers and beansprouts have been suspects. It is possible that the vegetables were contaminated with bacteria originally carried in soil or water; but the more likely source of the bacteria is animals. Pathogenic E. coli are typically passed to humans from ruminant animals (cows or sheep) via faecal contamination in the food chain or through consumption of raw milk or meat products.
But how do pathogenic E. coli arise in the first place? This is where bacteriophage come in. The bacterium in this outbreak, currently recognised as strain O104:H4, makes Shiga toxin, which is responsible for the severe diarrhoea and kidney damage in patients whose E. coli infections develop into haemolytic uremic syndrome (HUS). The genes for the Shiga toxin are not actually bacterial genes, but phage genes being expressed by infected bacteria. So when an E. coli bacterium gets infected with a Shiga-toxin-producing phage, it becomes pathogenic to humans.
Our use of antibiotics may be helping those viral genes to spread. If bacteria are exposed to some types of antibiotics they undergo what is called the SOS response, which induces the phage to start replicating. Active replication of the phage causes the bacterial cells to burst open, which releases the phage. It also releases the toxin, which is why antibiotics are not usually used to treat E. coli infections (see 'Europe's E. coli outbreak: time for the antibiotics?').
The cost of protection
One of the many unusual characteristics of strain O104:H4 is that it has resistance genes to multiple classes of antibiotics. This suggests that wherever the bacteria have come from, there has been selective pressure to resist antibiotics. Heather Allison, a microbiologist at the University of Liverpool, UK, and David Acheson, a managing director for food safety at consulting firm Leavitt Partners in Washington DC, agree it is plausible that exposure to antibiotics — in agricultural use or in the environment — might be enhancing the spread of Shiga-toxin-producing phage.
Acheson worked on this question when he led a research group at Tufts University in Medford, Massachusetts, studying the molecular pathogenesis of Shiga-toxin-producing E. coli in the 1990s. He says they saw Shiga-toxin-producing phage transfer between E. coli in response to sub-therapeutic levels of the antibiotic ciprofloxacin in vitro and in the intestines of mice.
"They do it in the laboratory," he says, "but it's hard to show it happens in the environment." He is convinced it does, though. "The potential for the creation of new pathogens via phage release is absolutely a factor in the broader environmental danger of overuse of antibiotics."
Agricultural use of antibiotics is a possible suspect. "Phage are particularly abundant in the guts of ruminants", says Alfredo Caprioli, from the European Reference Laboratory for verotoxin-producing E. coli in Rome, Italy (verotoxin is another name for Shiga toxin). And the gut is one place in which the phage move between different bacteria, and new pathogenic bacterial strains emerge.
Shiga toxins have been causing diarrhoeal disease in humans for centuries — the bacterial genus Shigella and the Shiga toxins were first named for Kiyoshi Shiga, a Japanese medical doctor who identified the bacterium during an outbreak of dysentery in Japan in 1897. According to Allison, Shiga-toxin producing phage probably picked up the genes encoding Shiga toxin from these bacteria, and since the 1980s have been spreading these virulent genes to other bacteria, including many strains of E. coli.
"We are seeing more and more Shiga-toxin-producing strains," says Alison Weiss, microbiologist at the University of Cincinnati in Ohio.
How have Shiga-toxin-producing phage spread so widely in just a few decades? Allison says they have unusual characteristics that make them very successful. They infect bacteria by binding to a protein called BamA on the surface of many bacterial cells, which gives them a broad range of hosts. Most phage can only infect a host cell once, but Shiga-toxin-producing phage can infect the same cell multiple times, giving them greater pathogenic potential. And they can survive outside their hosts, in water or soil, for example.
Weiss adds that carrying the phage also provides a survival advantage for the host bacteria. "Once the bacteria are out in the environment — say in manure — they are fed on by other microbes, such as protozoans. The toxins kill the other microbes, giving these bacteria an advantage."
Not only are more E. coli strains being infected with Shiga toxin, but it seems to be moving into different classes of bacteria. The genome of strain O104:H4 has been sequenced, and it shares many genes with enteroaggerative E. coli (EAEC) strains. "EAEC strains are not typically associated with zoonotic infections, and EAEC and Shiga toxin is a very unusual combination," says Caprioli.
This increased movement of Shiga-toxin-producing phage means that even more unusual and dangerous strains could be on the horizon.
Ambulatory pulse pressure as a novel predictor for long-term prognosis in essential hypertensive patients
Journal of Human Hypertension 25, 444-450 (July 2011) | doi:10.1038/jhh.2010.80
The prognostic value of ambulatory blood pressure (BP) monitoring for long-term prognosis varies in recent studies. The study aimed to investigate the role of ambulatory BP parameters in mortality and cardiovascular (CV) events in hypertensive patients. A series of 412 participants (59.3±4.0 years) who received ambulatory BP monitoring for their fluctuated BP, either untreated or treated since 1995, were enroled. The mortality and CV events were obtained by follow-up and linked to the National Death Registry in Taiwan. There were 233 untreated and 179 treated patients. The latter were older with more comorbidity when compared with the former. After follow-up for 8.5±1.7 years, both ambulatory systolic BP and pulse pressure (PP) could predict all-cause mortality, non-CV mortality, CV disease and stroke after adjusting for baseline covariates. However, only ambulatory PP could predict CV mortality and coronary heart disease. Ambulatory PP is better than ambulatory systolic BP, particularly in prediction of all-cause mortality. There was no predictive value of office BP in any outcome. In conclusion, ambulatory PP is a good predictor for long-term outcomes in hypertensive patients. The parameters of ambulatory rather than office BP could be applied for risk stratification either before or under antihypertensive treatment.
The prognostic value of ambulatory blood pressure (BP) monitoring for long-term prognosis varies in recent studies. The study aimed to investigate the role of ambulatory BP parameters in mortality and cardiovascular (CV) events in hypertensive patients. A series of 412 participants (59.3±4.0 years) who received ambulatory BP monitoring for their fluctuated BP, either untreated or treated since 1995, were enroled. The mortality and CV events were obtained by follow-up and linked to the National Death Registry in Taiwan. There were 233 untreated and 179 treated patients. The latter were older with more comorbidity when compared with the former. After follow-up for 8.5±1.7 years, both ambulatory systolic BP and pulse pressure (PP) could predict all-cause mortality, non-CV mortality, CV disease and stroke after adjusting for baseline covariates. However, only ambulatory PP could predict CV mortality and coronary heart disease. Ambulatory PP is better than ambulatory systolic BP, particularly in prediction of all-cause mortality. There was no predictive value of office BP in any outcome. In conclusion, ambulatory PP is a good predictor for long-term outcomes in hypertensive patients. The parameters of ambulatory rather than office BP could be applied for risk stratification either before or under antihypertensive treatment.
Blood pressure lowering effect of lactotripeptides assumed as functional foods: a meta-analysis of current available clinical trials
Journal of Human Hypertension 25, 425-436 (July 2011) | doi:10.1038/jhh.2010.85
The oral assumption of lactotripeptides Valine–Proline–Proline (VPP) and Isoleucine–Proline–Proline (IPP) as nutraceuticals or functional foods is supposed to improve blood pressure (BP) control by angiotensin-converting enzyme-inhibition. However, data derived from clinical trials have reached conflicting conclusions. To perform a meta-analysis of placebo-controlled clinical trials evaluating the anti-hypertensive effect of lactotripeptides assumed as nutraceuticals or functional foods. Trials identified using a defined search strategy in PubMed were included in the meta-analysis, and their pooled effect was estimated with a random effects model, weighting for the inverse of the variance. Heterogeneity, publication bias, subgroup and meta-regression analyses were performed. A total of 18 trials have been identified, the clinical data of which have been clearly reported. Pooled effect of peptides was a reduction of −3.73 mm Hg (95% CI: −6.70, −1.76) for systolic blood pressure (SBP) and 1.97 mm Hg (95% CI: −3.85, −0.64) for diastolic blood pressure (DBP). The effect was more evident in Asian patients (SBP=−6.93 mm Hg (95% CI: −10.95, −2.94); DBP=−3.98 mm Hg(95% CI: −5.38, −2.44)) than in Caucasian ones (SBP=−1.17 mm Hg (95% CI: −2.82, 0.72); DBP=−0.52 mm Hg (95% CI: −1.39, 0.13)), and apparently not related to age, baseline BP values, dose of lactotripeptides assumed or length of the treatment. VPP and IPP lactotripeptides assumed as functional foods may significantly reduce SBP particularly in Asian subjects. The relevance of this findings in other ethnicities or associated with different dietary pattern should to be further investigated.
The oral assumption of lactotripeptides Valine–Proline–Proline (VPP) and Isoleucine–Proline–Proline (IPP) as nutraceuticals or functional foods is supposed to improve blood pressure (BP) control by angiotensin-converting enzyme-inhibition. However, data derived from clinical trials have reached conflicting conclusions. To perform a meta-analysis of placebo-controlled clinical trials evaluating the anti-hypertensive effect of lactotripeptides assumed as nutraceuticals or functional foods. Trials identified using a defined search strategy in PubMed were included in the meta-analysis, and their pooled effect was estimated with a random effects model, weighting for the inverse of the variance. Heterogeneity, publication bias, subgroup and meta-regression analyses were performed. A total of 18 trials have been identified, the clinical data of which have been clearly reported. Pooled effect of peptides was a reduction of −3.73 mm Hg (95% CI: −6.70, −1.76) for systolic blood pressure (SBP) and 1.97 mm Hg (95% CI: −3.85, −0.64) for diastolic blood pressure (DBP). The effect was more evident in Asian patients (SBP=−6.93 mm Hg (95% CI: −10.95, −2.94); DBP=−3.98 mm Hg(95% CI: −5.38, −2.44)) than in Caucasian ones (SBP=−1.17 mm Hg (95% CI: −2.82, 0.72); DBP=−0.52 mm Hg (95% CI: −1.39, 0.13)), and apparently not related to age, baseline BP values, dose of lactotripeptides assumed or length of the treatment. VPP and IPP lactotripeptides assumed as functional foods may significantly reduce SBP particularly in Asian subjects. The relevance of this findings in other ethnicities or associated with different dietary pattern should to be further investigated.
Cortisol, dehydroepiandrosterone sulphate, their ratio and hypertension: evidence of associations in male veterans from the Vietnam Experience Study
Journal of Human Hypertension 25, 418-424 (July 2011) | doi:10.1038/jhh.2011.6
Although clinical observations implicate cortisol in hypertension, the epidemiological evidence is less compelling. Little is known about the relationship between dehydroepiandrosterone sulphate (DHEAS) and hypertension, and nothing about the association with the cortisol:DHEAS ratio. The present analyses of data obtained from Vietnam-era US veterans examined the associations between cortisol, DHEAS, their ratio and hypertension. Participants were 4180 male veterans. From military files, telephone interviews and a medical examination, sociodemographic and health data were collected. At medical examination, a fasted morning blood sample was collected to assay serum cortisol and DHEAS, blood pressure measured and body mass index (BMI) determined. Hypertension was defined by having one of the following: a reported physician diagnosis, taking antihypertensive medication, an average systolic blood pressure 140 mm Hg and an average diastolic blood pressure 90 mm Hg. Cortisol and the cortisol:DHEAS ratio were positively associated with hypertension (P<0.001), whereas DHEAS was negatively associated; the latter relationship was attenuated to non-significance (P=0.06) in models that adjusted for age, sociodemographics, place of service, health behaviours and BMI. The present analyses provide confirmation of a positive association between cortisol and the cortisol:DHEAS ratio and population hypertension.
Although clinical observations implicate cortisol in hypertension, the epidemiological evidence is less compelling. Little is known about the relationship between dehydroepiandrosterone sulphate (DHEAS) and hypertension, and nothing about the association with the cortisol:DHEAS ratio. The present analyses of data obtained from Vietnam-era US veterans examined the associations between cortisol, DHEAS, their ratio and hypertension. Participants were 4180 male veterans. From military files, telephone interviews and a medical examination, sociodemographic and health data were collected. At medical examination, a fasted morning blood sample was collected to assay serum cortisol and DHEAS, blood pressure measured and body mass index (BMI) determined. Hypertension was defined by having one of the following: a reported physician diagnosis, taking antihypertensive medication, an average systolic blood pressure 140 mm Hg and an average diastolic blood pressure 90 mm Hg. Cortisol and the cortisol:DHEAS ratio were positively associated with hypertension (P<0.001), whereas DHEAS was negatively associated; the latter relationship was attenuated to non-significance (P=0.06) in models that adjusted for age, sociodemographics, place of service, health behaviours and BMI. The present analyses provide confirmation of a positive association between cortisol and the cortisol:DHEAS ratio and population hypertension.
Autism linked to hundreds of spontaneous genetic mutations
9 June 2011 | Nature | doi:10.1038/news.2011.359
Analysis suggests that girls are partially shielded from effects of the changes.
The most comprehensive search yet for spontaneous genetic mutations associated with autism spectrum disorders suggests that hundreds of regions in the genome may have a hand in causing such conditions.
Analyses reported in three papers published this week in Neuron1,2,3 dramatically expand the list of known genetic culprits. Two of the studies also shed light on a long-standing mystery: why are boys four times more likely to have autism than girls1,2? The researchers found that girls with autism tend to have many more mutated genes than boys with the disorder, suggesting that it generally takes a larger genomic change to cause autism in girls.
Autism is difficult to pin down. A wide range of symptoms, many involving difficulties in social interactions and communication, are united under the diagnoses of autism spectrum disorders. And although it is estimated that such conditions are more than 90% heritable, quests to find common mutations associated with them have not yet yielded any reproducible hits, says Stephen Scherer, a geneticist at the Hospital for Sick Children in Toronto, Canada, who was not involved in any of the studies.
"Autism is a heterogeneous disease, both clinically and genetically," he notes.
Spontaneity counts
In 2007, Michael Wigler, a geneticist at Cold Spring Harbor Laboratory in New York, and his colleagues showed that spontaneous mutations — those that arise for the first time in an individual, rather than being inherited — are important in about half of all cases of autism4 (see New mutations implicated in half of autism cases). A follow-up study5 in 2010, of 996 autistic individuals, found that people with autism carry a heavy load of rare duplications or deletions in regions of the genome that contain genes.
ow Wigler and his group, as well as a team headed up by Matthew State, a geneticist at the Yale University School of Medicine in New Haven, Connecticut, have expanded on that search, using higher-resolution techniques to trawl through the genome1,3. The researchers searched the DNA of more than 1,000 individuals with autism and their unaffected family members, looking for rare mutations that duplicate or delete segments of the genetic code. The teams focused largely on spontaneous mutations.
Their results indicate that spontaneous duplications or deletions of at least 130 sites in the genome could contribute to the risk of autism. Wigler believes that in total there are closer to 400 such sites. "It is a large number," he acknowledges, and that will make it harder to develop therapies that will benefit a large fraction of patients. "Given the number of genes that might cause autism, one shouldn't expect that one treatment is going to cure them all," says Wigler.
State's team made an intriguing finding in a segment of chromosome 7. Deletion of the region is associated with Williams–Beuren Syndrome, a condition that is linked to hypersocial behaviour. Duplication of the same region, they found, is associated with autism, which is linked to antisocial behaviour3.
The region spans many genes, and for now it is unclear which might be responsible for the effects. "But there's clearly something there that's highly relevant to social behaviour," says State. "The neurobiology of that region is going to be extraordinarily interesting."
Working together
Wigler also teamed up with Dennis Vitkup, a computational biologist at Columbia University in New York City, to learn more about the neurobiology of the rare variants that his analysis had uncovered. The team analysed the relationships among spontaneously mutated genes that were likely to be involved in brain function, and found that many clustered into a large network that governs the creation and activity of connections between nerve cells2.
Vitkup's team is now trying to determine whether the network that they have discovered could be used to construct a diagnostic test for autism.
Overall, the results have dramatically lengthened the list of genes that may have a role in causing autism, says Scherer. "This gives us a lot more data that we can use to start to pin autism down," he says.
One finding that will be pursued further is that girls are somehow shielded from the effects of mutations that are linked to autism in boys. Wigler's team found that autistic girls tended to have deletions or duplications in more genes than autistic boys.
That, says Scherer, suggests that one approach to developing therapies may lie in determining what protects the female brain from autism — and then activating those pathways in boys. "If you want to think about an approach to therapeutic intervention," he says, "perhaps the lessons to be learned are in the females."
References
Levy, D. et al. Neuron doi:10.1016/j.neuron.2011.05.015 (2011).
Gilman, S. R. et al. Neuron doi:10.1016/j.neuron.2011.05.021 (2011).
Sanders, S. J. et al. Neuron doi:10.1016/j.neuron.2011.05.002 (2011).
Zhao, X., et al. Proc. Natl Acad. Sci. USA 104, 12831-12836 (2007). | Article | ChemPort |
Pinto, D., et al. Nature 466, 368-372 (2010). | Article | ISI | ChemPort |
Analysis suggests that girls are partially shielded from effects of the changes.
The most comprehensive search yet for spontaneous genetic mutations associated with autism spectrum disorders suggests that hundreds of regions in the genome may have a hand in causing such conditions.
Analyses reported in three papers published this week in Neuron1,2,3 dramatically expand the list of known genetic culprits. Two of the studies also shed light on a long-standing mystery: why are boys four times more likely to have autism than girls1,2? The researchers found that girls with autism tend to have many more mutated genes than boys with the disorder, suggesting that it generally takes a larger genomic change to cause autism in girls.
Autism is difficult to pin down. A wide range of symptoms, many involving difficulties in social interactions and communication, are united under the diagnoses of autism spectrum disorders. And although it is estimated that such conditions are more than 90% heritable, quests to find common mutations associated with them have not yet yielded any reproducible hits, says Stephen Scherer, a geneticist at the Hospital for Sick Children in Toronto, Canada, who was not involved in any of the studies.
"Autism is a heterogeneous disease, both clinically and genetically," he notes.
Spontaneity counts
In 2007, Michael Wigler, a geneticist at Cold Spring Harbor Laboratory in New York, and his colleagues showed that spontaneous mutations — those that arise for the first time in an individual, rather than being inherited — are important in about half of all cases of autism4 (see New mutations implicated in half of autism cases). A follow-up study5 in 2010, of 996 autistic individuals, found that people with autism carry a heavy load of rare duplications or deletions in regions of the genome that contain genes.
ow Wigler and his group, as well as a team headed up by Matthew State, a geneticist at the Yale University School of Medicine in New Haven, Connecticut, have expanded on that search, using higher-resolution techniques to trawl through the genome1,3. The researchers searched the DNA of more than 1,000 individuals with autism and their unaffected family members, looking for rare mutations that duplicate or delete segments of the genetic code. The teams focused largely on spontaneous mutations.
Their results indicate that spontaneous duplications or deletions of at least 130 sites in the genome could contribute to the risk of autism. Wigler believes that in total there are closer to 400 such sites. "It is a large number," he acknowledges, and that will make it harder to develop therapies that will benefit a large fraction of patients. "Given the number of genes that might cause autism, one shouldn't expect that one treatment is going to cure them all," says Wigler.
State's team made an intriguing finding in a segment of chromosome 7. Deletion of the region is associated with Williams–Beuren Syndrome, a condition that is linked to hypersocial behaviour. Duplication of the same region, they found, is associated with autism, which is linked to antisocial behaviour3.
The region spans many genes, and for now it is unclear which might be responsible for the effects. "But there's clearly something there that's highly relevant to social behaviour," says State. "The neurobiology of that region is going to be extraordinarily interesting."
Working together
Wigler also teamed up with Dennis Vitkup, a computational biologist at Columbia University in New York City, to learn more about the neurobiology of the rare variants that his analysis had uncovered. The team analysed the relationships among spontaneously mutated genes that were likely to be involved in brain function, and found that many clustered into a large network that governs the creation and activity of connections between nerve cells2.
Vitkup's team is now trying to determine whether the network that they have discovered could be used to construct a diagnostic test for autism.
Overall, the results have dramatically lengthened the list of genes that may have a role in causing autism, says Scherer. "This gives us a lot more data that we can use to start to pin autism down," he says.
One finding that will be pursued further is that girls are somehow shielded from the effects of mutations that are linked to autism in boys. Wigler's team found that autistic girls tended to have deletions or duplications in more genes than autistic boys.
That, says Scherer, suggests that one approach to developing therapies may lie in determining what protects the female brain from autism — and then activating those pathways in boys. "If you want to think about an approach to therapeutic intervention," he says, "perhaps the lessons to be learned are in the females."
References
Levy, D. et al. Neuron doi:10.1016/j.neuron.2011.05.015 (2011).
Gilman, S. R. et al. Neuron doi:10.1016/j.neuron.2011.05.021 (2011).
Sanders, S. J. et al. Neuron doi:10.1016/j.neuron.2011.05.002 (2011).
Zhao, X., et al. Proc. Natl Acad. Sci. USA 104, 12831-12836 (2007). | Article | ChemPort |
Pinto, D., et al. Nature 466, 368-372 (2010). | Article | ISI | ChemPort |
Caloric restriction, aerobic exercise training and soluble lectin-like oxidized LDL receptor-1 levels in overweight and obese post-menopausal women
International Journal of Obesity 35, 793-799 (June 2011) | doi:10.1038/ijo.2010.199
Background:
Elevated circulating levels of soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) have been observed in obese persons and are reduced by weight loss. However, it is not known whether combining caloric restriction (CR) with exercise training is better in reducing sLOX-1 levels than CR alone.
Objective:
We examined whether the addition of aerobic exercise to a weight loss intervention differentially affects sLOX-1 levels in 61 abdominally obese post-menopausal women randomly assigned to a CR only (n=22), CR+moderate-intensity exercise (n=22) or CR+vigorous-intensity exercise (n=17) intervention for 20 weeks. The caloric deficit was ~2800 kcal per week for all groups.
Results:
The intervention groups were similar at baseline with respect to body weight, body composition, lipids and blood pressure. However, plasma sLOX-1 levels were higher in the CR-only group (99.90±8.23 pg ml−1) compared with both the CR+moderate-intensity exercise (69.39±8.23 pg ml−1, P=0.01) and the CR+vigorous-intensity exercise (72.83±9.36 pg ml−1, P=0.03) groups. All three interventions significantly reduced body weight (~14%), body fat and waist and hip circumferences to a similar degree. These changes were accompanied by a 23% reduction in sLOX-1 levels overall (−19.00±30.08 pg ml−1, P<0.0001), which did not differ among intervention groups (P=0.13). Changes in body weight, body fat and maximal oxygen consumption (VO2 max) were not correlated with changes in sLOX-1 levels. In multiple regression analyses in all women combined, baseline sLOX-1 levels (β=−0.70±0.06, P<0.0001), age (β=0.92±0.43, P=0.03) and baseline body mass index (BMI) (β=1.88±0.66, P=0.006) were independent predictors of the change in sLOX-1 with weight loss.
Conclusions:
Weight loss interventions of equal energy deficit have similar effects on sLOX-1 levels in overweight and obese post-menopausal women, with the addition of aerobic exercise having no added benefit when performed in conjunction with CR.
Background:
Elevated circulating levels of soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) have been observed in obese persons and are reduced by weight loss. However, it is not known whether combining caloric restriction (CR) with exercise training is better in reducing sLOX-1 levels than CR alone.
Objective:
We examined whether the addition of aerobic exercise to a weight loss intervention differentially affects sLOX-1 levels in 61 abdominally obese post-menopausal women randomly assigned to a CR only (n=22), CR+moderate-intensity exercise (n=22) or CR+vigorous-intensity exercise (n=17) intervention for 20 weeks. The caloric deficit was ~2800 kcal per week for all groups.
Results:
The intervention groups were similar at baseline with respect to body weight, body composition, lipids and blood pressure. However, plasma sLOX-1 levels were higher in the CR-only group (99.90±8.23 pg ml−1) compared with both the CR+moderate-intensity exercise (69.39±8.23 pg ml−1, P=0.01) and the CR+vigorous-intensity exercise (72.83±9.36 pg ml−1, P=0.03) groups. All three interventions significantly reduced body weight (~14%), body fat and waist and hip circumferences to a similar degree. These changes were accompanied by a 23% reduction in sLOX-1 levels overall (−19.00±30.08 pg ml−1, P<0.0001), which did not differ among intervention groups (P=0.13). Changes in body weight, body fat and maximal oxygen consumption (VO2 max) were not correlated with changes in sLOX-1 levels. In multiple regression analyses in all women combined, baseline sLOX-1 levels (β=−0.70±0.06, P<0.0001), age (β=0.92±0.43, P=0.03) and baseline body mass index (BMI) (β=1.88±0.66, P=0.006) were independent predictors of the change in sLOX-1 with weight loss.
Conclusions:
Weight loss interventions of equal energy deficit have similar effects on sLOX-1 levels in overweight and obese post-menopausal women, with the addition of aerobic exercise having no added benefit when performed in conjunction with CR.
Effects of dietary fat modification on insulin sensitivity and on other risk factors of the metabolic syndrome—LIPGENE: a European randomized dietary intervention study
International Journal of Obesity 35, 800-809 (June 2011) | doi:10.1038/ijo.2010.209
Background:
Excessive energy intake and obesity lead to the metabolic syndrome (MetS). Dietary saturated fatty acids (SFAs) may be particularly detrimental on insulin sensitivity (SI) and on other components of the MetS.
Objective:
This study determined the relative efficacy of reducing dietary SFA, by isoenergetic alteration of the quality and quantity of dietary fat, on risk factors associated with MetS.
Design:
A free-living, single-blinded dietary intervention study.
Subjects and Methods:
MetS subjects (n=417) from eight European countries completed the randomized dietary intervention study with four isoenergetic diets distinct in fat quantity and quality: high-SFA; high-monounsaturated fatty acids and two low-fat, high-complex carbohydrate (LFHCC) diets, supplemented with long chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) (1.2 g per day) or placebo for 12 weeks. SI estimated from an intravenous glucose tolerance test (IVGTT) was the primary outcome measure. Lipid and inflammatory markers associated with MetS were also determined.
Results:
In weight-stable subjects, reducing dietary SFA intake had no effect on SI, total and low-density lipoprotein cholesterol concentration, inflammation or blood pressure in the entire cohort. The LFHCC n-3 PUFA diet reduced plasma triacylglycerol (TAG) and non-esterified fatty acid concentrations (P<0.01), particularly in men.
Conclusion:
There was no effect of reducing SFA on SI in weight-stable obese MetS subjects. LC n-3 PUFA supplementation, in association with a low-fat diet, improved TAG-related MetS risk profiles.
Background:
Excessive energy intake and obesity lead to the metabolic syndrome (MetS). Dietary saturated fatty acids (SFAs) may be particularly detrimental on insulin sensitivity (SI) and on other components of the MetS.
Objective:
This study determined the relative efficacy of reducing dietary SFA, by isoenergetic alteration of the quality and quantity of dietary fat, on risk factors associated with MetS.
Design:
A free-living, single-blinded dietary intervention study.
Subjects and Methods:
MetS subjects (n=417) from eight European countries completed the randomized dietary intervention study with four isoenergetic diets distinct in fat quantity and quality: high-SFA; high-monounsaturated fatty acids and two low-fat, high-complex carbohydrate (LFHCC) diets, supplemented with long chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) (1.2 g per day) or placebo for 12 weeks. SI estimated from an intravenous glucose tolerance test (IVGTT) was the primary outcome measure. Lipid and inflammatory markers associated with MetS were also determined.
Results:
In weight-stable subjects, reducing dietary SFA intake had no effect on SI, total and low-density lipoprotein cholesterol concentration, inflammation or blood pressure in the entire cohort. The LFHCC n-3 PUFA diet reduced plasma triacylglycerol (TAG) and non-esterified fatty acid concentrations (P<0.01), particularly in men.
Conclusion:
There was no effect of reducing SFA on SI in weight-stable obese MetS subjects. LC n-3 PUFA supplementation, in association with a low-fat diet, improved TAG-related MetS risk profiles.
Effects of lupin-enriched foods on body composition and cardiovascular disease risk factors: a 12-month randomized controlled weight loss trial
International Journal of Obesity 35, 810-819 (June 2011) | doi:10.1038/ijo.2010.213
Background:
Regular consumption of diets with increased protein or fibre intakes may benefit body weight and composition and cardiovascular disease risk factors. Lupin flour is a novel food ingredient high in protein and fibre.
Objective:
To investigate the effects of a lupin-enriched diet, during and following energy restriction, on body weight and composition and cardiovascular disease risk factors in overweight individuals.
Design:
Participants (n=131) were recruited to a 12-month parallel-design trial. They were randomly assigned to consume lupin-enriched foods or matching high-carbohydrate control foods. All participants underwent 3 months of weight loss, 1 month of weight stabilization and 8 months of weight maintenance. Body weight and composition and cardiovascular disease risk factors were assessed at baseline, 4 and 12 months.
Results:
Lupin, relative to control, did not significantly influence (mean difference (95% CI)) weight loss at 4 months (0.1 kg (−1.2, 1.4)) and 12 months (−0.6 kg (−2.0, 0.8)), maintenance of weight loss from 4 to 12 months (−0.7 kg (−1.83, 0.48)) or measures of body fat and fat-free mass. Relative to control, 24-h ambulatory systolic (−1.3 mm Hg (−2.4, −0.3), P=0.016) and diastolic (−1.0 mm Hg (−1.9, −0.2), P=0.021) blood pressures were lower at 12 months but not at 4 months; fasting insulin concentrations and homeostasis model assessment (HOMA) scores were significantly lower at 4 months (−1.2 mU l–1 (−1.3, −1.1), P=0.004 and −0.6 units (−1.0, −0.19), P=0.004) and 12 months (−1.3 mU l–1 (−1.4, −1.1), P<0.001 and −0.7 units (−1.1, −0.24), P=0.002).
Conclusions:
A diet higher in protein and fibre derived from lupin-enriched foods does not enhance weight loss or improve the maintenance of weight loss. However, such a diet may provide cardiovascular health benefits in terms of insulin sensitivity and blood pressure.
Background:
Regular consumption of diets with increased protein or fibre intakes may benefit body weight and composition and cardiovascular disease risk factors. Lupin flour is a novel food ingredient high in protein and fibre.
Objective:
To investigate the effects of a lupin-enriched diet, during and following energy restriction, on body weight and composition and cardiovascular disease risk factors in overweight individuals.
Design:
Participants (n=131) were recruited to a 12-month parallel-design trial. They were randomly assigned to consume lupin-enriched foods or matching high-carbohydrate control foods. All participants underwent 3 months of weight loss, 1 month of weight stabilization and 8 months of weight maintenance. Body weight and composition and cardiovascular disease risk factors were assessed at baseline, 4 and 12 months.
Results:
Lupin, relative to control, did not significantly influence (mean difference (95% CI)) weight loss at 4 months (0.1 kg (−1.2, 1.4)) and 12 months (−0.6 kg (−2.0, 0.8)), maintenance of weight loss from 4 to 12 months (−0.7 kg (−1.83, 0.48)) or measures of body fat and fat-free mass. Relative to control, 24-h ambulatory systolic (−1.3 mm Hg (−2.4, −0.3), P=0.016) and diastolic (−1.0 mm Hg (−1.9, −0.2), P=0.021) blood pressures were lower at 12 months but not at 4 months; fasting insulin concentrations and homeostasis model assessment (HOMA) scores were significantly lower at 4 months (−1.2 mU l–1 (−1.3, −1.1), P=0.004 and −0.6 units (−1.0, −0.19), P=0.004) and 12 months (−1.3 mU l–1 (−1.4, −1.1), P<0.001 and −0.7 units (−1.1, −0.24), P=0.002).
Conclusions:
A diet higher in protein and fibre derived from lupin-enriched foods does not enhance weight loss or improve the maintenance of weight loss. However, such a diet may provide cardiovascular health benefits in terms of insulin sensitivity and blood pressure.
Vascular reactivity at rest and during exercise in middle-aged obese men: effects of short-term, low-intensity, exercise training
International Journal of Obesity 35, 820-828 (June 2011) | doi:10.1038/ijo.2010.206
Objective:
Although increased blood flow (BF) in exercising muscles is thought to be impaired in obese subjects and may contribute to physical inactivity, data are scarce in this regard and the involvement of endothelium dysfunction remains partly hypothetical.
Methods:
A total of 16 middle-aged obese men (body mass index, BMI30 kg m−2) and 16 normal-weight men (BMI<25 kg m−2), matched for age, were recruited. We used ultrasonography to compare intima-media thickness (IMT) and distensibility of the carotid artery, flow-mediated dilation (FMD), nitrate-dependent dilation (NDD) and peak BF during post-ischemic hyperemia in the brachial artery (a conduit artery), and leg BF during knee-extensor exercise (indicative of resistance vessel function) in obese and in normal-weight men. In addition, 10 obese men participated in an 8 week individualized low-intensity training program.
Results:
Compared with normal-weight men, obese men had higher carotid IMT (0.50±0.01 vs 0.62±0.04 mm, P<0.05) but lower carotid distensibility (0.26±0.03 vs 0.11±0.03 mm Hg−1 10−2, P<0.05), FMD (5.7±0.4 vs 3.3±0.5%, P<0.05) and peak BF during post-ischemic hyperemia (398±52 vs 229±24%, P<0.05), despite similar maximal shear rate, without NDD differences. Lower limb BF (ml min−1 100 g−1) increased significantly from rest to maximal exercise in both groups with lower values in obese men (at peak power, 36.9±1.6 vs 31.5+2.2 ml min−1 100 g−1, P<0.05). Exercise training normalized carotid distensibility (0.14±0.04 before vs 0.23±0.03 mm Hg−1 10−2 after training, P=0.09) and FMD (2.7±0.4 before vs 4.8±0.5% after training, P<0.05), but did not improve brachial post-ischemic peak BF or exercising leg BF.
Conclusions:
In obese men, conduit and resistance vessel reactivity is depressed, but a short-term low-intensity exercise training improves distensibility and endothelium dependent vasodilation in the large conduit artery, but not post ischemic or exercise muscle BF.
Objective:
Although increased blood flow (BF) in exercising muscles is thought to be impaired in obese subjects and may contribute to physical inactivity, data are scarce in this regard and the involvement of endothelium dysfunction remains partly hypothetical.
Methods:
A total of 16 middle-aged obese men (body mass index, BMI30 kg m−2) and 16 normal-weight men (BMI<25 kg m−2), matched for age, were recruited. We used ultrasonography to compare intima-media thickness (IMT) and distensibility of the carotid artery, flow-mediated dilation (FMD), nitrate-dependent dilation (NDD) and peak BF during post-ischemic hyperemia in the brachial artery (a conduit artery), and leg BF during knee-extensor exercise (indicative of resistance vessel function) in obese and in normal-weight men. In addition, 10 obese men participated in an 8 week individualized low-intensity training program.
Results:
Compared with normal-weight men, obese men had higher carotid IMT (0.50±0.01 vs 0.62±0.04 mm, P<0.05) but lower carotid distensibility (0.26±0.03 vs 0.11±0.03 mm Hg−1 10−2, P<0.05), FMD (5.7±0.4 vs 3.3±0.5%, P<0.05) and peak BF during post-ischemic hyperemia (398±52 vs 229±24%, P<0.05), despite similar maximal shear rate, without NDD differences. Lower limb BF (ml min−1 100 g−1) increased significantly from rest to maximal exercise in both groups with lower values in obese men (at peak power, 36.9±1.6 vs 31.5+2.2 ml min−1 100 g−1, P<0.05). Exercise training normalized carotid distensibility (0.14±0.04 before vs 0.23±0.03 mm Hg−1 10−2 after training, P=0.09) and FMD (2.7±0.4 before vs 4.8±0.5% after training, P<0.05), but did not improve brachial post-ischemic peak BF or exercising leg BF.
Conclusions:
In obese men, conduit and resistance vessel reactivity is depressed, but a short-term low-intensity exercise training improves distensibility and endothelium dependent vasodilation in the large conduit artery, but not post ischemic or exercise muscle BF.
Meal size can be decreased in obese subjects through pharmacological acceleration of gastric emptying (The OBERYTH trial)
International Journal of Obesity 35, 829-837 (June 2011) | doi:10.1038/ijo.2010.210
Background:
Entry of nutrients into the small intestine activates neuro-hormonal signals that regulate food intake through induction of satiation.
Objective:
To evaluate whether caloric intake can be decreased by pharmacologically accelerating gastric emptying (GE) of nutrients into the small intestine.
Methods:
Subjects were tested in 2 days, at baseline (day1) and after randomly receiving, in a double-blind manner, a 1 h infusion of erythromycin (3 mg Kg−1, to accelerate GE) or placebo (day 2). Ad libitum caloric intake and postprandial gastrointestinal symptoms were evaluated using a validated nutrient drink test, simultaneously measuring gastric by scintigraphy. Plasma levels of satiation factors were also measured to evaluate their role in the modification of caloric intake and postprandial symptoms. Acceleration of GE was assessed as the difference in percentage emptied between day 2 and day 1 (DGE). The effects of DGE on caloric intake and symptoms were evaluated using multiple (lineal) regression.
Results:
Among 30 overweight/obese subjects (24F and 6 M), 15 received erythromycin and 15 placebo. The overall median age was 36 years (IQR: 30–42) and body mass index was 30 Kg m−2 (IQR: 27–36). Subjects receiving erythromycin on day 2 presented accelerated GE as compared with placebo (P=0.0002). DGE at 15 min after initiating eating had a significant effect on prospective caloric intake (P=0.004). From the best-fitted regression model (R 2=81%, P<0.0001), a 10% increase in GE at 15 min induced on an average a 135±43.5 Kcal decrease in caloric intake. Postprandial increase in cholecystokinin (CCK) (P=0.03) and insulin (P=0.02) was associated with decreased caloric intake. Acceleration of GE at 60 min after initiating eating increased postprandial symptom scores measured 30 min after the completion of food consumption (P=0.01). Postprandial increase in CCK (P=0.002) and PP (P=0.02) was associated with postprandial symptoms.
Conclusion:
Meal size can be reduced in overweight/obese subjects by pharmacologically accelerating GE. This may be a reasonable target in obesity management.
Background:
Entry of nutrients into the small intestine activates neuro-hormonal signals that regulate food intake through induction of satiation.
Objective:
To evaluate whether caloric intake can be decreased by pharmacologically accelerating gastric emptying (GE) of nutrients into the small intestine.
Methods:
Subjects were tested in 2 days, at baseline (day1) and after randomly receiving, in a double-blind manner, a 1 h infusion of erythromycin (3 mg Kg−1, to accelerate GE) or placebo (day 2). Ad libitum caloric intake and postprandial gastrointestinal symptoms were evaluated using a validated nutrient drink test, simultaneously measuring gastric by scintigraphy. Plasma levels of satiation factors were also measured to evaluate their role in the modification of caloric intake and postprandial symptoms. Acceleration of GE was assessed as the difference in percentage emptied between day 2 and day 1 (DGE). The effects of DGE on caloric intake and symptoms were evaluated using multiple (lineal) regression.
Results:
Among 30 overweight/obese subjects (24F and 6 M), 15 received erythromycin and 15 placebo. The overall median age was 36 years (IQR: 30–42) and body mass index was 30 Kg m−2 (IQR: 27–36). Subjects receiving erythromycin on day 2 presented accelerated GE as compared with placebo (P=0.0002). DGE at 15 min after initiating eating had a significant effect on prospective caloric intake (P=0.004). From the best-fitted regression model (R 2=81%, P<0.0001), a 10% increase in GE at 15 min induced on an average a 135±43.5 Kcal decrease in caloric intake. Postprandial increase in cholecystokinin (CCK) (P=0.03) and insulin (P=0.02) was associated with decreased caloric intake. Acceleration of GE at 60 min after initiating eating increased postprandial symptom scores measured 30 min after the completion of food consumption (P=0.01). Postprandial increase in CCK (P=0.002) and PP (P=0.02) was associated with postprandial symptoms.
Conclusion:
Meal size can be reduced in overweight/obese subjects by pharmacologically accelerating GE. This may be a reasonable target in obesity management.
Association between attention-deficit/hyperactivity disorder symptoms and obesity and hypertension in early adulthood: a population-based study
International Journal of Obesity 35, 852-862 (June 2011) | doi:10.1038/ijo.2010.214
Objective:
To examine the associations between attention-deficit/hyperactivity disorder (ADHD) symptoms, obesity and hypertension in young adults in a large population-based cohort.
Design, Setting and Participants:
The study population consisted of 15 197 respondents from the National Longitudinal Study of Adolescent Health, a nationally representative sample of adolescents followed from 1995 to 2009 in the United States. Multinomial logistic and logistic models examined the odds of overweight, obesity and hypertension in adulthood in relation to retrospectively reported ADHD symptoms. Latent curve modeling was used to assess the association between symptoms and naturally occurring changes in body mass index (BMI) from adolescence to adulthood.
Results:
Linear association was identified between the number of inattentive (IN) and hyperactive/impulsive (HI) symptoms and waist circumference, BMI, diastolic blood pressure and systolic blood pressure (all P-values for trend <0.05). Controlling for demographic variables, physical activity, alcohol use, smoking and depressive symptoms, those with three or more HI or IN symptoms had the highest odds of obesity (HI 3+, odds ratio (OR)=1.50, 95% confidence interval (CI)=1.22−2.83; IN 3+, OR=1.21, 95% CI=1.02−1.44) compared with those with no HI or IN symptoms. HI symptoms at the 3+ level were significantly associated with a higher OR of hypertension (HI 3+, OR=1.24, 95% CI=1.01−1.51; HI continuous, OR=1.04, 95% CI=1.00−1.09), but associations were nonsignificant when models were adjusted for BMI. Latent growth modeling results indicated that compared with those reporting no HI or IN symptoms, those reporting 3 or more symptoms had higher initial levels of BMI during adolescence. Only HI symptoms were associated with change in BMI.
Conclusion:
Self-reported ADHD symptoms were associated with adult BMI and change in BMI from adolescence to adulthood, providing further evidence of a link between ADHD symptoms and obesity.
Objective:
To examine the associations between attention-deficit/hyperactivity disorder (ADHD) symptoms, obesity and hypertension in young adults in a large population-based cohort.
Design, Setting and Participants:
The study population consisted of 15 197 respondents from the National Longitudinal Study of Adolescent Health, a nationally representative sample of adolescents followed from 1995 to 2009 in the United States. Multinomial logistic and logistic models examined the odds of overweight, obesity and hypertension in adulthood in relation to retrospectively reported ADHD symptoms. Latent curve modeling was used to assess the association between symptoms and naturally occurring changes in body mass index (BMI) from adolescence to adulthood.
Results:
Linear association was identified between the number of inattentive (IN) and hyperactive/impulsive (HI) symptoms and waist circumference, BMI, diastolic blood pressure and systolic blood pressure (all P-values for trend <0.05). Controlling for demographic variables, physical activity, alcohol use, smoking and depressive symptoms, those with three or more HI or IN symptoms had the highest odds of obesity (HI 3+, odds ratio (OR)=1.50, 95% confidence interval (CI)=1.22−2.83; IN 3+, OR=1.21, 95% CI=1.02−1.44) compared with those with no HI or IN symptoms. HI symptoms at the 3+ level were significantly associated with a higher OR of hypertension (HI 3+, OR=1.24, 95% CI=1.01−1.51; HI continuous, OR=1.04, 95% CI=1.00−1.09), but associations were nonsignificant when models were adjusted for BMI. Latent growth modeling results indicated that compared with those reporting no HI or IN symptoms, those reporting 3 or more symptoms had higher initial levels of BMI during adolescence. Only HI symptoms were associated with change in BMI.
Conclusion:
Self-reported ADHD symptoms were associated with adult BMI and change in BMI from adolescence to adulthood, providing further evidence of a link between ADHD symptoms and obesity.
Phenotypic and genetic variation in leptin as determinants of weight regain
International Journal of Obesity 35, 785-792 (June 2011) | doi:10.1038/ijo.2010.217
Aims:
Over 75% of obese subjects fail to maintain their weight following weight loss interventions. We aimed to identify phenotypic and genetic markers associated with weight maintenance/regain following a dietary intervention.
Subjects and methods:
In the 2-year Dietary Intervention Randomized Controlled Trial, we assessed potential predictors for weight changes during the ‘weight loss phase’ (0–6 months) and the ‘weight maintenance/regain phase’ (7–24 months). Genetic variation between study participants was studied using single-nucleotide polymorphisms in the leptin gene (LEP).
Results:
Mean weight reduction was −5.5% after 6 months, with a mean weight regain of 1.2% of baseline weight during the subsequent 7–24 months. In a multivariate regression model, higher baseline high-molecular-weight adiponectin was the only biomarker predictor of greater success in 0- to 6-month weight loss (β=−0.222, P-value=0.044). In a multivariate regression model adjusted for 6-month changes in weight and various biomarkers, 6-month plasma leptin reduction exhibited the strongest positive association with 6-month weight loss (β=0.505, P-value<0.001). Conversely, 6-month plasma leptin reduction independently predicted weight regain during the following 18 months (β=−0.131, P-value<0.013). Weight regain was higher among participants who had a greater (top tertiles) 6-month decrease in both weight and leptin (+3.4% (95% confidence interval 2.1–4.8)) as compared with those in the lowest combined tertiles (+0.2% (95% confidence interval −1.1 to 1.4)); P-value<0.001. Weight regain was further significantly and independently associated with genetic variations in LEP (P=0.006 for both rs4731426 and rs2071045). Adding genetic data to the phenotypic multivariate model increased its predictive value for weight regain by 34%.
Conclusion:
Although greater reduction in leptin concentrations during the initial phase of a dietary intervention is associated with greater weight loss in the short term, plasma leptin reduction, combined with the degree of initial weight loss and with genetic variations in the LEP gene, constitutes a significant predictor of subsequent long-term weight regain.
Aims:
Over 75% of obese subjects fail to maintain their weight following weight loss interventions. We aimed to identify phenotypic and genetic markers associated with weight maintenance/regain following a dietary intervention.
Subjects and methods:
In the 2-year Dietary Intervention Randomized Controlled Trial, we assessed potential predictors for weight changes during the ‘weight loss phase’ (0–6 months) and the ‘weight maintenance/regain phase’ (7–24 months). Genetic variation between study participants was studied using single-nucleotide polymorphisms in the leptin gene (LEP).
Results:
Mean weight reduction was −5.5% after 6 months, with a mean weight regain of 1.2% of baseline weight during the subsequent 7–24 months. In a multivariate regression model, higher baseline high-molecular-weight adiponectin was the only biomarker predictor of greater success in 0- to 6-month weight loss (β=−0.222, P-value=0.044). In a multivariate regression model adjusted for 6-month changes in weight and various biomarkers, 6-month plasma leptin reduction exhibited the strongest positive association with 6-month weight loss (β=0.505, P-value<0.001). Conversely, 6-month plasma leptin reduction independently predicted weight regain during the following 18 months (β=−0.131, P-value<0.013). Weight regain was higher among participants who had a greater (top tertiles) 6-month decrease in both weight and leptin (+3.4% (95% confidence interval 2.1–4.8)) as compared with those in the lowest combined tertiles (+0.2% (95% confidence interval −1.1 to 1.4)); P-value<0.001. Weight regain was further significantly and independently associated with genetic variations in LEP (P=0.006 for both rs4731426 and rs2071045). Adding genetic data to the phenotypic multivariate model increased its predictive value for weight regain by 34%.
Conclusion:
Although greater reduction in leptin concentrations during the initial phase of a dietary intervention is associated with greater weight loss in the short term, plasma leptin reduction, combined with the degree of initial weight loss and with genetic variations in the LEP gene, constitutes a significant predictor of subsequent long-term weight regain.
Central regulation of feeding behavior during social isolation of rat: evidence for the role of endogenous CART system
International Journal of Obesity 35, 773-784 (June 2011) | doi:10.1038/ijo.2010.231
Objective:
Although hyperphagia and body weight gain are well-recognized consequences of social isolation, the underlying mechanisms are not understood. The aim of this work is to test the possibility that the endogenous cocaine- and amphetamine-regulated transcript peptide (CART) may be involved in the process.
Design:
Socially isolated rats were screened for increase in food intake and body weight, and the modifications of these parameters by CART were evaluated. Furthermore, isolated animals were re-socialized and screened for reversal of these effects. Response of the endogenous CART system, in certain hypothalamic nuclei of the isolated and re-socialized rats, was evaluated with immunohistochemistry.
Subjects:
Fifty days old naive male Sprague–Dawley rats were used.
Measurements:
The effects of CART/CART antibody on the social isolation and subsequent re-socialization on feeding and body weight changes were monitored. Moreover, the immunohistochemical response of endogenous CART system to social isolation and re-socialization was analyzed morphometrically.
Results:
While social isolation of rats for a period of 6 weeks caused progressive increase in food consumption and body weight gain, these rats showed a significant reduction in food intake and body weight when injected daily with CART via intracerebroventricular (i.c.v.) route, for the following 7 days. The re-socialization of isolated rats reduced food intake and body weight to the control levels. These effects of re-socialization were attenuated by immunoneutralization of the endogenous CART by i.c.v. CART antibody. Social isolation also resulted in a drastic reduction in CART immunoreactivity in the cells and/or fibers in the hypothalamic areas like dorsomedial, ventromedial, lateral, paraventricular and arcuate nuclei, recognized for their role in feeding. On the other hand, the CART immunoreactivity profile was fully restored following 7 days of re-socialization of the isolation-reared rats.
Conclusion:
Social isolation might down-regulate the hypothalamic CART-containing system, which in turn may lead to increase in food intake and body weight.
Objective:
Although hyperphagia and body weight gain are well-recognized consequences of social isolation, the underlying mechanisms are not understood. The aim of this work is to test the possibility that the endogenous cocaine- and amphetamine-regulated transcript peptide (CART) may be involved in the process.
Design:
Socially isolated rats were screened for increase in food intake and body weight, and the modifications of these parameters by CART were evaluated. Furthermore, isolated animals were re-socialized and screened for reversal of these effects. Response of the endogenous CART system, in certain hypothalamic nuclei of the isolated and re-socialized rats, was evaluated with immunohistochemistry.
Subjects:
Fifty days old naive male Sprague–Dawley rats were used.
Measurements:
The effects of CART/CART antibody on the social isolation and subsequent re-socialization on feeding and body weight changes were monitored. Moreover, the immunohistochemical response of endogenous CART system to social isolation and re-socialization was analyzed morphometrically.
Results:
While social isolation of rats for a period of 6 weeks caused progressive increase in food consumption and body weight gain, these rats showed a significant reduction in food intake and body weight when injected daily with CART via intracerebroventricular (i.c.v.) route, for the following 7 days. The re-socialization of isolated rats reduced food intake and body weight to the control levels. These effects of re-socialization were attenuated by immunoneutralization of the endogenous CART by i.c.v. CART antibody. Social isolation also resulted in a drastic reduction in CART immunoreactivity in the cells and/or fibers in the hypothalamic areas like dorsomedial, ventromedial, lateral, paraventricular and arcuate nuclei, recognized for their role in feeding. On the other hand, the CART immunoreactivity profile was fully restored following 7 days of re-socialization of the isolation-reared rats.
Conclusion:
Social isolation might down-regulate the hypothalamic CART-containing system, which in turn may lead to increase in food intake and body weight.
Pigment epithelium-derived factor (PEDF) is one of the most abundant proteins secreted by human adipocytes and induces insulin resistance and inflammatory signaling in muscle and fat cells
International Journal of Obesity 35, 762-772 (June 2011) | doi:10.1038/ijo.2010.212
Objective:
Pigment epithelium-derived factor (PEDF) is a multifunctional protein with neurotrophic and anti-angiogenic properties. More recently it became evident that PEDF is upregulated in patients with type 2 diabetes and also contributes to insulin resistance in mice. During characterization of the secretome of in vitro differentiated human adipocytes by two-dimensional polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization-MS, we found that PEDF is one of the most abundant proteins released by adipocytes. The aim of this study was to investigate the regulation and autocrine function of PEDF in human adipocytes and to determine its paracrine effects on human skeletal muscle cells (hSkMC) and human smooth muscle cells (hSMC).d
Methods and results:
Human primary adipocytes secrete 130 ng ml−1 PEDF over 24 h from 1 million cells, which is extremely high as compared with adiponectin, interleukin-6 (IL-6) or IL-8. This release of PEDF is significantly higher than from other primary cells, such as adipose-tissue located macrophages (50-times), hSkMC and hSMC (5-times). PEDF protein expression significantly increases during adipogenesis, which is paralleled by increased PEDF secretion. Furthermore, tumor necrosis factor-α and hypoxia significantly downregulate PEDF protein levels. PEDF secretion was significantly reduced by troglitazone and hypoxia and significantly increased by insulin. Treatment of adipocytes and hSkMC with PEDF induced insulin resistance in adipocytes, skeletal and smooth muscle cells at the level of insulin-stimulated Akt phosphorylation, which was dose dependent and more prominent in adipocytes. Furthermore, inflammatory nuclear factor-κB (NF-κB) signaling was induced by PEDF. In hSMC, PEDF induced proliferation (1.7-fold) and acutely activated proliferative and inflammatory signaling pathways (NF-κB, p38 mitogen-activated protein kinase and mammalian target of rapamycin).
Conclusion:
PEDF is one of the most abundant adipokines and its secretion is inversely regulated by insulin and hypoxia. PEDF induces insulin resistance in adipocytes and hSkMC and leads to inflammatory signaling in hSMC. Because of these diverse actions, PEDF is a key adipokine, which could have an important role in diabetes and obesity-related disorders.
Objective:
Pigment epithelium-derived factor (PEDF) is a multifunctional protein with neurotrophic and anti-angiogenic properties. More recently it became evident that PEDF is upregulated in patients with type 2 diabetes and also contributes to insulin resistance in mice. During characterization of the secretome of in vitro differentiated human adipocytes by two-dimensional polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization-MS, we found that PEDF is one of the most abundant proteins released by adipocytes. The aim of this study was to investigate the regulation and autocrine function of PEDF in human adipocytes and to determine its paracrine effects on human skeletal muscle cells (hSkMC) and human smooth muscle cells (hSMC).d
Methods and results:
Human primary adipocytes secrete 130 ng ml−1 PEDF over 24 h from 1 million cells, which is extremely high as compared with adiponectin, interleukin-6 (IL-6) or IL-8. This release of PEDF is significantly higher than from other primary cells, such as adipose-tissue located macrophages (50-times), hSkMC and hSMC (5-times). PEDF protein expression significantly increases during adipogenesis, which is paralleled by increased PEDF secretion. Furthermore, tumor necrosis factor-α and hypoxia significantly downregulate PEDF protein levels. PEDF secretion was significantly reduced by troglitazone and hypoxia and significantly increased by insulin. Treatment of adipocytes and hSkMC with PEDF induced insulin resistance in adipocytes, skeletal and smooth muscle cells at the level of insulin-stimulated Akt phosphorylation, which was dose dependent and more prominent in adipocytes. Furthermore, inflammatory nuclear factor-κB (NF-κB) signaling was induced by PEDF. In hSMC, PEDF induced proliferation (1.7-fold) and acutely activated proliferative and inflammatory signaling pathways (NF-κB, p38 mitogen-activated protein kinase and mammalian target of rapamycin).
Conclusion:
PEDF is one of the most abundant adipokines and its secretion is inversely regulated by insulin and hypoxia. PEDF induces insulin resistance in adipocytes and hSkMC and leads to inflammatory signaling in hSMC. Because of these diverse actions, PEDF is a key adipokine, which could have an important role in diabetes and obesity-related disorders.
Efficacy of and resistance to anti-IGF-1R therapies in Ewing's sarcoma is dependent on insulin receptor signaling
Oncogene 30, 2730-2740 (16 June 2011) | doi:10.1038/onc.2010.640
Identification of patient selection criteria and understanding of the potential mechanisms involved in the development of resistance are crucial for an appropriate and successful design of clinical trials with anti-insulin-like growth factor (IGF)-1R therapies. Few Ewing's sarcomas are highly sensitive to IGF-1R targeting and understanding the reason why, may hold the secret to improve successful treatments. In this paper, we show that a major mechanism of resistance to highly specific inhibitors of IGF-1R, either antibodies or tyrosine kinase inhibitors may involve enhanced insulin receptor (IR)-A homodimer formation and IGF-2 production. Resistant cells are able to switch from IGF-1/IGF-1R to IGF-2/IR-A dependency to maintain sustained activation of AKT and ERK1/2, proliferation, migration and metastasis. These cells also showed higher proliferative response to insulin, in keeping with a switch towards insulin pathways sustaining proliferation and malignancy, rather than metabolism. Our findings demonstrate a role for IR-A in eliciting intrinsic and adaptive resistance to anti-IGF-1R therapies. Thus, we indicate that tumors with low IGF-1R:IR ratio are unlikely to greatly benefit from anti-IGF-1R therapies and that the efficacy of anti-IGF-1R therapies should be evaluated in relationship to the IR-A:IGF-1R ratio in cancer cells. Moreover, we provide evidences supporting IR-A as an important target in sarcoma therapy.
Identification of patient selection criteria and understanding of the potential mechanisms involved in the development of resistance are crucial for an appropriate and successful design of clinical trials with anti-insulin-like growth factor (IGF)-1R therapies. Few Ewing's sarcomas are highly sensitive to IGF-1R targeting and understanding the reason why, may hold the secret to improve successful treatments. In this paper, we show that a major mechanism of resistance to highly specific inhibitors of IGF-1R, either antibodies or tyrosine kinase inhibitors may involve enhanced insulin receptor (IR)-A homodimer formation and IGF-2 production. Resistant cells are able to switch from IGF-1/IGF-1R to IGF-2/IR-A dependency to maintain sustained activation of AKT and ERK1/2, proliferation, migration and metastasis. These cells also showed higher proliferative response to insulin, in keeping with a switch towards insulin pathways sustaining proliferation and malignancy, rather than metabolism. Our findings demonstrate a role for IR-A in eliciting intrinsic and adaptive resistance to anti-IGF-1R therapies. Thus, we indicate that tumors with low IGF-1R:IR ratio are unlikely to greatly benefit from anti-IGF-1R therapies and that the efficacy of anti-IGF-1R therapies should be evaluated in relationship to the IR-A:IGF-1R ratio in cancer cells. Moreover, we provide evidences supporting IR-A as an important target in sarcoma therapy.
The human DEK oncogene stimulates β-catenin signaling, invasion and mammosphere formation in breast cancer
Oncogene 30, 2741-2752 (16 June 2011) | doi:10.1038/onc.2011.2
Breast cancer is a major cause of cancer-related deaths in American women; therefore, the identification of novel breast cancer-related molecules for the discovery of new markers and drug targets remains essential. The human DEK gene, which encodes a chromatin-binding protein and DNA topology regulator, is upregulated in many types of cancer. DEK has been implicated as an oncogene in breast cancer based on mRNA expression studies, but its functional significance in breast cancer growth and progression has not yet been tested directly. We demonstrate that DEK is highly expressed in breast cancer cells compared with normal tissue, and functionally important for cellular growth, invasion and mammosphere formation. DEK overexpression in non-tumorigenic MCF10A cells resulted in increased growth and motility, with a concomitant downregulation of E-cadherin. Conversely, DEK knockdown in MCF7 and MDA-MB-468 breast cancer cells resulted in decreased growth and motility with upregulation of E-cadherin. The use of DEK-proficient and -deficient breast cancer cells in orthotopic xenografts provided further in vivo evidence that DEK contributes to tumor growth. Activation of the β-catenin signaling pathway is important for normal and cancer stem cell character, growth and metastasis. We show that DEK expression stimulated, and DEK knockdown repressed β-catenin nuclear translocation and activity. Importantly, the expression of constitutively active β-catenin rescued breast cancer invasion defects of DEK knockdown cells. Together, our data indicate that DEK expression stimulates the growth, stem cell character and motility of breast cancer cells, and that DEK-dependent cellular invasion occurs at least in part via β-catenin activation.
Breast cancer is a major cause of cancer-related deaths in American women; therefore, the identification of novel breast cancer-related molecules for the discovery of new markers and drug targets remains essential. The human DEK gene, which encodes a chromatin-binding protein and DNA topology regulator, is upregulated in many types of cancer. DEK has been implicated as an oncogene in breast cancer based on mRNA expression studies, but its functional significance in breast cancer growth and progression has not yet been tested directly. We demonstrate that DEK is highly expressed in breast cancer cells compared with normal tissue, and functionally important for cellular growth, invasion and mammosphere formation. DEK overexpression in non-tumorigenic MCF10A cells resulted in increased growth and motility, with a concomitant downregulation of E-cadherin. Conversely, DEK knockdown in MCF7 and MDA-MB-468 breast cancer cells resulted in decreased growth and motility with upregulation of E-cadherin. The use of DEK-proficient and -deficient breast cancer cells in orthotopic xenografts provided further in vivo evidence that DEK contributes to tumor growth. Activation of the β-catenin signaling pathway is important for normal and cancer stem cell character, growth and metastasis. We show that DEK expression stimulated, and DEK knockdown repressed β-catenin nuclear translocation and activity. Importantly, the expression of constitutively active β-catenin rescued breast cancer invasion defects of DEK knockdown cells. Together, our data indicate that DEK expression stimulates the growth, stem cell character and motility of breast cancer cells, and that DEK-dependent cellular invasion occurs at least in part via β-catenin activation.
E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression
Oncogene 30, 2753-2766 (16 June 2011) | doi:10.1038/onc.2011.6
E-cadherin is a cell–cell adhesion protein and tumor suppressor that is silenced in many malignancies. E-cadherin is thought to suppress tumor cell growth by antagonizing β-catenin signaling. However, the role of E-cadherin in ovarian cancer progression is still controversial. In this study, we showed that loss of E-cadherin induced ovarian cancer cell growth and constitutive activation of phosphoinositide 3-kinase (PI3K)/Akt signaling by the inhibition of phosphatase and tensin homolog (PTEN) transcription through the downregulation of early growth response gene 1 (Egr1). In addition, immunofluorescence microscopy and T-cell factor promoter/luciferase reporter assays showed that E-cadherin loss was associated with enhanced nuclear β-catenin signaling. Constitutive activation of PI3K/Akt signaling reinforced nuclear β-catenin signaling by inactivating glycogen synthase kinase-3β indicating cross-talk between the PI3K/Akt and β-catenin signaling pathways. Finally, we found that E-cadherin negatively regulates tumor cell growth, in part, by positively regulating PTEN expression via β-catenin-mediated Egr1 regulation, thus influencing PI3K/Akt signaling. In summary, endogenous E-cadherin inhibits PI3K/Akt signaling by antagonizing β-catenin-Egr1-mediated repression of PTEN expression. Thus, the loss of E-cadherin itself may contribute to dysregulated PI3K/Akt signaling through its effects on PTEN, or it may exacerbate the frequent activation of PI3K/Akt signaling that occurs as a result of overexpression, mutation and/or amplification.
E-cadherin is a cell–cell adhesion protein and tumor suppressor that is silenced in many malignancies. E-cadherin is thought to suppress tumor cell growth by antagonizing β-catenin signaling. However, the role of E-cadherin in ovarian cancer progression is still controversial. In this study, we showed that loss of E-cadherin induced ovarian cancer cell growth and constitutive activation of phosphoinositide 3-kinase (PI3K)/Akt signaling by the inhibition of phosphatase and tensin homolog (PTEN) transcription through the downregulation of early growth response gene 1 (Egr1). In addition, immunofluorescence microscopy and T-cell factor promoter/luciferase reporter assays showed that E-cadherin loss was associated with enhanced nuclear β-catenin signaling. Constitutive activation of PI3K/Akt signaling reinforced nuclear β-catenin signaling by inactivating glycogen synthase kinase-3β indicating cross-talk between the PI3K/Akt and β-catenin signaling pathways. Finally, we found that E-cadherin negatively regulates tumor cell growth, in part, by positively regulating PTEN expression via β-catenin-mediated Egr1 regulation, thus influencing PI3K/Akt signaling. In summary, endogenous E-cadherin inhibits PI3K/Akt signaling by antagonizing β-catenin-Egr1-mediated repression of PTEN expression. Thus, the loss of E-cadherin itself may contribute to dysregulated PI3K/Akt signaling through its effects on PTEN, or it may exacerbate the frequent activation of PI3K/Akt signaling that occurs as a result of overexpression, mutation and/or amplification.
Onconase mediated NFKβ downregulation in malignant pleural mesothelioma
Oncogene 30, 2767-2777 (16 June 2011) | doi:10.1038/onc.2010.643
Treatment of malignant pleural mesothelioma (MPM) with Ranpirnase (Onconase) results in disruption of protein translation and cell apoptosis. We hypothesize that Onconase exerts an effect via downregulation of nuclear factor kappa B (NFKβ) by specific microRNAs (miRNAs) and that interference of this pathway could have implications for MPM resistance to chemotherapy. Three immortalized MPM cell lines (H2959, H2373 and H2591) were exposed to Onconase at 0–20 μg/ml. Cell counts were measured at 48 and 72 h. Gene expression in miRNA-enriched RNA was validated by reverse transcription–PCR (RT–PCR). The functional implications of miRNA expression were evaluated by transfecting miRNA mimics or inhibitors into MPM cell lines, and performing Matrigel invasion, cell proliferation, soft agar colony formation and scratch closure assays. Effects on NFKβ expression and downstream targets including ABC transporters, BCL-xl and IAP were assessed by RT–PCR and western blotting. Treatment with 20 μg/ml of Onconase significantly decreased cell count and invasion. Hsa-miR-17* was significantly upregulated and hsa-miR-30c was significantly downregulated by Onconase treatment in all cell lines. Forced expression of hsa-miR-17* mimic and hsa-miR-30c inhibitor each significantly decreased functional activity of Onconase in all assays. NFKB1 (p50) expression and downstream targets were also decreased with Onconase treatment, as well as with forced expression of miRNA mimic and inhibitors. Onconase treatment caused a significant decrease in cell proliferation, invasion and in expression of certain miRNAs. Recapitulation of the resultant miRNA expression pattern with hsa-miR-17* mimic and hsa-miR-30c inhibitor resulted in downregulation of NFKB1 and reduced malignant behavior in functional assays. Thus, Onconase likely exerts its antitumor effect through these miRNAs.
Treatment of malignant pleural mesothelioma (MPM) with Ranpirnase (Onconase) results in disruption of protein translation and cell apoptosis. We hypothesize that Onconase exerts an effect via downregulation of nuclear factor kappa B (NFKβ) by specific microRNAs (miRNAs) and that interference of this pathway could have implications for MPM resistance to chemotherapy. Three immortalized MPM cell lines (H2959, H2373 and H2591) were exposed to Onconase at 0–20 μg/ml. Cell counts were measured at 48 and 72 h. Gene expression in miRNA-enriched RNA was validated by reverse transcription–PCR (RT–PCR). The functional implications of miRNA expression were evaluated by transfecting miRNA mimics or inhibitors into MPM cell lines, and performing Matrigel invasion, cell proliferation, soft agar colony formation and scratch closure assays. Effects on NFKβ expression and downstream targets including ABC transporters, BCL-xl and IAP were assessed by RT–PCR and western blotting. Treatment with 20 μg/ml of Onconase significantly decreased cell count and invasion. Hsa-miR-17* was significantly upregulated and hsa-miR-30c was significantly downregulated by Onconase treatment in all cell lines. Forced expression of hsa-miR-17* mimic and hsa-miR-30c inhibitor each significantly decreased functional activity of Onconase in all assays. NFKB1 (p50) expression and downstream targets were also decreased with Onconase treatment, as well as with forced expression of miRNA mimic and inhibitors. Onconase treatment caused a significant decrease in cell proliferation, invasion and in expression of certain miRNAs. Recapitulation of the resultant miRNA expression pattern with hsa-miR-17* mimic and hsa-miR-30c inhibitor resulted in downregulation of NFKB1 and reduced malignant behavior in functional assays. Thus, Onconase likely exerts its antitumor effect through these miRNAs.
Integrin-linked kinase regulates melanoma angiogenesis by activating NF-κB/interleukin-6 signaling pathway
Oncogene 30, 2778-2788 (16 June 2011) | doi:10.1038/onc.2010.644
Integrin-linked kinase (ILK) is a highly conserved serine–threonine protein kinase involved in cell–extracellular matrix interactions, cytoskeletal organization and cell signaling. Overexpression of ILK in epithelial cells leads to anchorage-independent growth with increased cell cycle progression. Previously, we have shown that ILK upregulation strongly correlates with melanoma progression, invasion and inversely correlates with 5-year survival of melanoma patients. However, the molecular mechanism by which ILK enhances melanoma progression is currently unknown. In the present study, we found that proangiogenic molecule interleukin-6 (IL-6) is the downstream target of ILK in melanoma cells. ILK overexpression increased IL-6, whereas silencing of ILK suppressed IL-6 expression at both messenger RNA and protein levels. ILK also altered the activity and subcellular localization of nuclear factor-kappaB (NF-κB) subunit p65. We further found that ILK enhanced the IL-6 gene transcription by promoting the binding of NF-κB p65 to IL-6 promoter. Moreover, ILK overexpression in melanoma cells enhanced the tube-forming ability of endothelial cells in vitro and microvessel formation in vivo. ILK-induced tube and blood vessel formation of endothelial cells was significantly reduced upon IL-6 inhibition in ILK-overexpressing melanoma cells. To delineate the mechanism by which ILK-induced IL-6 production can enhance angiogenesis, further analysis of the downstream targets of IL-6 signaling showed an increased activity of the signal transducer and activator of transcription 3 (STAT3) in ILK-overexpressing cells. As STAT3 binds to vascular endothelial growth factor (VEGF) promoter, we found that VEGF levels were elevated in ILK-overexpressing cells and declined upon transfection of IL-6 small interfering RNA, suggesting that ILK may regulate VEGF expression through IL-6 pathway by activating STAT3.
Integrin-linked kinase (ILK) is a highly conserved serine–threonine protein kinase involved in cell–extracellular matrix interactions, cytoskeletal organization and cell signaling. Overexpression of ILK in epithelial cells leads to anchorage-independent growth with increased cell cycle progression. Previously, we have shown that ILK upregulation strongly correlates with melanoma progression, invasion and inversely correlates with 5-year survival of melanoma patients. However, the molecular mechanism by which ILK enhances melanoma progression is currently unknown. In the present study, we found that proangiogenic molecule interleukin-6 (IL-6) is the downstream target of ILK in melanoma cells. ILK overexpression increased IL-6, whereas silencing of ILK suppressed IL-6 expression at both messenger RNA and protein levels. ILK also altered the activity and subcellular localization of nuclear factor-kappaB (NF-κB) subunit p65. We further found that ILK enhanced the IL-6 gene transcription by promoting the binding of NF-κB p65 to IL-6 promoter. Moreover, ILK overexpression in melanoma cells enhanced the tube-forming ability of endothelial cells in vitro and microvessel formation in vivo. ILK-induced tube and blood vessel formation of endothelial cells was significantly reduced upon IL-6 inhibition in ILK-overexpressing melanoma cells. To delineate the mechanism by which ILK-induced IL-6 production can enhance angiogenesis, further analysis of the downstream targets of IL-6 signaling showed an increased activity of the signal transducer and activator of transcription 3 (STAT3) in ILK-overexpressing cells. As STAT3 binds to vascular endothelial growth factor (VEGF) promoter, we found that VEGF levels were elevated in ILK-overexpressing cells and declined upon transfection of IL-6 small interfering RNA, suggesting that ILK may regulate VEGF expression through IL-6 pathway by activating STAT3.
Combined effects of novel heat shock protein 90 inhibitor NVP-AUY922 and nilotinib in a random mutagenesis screen
Oncogene 30, 2789-2797 (16 June 2011) | doi:10.1038/onc.2011.3
To overcome imatinib resistance, more potent ABL tyrosine kinase inhibitors (TKIs), such as nilotinib and dasatinib have been developed, with demonstrable preclinical activity against most imatinib-resistant BCR–ABL kinase domain mutations, with the exception of T315I. However, imatinib-resistant patients already harboring mutations have a higher likelihood of developing further mutations under the selective pressure of potent ABL TKIs. NVP-AUY922 (Novartis) is a novel 4,5-diaryloxazole adenosine triphosphate-binding site heat shock protein 90 (HSP90) inhibitor, which has been shown to inhibit the chaperone function of HSP90 and deplete the levels of HSP90 client protein including BCR–ABL. In this study, we investigated the combined effects of AUY922 and nilotinib on random mutagenesis for BCR–ABL mutation (Blood, 109; 5011, 2007). Compared with single agents, combination with AUY922 and nilotinib was more effective at reducing the outgrowth of resistant cell clones. No outgrowth was observed in the presence of 2 μM of nilotinib and 20 nM of AUY922. The observed data from the isobologram indicated the synergistic effect of simultaneous exposure to AUY922 and nilotinib even in BaF3 cells expressing BCR–ABL mutants including T315I. In vivo studies also demonstrated that the combination of AUY922 and nilotinib prolonged the survival of mice transplanted with mixture of BaF3 cells expressing wild-type BCR–ABL and mutant forms. Taken together, this study shows that the combination of AUY922 and nilotinib exhibits a desirable therapeutic index that can reduce the in vivo growth of mutant forms of BCR–ABL-expressing cells.
To overcome imatinib resistance, more potent ABL tyrosine kinase inhibitors (TKIs), such as nilotinib and dasatinib have been developed, with demonstrable preclinical activity against most imatinib-resistant BCR–ABL kinase domain mutations, with the exception of T315I. However, imatinib-resistant patients already harboring mutations have a higher likelihood of developing further mutations under the selective pressure of potent ABL TKIs. NVP-AUY922 (Novartis) is a novel 4,5-diaryloxazole adenosine triphosphate-binding site heat shock protein 90 (HSP90) inhibitor, which has been shown to inhibit the chaperone function of HSP90 and deplete the levels of HSP90 client protein including BCR–ABL. In this study, we investigated the combined effects of AUY922 and nilotinib on random mutagenesis for BCR–ABL mutation (Blood, 109; 5011, 2007). Compared with single agents, combination with AUY922 and nilotinib was more effective at reducing the outgrowth of resistant cell clones. No outgrowth was observed in the presence of 2 μM of nilotinib and 20 nM of AUY922. The observed data from the isobologram indicated the synergistic effect of simultaneous exposure to AUY922 and nilotinib even in BaF3 cells expressing BCR–ABL mutants including T315I. In vivo studies also demonstrated that the combination of AUY922 and nilotinib prolonged the survival of mice transplanted with mixture of BaF3 cells expressing wild-type BCR–ABL and mutant forms. Taken together, this study shows that the combination of AUY922 and nilotinib exhibits a desirable therapeutic index that can reduce the in vivo growth of mutant forms of BCR–ABL-expressing cells.
Apoptosis and acute kidney injury
Kidney International 80, 29-40 (July (1) 2011) | doi:10.1038/ki.2011.120
Improved mechanistic understanding of renal cell death in acute kidney injury (AKI) has generated new therapeutic targets. Clearly, the classic lesion of acute tubular necrosis is not adequate to describe the consequences of renal ischemia, nephrotoxin exposure, or sepsis on glomerular filtration rate. Experimental evidence supports a pathogenic role for apoptosis in AKI. Interestingly, proximal tubule epithelial cells are highly susceptible to apoptosis, and injury at this site contributes to organ failure. During apoptosis, well-orchestrated events converge at the mitochondrion, the organelle that integrates life and death signals generated by the BCL2 (B-cell lymphoma 2) protein family. Death requires the ‘perfect storm’ for outer mitochondrial membrane injury to release its cellular ‘executioners’. The complexity of this process affords new targets for effective interventions, both before and after renal insults. Inhibiting apoptosis appears to be critical, because circulating factors released by the injured kidney induce apoptosis and inflammation in distant organs including the heart, lung, liver, and brain, potentially contributing to the high morbidity and mortality associated with AKI. Manipulation of known stress kinases upstream of mitochondrial injury, induction of endogenous, anti-apoptotic proteins, and improved understanding of the timing and consequences of renal cell apoptosis will inevitably improve the outcome of human AKI.
Improved mechanistic understanding of renal cell death in acute kidney injury (AKI) has generated new therapeutic targets. Clearly, the classic lesion of acute tubular necrosis is not adequate to describe the consequences of renal ischemia, nephrotoxin exposure, or sepsis on glomerular filtration rate. Experimental evidence supports a pathogenic role for apoptosis in AKI. Interestingly, proximal tubule epithelial cells are highly susceptible to apoptosis, and injury at this site contributes to organ failure. During apoptosis, well-orchestrated events converge at the mitochondrion, the organelle that integrates life and death signals generated by the BCL2 (B-cell lymphoma 2) protein family. Death requires the ‘perfect storm’ for outer mitochondrial membrane injury to release its cellular ‘executioners’. The complexity of this process affords new targets for effective interventions, both before and after renal insults. Inhibiting apoptosis appears to be critical, because circulating factors released by the injured kidney induce apoptosis and inflammation in distant organs including the heart, lung, liver, and brain, potentially contributing to the high morbidity and mortality associated with AKI. Manipulation of known stress kinases upstream of mitochondrial injury, induction of endogenous, anti-apoptotic proteins, and improved understanding of the timing and consequences of renal cell apoptosis will inevitably improve the outcome of human AKI.
Scar wars: mapping the fate of epithelial–mesenchymal–myofibroblast transition
Kidney International 80, 41-50 (July (1) 2011) | doi:10.1038/ki.2011.77
The hypothesis that epithelial–mesenchymal transition (EMT) might be a contributor to the accumulation of fibroblasts and myofibroblasts (MFs) in the kidney during fibrogenesis was postulated 15 years ago. This paradigm offered an elegant explanation of how the loss of epithelial functions is coupled to the gain of deleterious mesenchymal functions; for example, excessive matrix deposition. Moreover, it interpreted chronic kidney disease in a developmental context: because the tubular epithelium originates from the metanephric mesenchyme, EMT can be viewed as a dedifferentiation process in response to injury, which might serve healing or—if dysregulated—might facilitate fibrosis. Several observations support the role of EMT in renal fibrosis: (1) Tubular cells can transform to fibroblasts and MFs in vitro. (2) Histological ‘snapshots’ reveal the coexistence of epithelial and mesenchymal markers in transitioning tubular cells in fibrosis models and human kidney diseases. (3) Early lineage-tracing experiments detected mesenchymal markers in the genetically tagged epithelium. However, the paradigm has been recently challenged; new fate-mapping studies found no evidence for the expression of (myo)fibroblast markers in the epithelium during fibrogenesis. This review summarizes the key findings and caveats, aiming at a balanced view, which neither overestimates the role of the epithelium in MF generation nor denies the importance of epithelial plasticity in fibrogenesis.
The hypothesis that epithelial–mesenchymal transition (EMT) might be a contributor to the accumulation of fibroblasts and myofibroblasts (MFs) in the kidney during fibrogenesis was postulated 15 years ago. This paradigm offered an elegant explanation of how the loss of epithelial functions is coupled to the gain of deleterious mesenchymal functions; for example, excessive matrix deposition. Moreover, it interpreted chronic kidney disease in a developmental context: because the tubular epithelium originates from the metanephric mesenchyme, EMT can be viewed as a dedifferentiation process in response to injury, which might serve healing or—if dysregulated—might facilitate fibrosis. Several observations support the role of EMT in renal fibrosis: (1) Tubular cells can transform to fibroblasts and MFs in vitro. (2) Histological ‘snapshots’ reveal the coexistence of epithelial and mesenchymal markers in transitioning tubular cells in fibrosis models and human kidney diseases. (3) Early lineage-tracing experiments detected mesenchymal markers in the genetically tagged epithelium. However, the paradigm has been recently challenged; new fate-mapping studies found no evidence for the expression of (myo)fibroblast markers in the epithelium during fibrogenesis. This review summarizes the key findings and caveats, aiming at a balanced view, which neither overestimates the role of the epithelium in MF generation nor denies the importance of epithelial plasticity in fibrogenesis.
Relative contributions of mitochondria and NADPH oxidase to deoxycorticosterone acetate-salt hypertension in mice
Kidney International 80, 51-60 (July (1) 2011) | doi:10.1038/ki.2011.29
We assessed the relative contribution of the mitochondrial respiratory chain and NADPH (nicotinamide adenine dinucleotide phosphate) oxidase to deoxycorticosterone acetate (DOCA)-salt hypertension in mice. The daily mean arterial pressure was monitored by radiotelemetry in DOCA-salt-treated mice given vehicle or the mitochondrial respiratory chain complex I inhibitor rotenone. This treatment produced remarkable attenuation of DOCA-salt hypertension. Similar results were obtained with other inhibitors of mitochondrial function, including 5-hydroxydecanoate (specific for mitochondrial potassium-ATP channels), benzylguanidine (complexes I and III), and the cell-permeable manganese tetrakis (4-benzoic acid) porphyrin (a mimic of mitochondrial superoxide dismutase). In parallel with the blood pressure-lowering effect of rotenone, the DOCA-salt-induced increases in urinary 8-isoprostane excretion and in reactive oxygen species production of isolated kidney mitochondria were both significantly attenuated. Conversely, the DOCA-salt-induced reduction of urinary nitrate/nitrite excretion was significantly elevated. Following DOCA-salt treatment, mice deficient in NADPH oxidase subunits gp91phox or p47phox exhibited a partial attenuation of the hypertensive response at early but not later time points. Thus, the mitochondrial respiratory chain is a major source of oxidative stress in DOCA-salt hypertension, whereas NADPH oxidase may have a relatively minor role during the early stage of hypertension.
We assessed the relative contribution of the mitochondrial respiratory chain and NADPH (nicotinamide adenine dinucleotide phosphate) oxidase to deoxycorticosterone acetate (DOCA)-salt hypertension in mice. The daily mean arterial pressure was monitored by radiotelemetry in DOCA-salt-treated mice given vehicle or the mitochondrial respiratory chain complex I inhibitor rotenone. This treatment produced remarkable attenuation of DOCA-salt hypertension. Similar results were obtained with other inhibitors of mitochondrial function, including 5-hydroxydecanoate (specific for mitochondrial potassium-ATP channels), benzylguanidine (complexes I and III), and the cell-permeable manganese tetrakis (4-benzoic acid) porphyrin (a mimic of mitochondrial superoxide dismutase). In parallel with the blood pressure-lowering effect of rotenone, the DOCA-salt-induced increases in urinary 8-isoprostane excretion and in reactive oxygen species production of isolated kidney mitochondria were both significantly attenuated. Conversely, the DOCA-salt-induced reduction of urinary nitrate/nitrite excretion was significantly elevated. Following DOCA-salt treatment, mice deficient in NADPH oxidase subunits gp91phox or p47phox exhibited a partial attenuation of the hypertensive response at early but not later time points. Thus, the mitochondrial respiratory chain is a major source of oxidative stress in DOCA-salt hypertension, whereas NADPH oxidase may have a relatively minor role during the early stage of hypertension.
Decreased bone density and increased phosphaturia in gene-targeted mice lacking functional serum- and glucocorticoid-inducible kinase 3
Kidney International 80, 61-67 (July (1) 2011) | doi:10.1038/ki.2011.67
Insulin and growth factors activate the phosphatidylinositide-3-kinase pathway, leading to stimulation of several kinases including serum- and glucocorticoid-inducible kinase isoform SGK3, a transport regulating kinase. Here, we explored the contribution of SGK3 to the regulation of renal tubular phosphate transport. Coexpression of SGK3 and sodium-phosphate cotransporter IIa significantly enhanced the phosphate-induced current in Xenopus oocytes. In sgk3 knockout and wild-type mice on a standard diet, fluid intake, glomerular filtration and urine flow rates, and urinary calcium ion excretion were similar. However, fractional urinary phosphate excretion was slightly but significantly larger in the knockout than in wild-type mice. Plasma calcium ion, phosphate concentration, and plasma parathyroid hormone levels were not significantly different between the two genotypes, but plasma calcitriol and fibroblast growth factor 23 concentrations were significantly lower in the knockout than in wild-type mice. Moreover, bone density was significantly lower in the knockouts than in wild-type mice. Histological analysis of the femur did not show any differences in cortical bone but there was slightly less prominent trabecular bone in sgk3 knockout mice. Thus, SGK3 has a subtle but significant role in the regulation of renal tubular phosphate transport and bone density.
Insulin and growth factors activate the phosphatidylinositide-3-kinase pathway, leading to stimulation of several kinases including serum- and glucocorticoid-inducible kinase isoform SGK3, a transport regulating kinase. Here, we explored the contribution of SGK3 to the regulation of renal tubular phosphate transport. Coexpression of SGK3 and sodium-phosphate cotransporter IIa significantly enhanced the phosphate-induced current in Xenopus oocytes. In sgk3 knockout and wild-type mice on a standard diet, fluid intake, glomerular filtration and urine flow rates, and urinary calcium ion excretion were similar. However, fractional urinary phosphate excretion was slightly but significantly larger in the knockout than in wild-type mice. Plasma calcium ion, phosphate concentration, and plasma parathyroid hormone levels were not significantly different between the two genotypes, but plasma calcitriol and fibroblast growth factor 23 concentrations were significantly lower in the knockout than in wild-type mice. Moreover, bone density was significantly lower in the knockouts than in wild-type mice. Histological analysis of the femur did not show any differences in cortical bone but there was slightly less prominent trabecular bone in sgk3 knockout mice. Thus, SGK3 has a subtle but significant role in the regulation of renal tubular phosphate transport and bone density.
Aberrant glycosylation of IgA1 is inherited in both pediatric IgA nephropathy and Henoch–Schönlein purpura nephritis
Kidney International 80, 79-87 (July (1) 2011) | doi:10.1038/ki.2011.16
Serum galactose-deficient immunoglobulin A1 (Gd-IgA1) is an inherited risk factor for adult IgA nephropathy (IgAN). In this paper, we determined the heritability of serum Gd-IgA1 levels in children with IgAN and Henoch–Schönlein purpura nephritis (HSPN), two disorders with clinical phenotypes sharing common pathogenic mechanisms. Serum Gd-IgA1 concentrations were quantified using a Helix aspersa-lectin-based enzyme-linked immunosorbent assay. As a group, 34 children with either disorder (20 with HSPN and 14 with IgAN) had significantly higher Gd-IgA1 levels compared with 51 age- and ethnicity-matched pediatric controls. Serum levels of Gd-IgA1 were also elevated in a large fraction of 54 first-degree relatives of pediatric IgAN and HSPN patients compared with 141 unrelated healthy adult controls. A unilineal transmission of the trait was found in 17, bilineal transmission in 1, and sporadic occurrence in 5 of 23 families when both parents and the patient were analyzed. There was a significant age-, gender-, and household-adjusted heritability of serum galactose-deficient IgA1 estimated at 76% in pediatric IgAN and at 64% in HSPN patients. Thus, serum galactose-deficient IgA1 levels are highly inherited in pediatric patients with IgAN and HSPN, providing support for another shared pathogenic link between these disorders.
Serum galactose-deficient immunoglobulin A1 (Gd-IgA1) is an inherited risk factor for adult IgA nephropathy (IgAN). In this paper, we determined the heritability of serum Gd-IgA1 levels in children with IgAN and Henoch–Schönlein purpura nephritis (HSPN), two disorders with clinical phenotypes sharing common pathogenic mechanisms. Serum Gd-IgA1 concentrations were quantified using a Helix aspersa-lectin-based enzyme-linked immunosorbent assay. As a group, 34 children with either disorder (20 with HSPN and 14 with IgAN) had significantly higher Gd-IgA1 levels compared with 51 age- and ethnicity-matched pediatric controls. Serum levels of Gd-IgA1 were also elevated in a large fraction of 54 first-degree relatives of pediatric IgAN and HSPN patients compared with 141 unrelated healthy adult controls. A unilineal transmission of the trait was found in 17, bilineal transmission in 1, and sporadic occurrence in 5 of 23 families when both parents and the patient were analyzed. There was a significant age-, gender-, and household-adjusted heritability of serum galactose-deficient IgA1 estimated at 76% in pediatric IgAN and at 64% in HSPN patients. Thus, serum galactose-deficient IgA1 levels are highly inherited in pediatric patients with IgAN and HSPN, providing support for another shared pathogenic link between these disorders.
An intergenic region on chromosome 13q33.3 is associated with the susceptibility to kidney disease in type 1 and 2 diabetes
Kidney International 80, 105-111 (July (1) 2011) | doi:10.1038/ki.2011.64
A genome-wide association scan of the Genetics of Kidneys in Diabetes (GoKinD) collections identified four novel susceptibility loci, located on chromosomes 7p14.3, 9q21.32, 11p15.4, and 13q33.3 associated with type 1 diabetic nephropathy. A recent evaluation of these loci in Japanese patients with type 2 diabetes supported an association at the 13q33.3 locus.
To follow up these findings, we determined whether single-nucleotide polymorphisms (SNPs) at these same four loci were associated with diabetic nephropathy in the Joslin Study of Genetics of Nephropathy in Type 2 Diabetes collection. A total of 6 SNPs across these loci were genotyped in 646 normoalbuminuric controls and in 743 nephropathy patients of European ancestry. A significant association was identified at the 13q33.3 locus (rs9521445: P=4.4 × 10−3). At this same locus, rs1411766 was also significantly associated with type 2 diabetic nephropathy (P=0.03). Meta-analysis of these data with those of the Japanese and GoKinD collections significantly improved the strength of the association (P=9.7 × 10−9). In addition, there was a significant association at the 11p15.4 locus (rs451041: P=0.02). Thus, associations identified in the GoKinD collections on chromosomes 11p15.4 (near the CARS gene) and 13q33.3 (within an intergenic region between MYO16 and IRS2) are susceptibility loci of kidney disease common to both type 1 and 2 diabetes.
A genome-wide association scan of the Genetics of Kidneys in Diabetes (GoKinD) collections identified four novel susceptibility loci, located on chromosomes 7p14.3, 9q21.32, 11p15.4, and 13q33.3 associated with type 1 diabetic nephropathy. A recent evaluation of these loci in Japanese patients with type 2 diabetes supported an association at the 13q33.3 locus.
To follow up these findings, we determined whether single-nucleotide polymorphisms (SNPs) at these same four loci were associated with diabetic nephropathy in the Joslin Study of Genetics of Nephropathy in Type 2 Diabetes collection. A total of 6 SNPs across these loci were genotyped in 646 normoalbuminuric controls and in 743 nephropathy patients of European ancestry. A significant association was identified at the 13q33.3 locus (rs9521445: P=4.4 × 10−3). At this same locus, rs1411766 was also significantly associated with type 2 diabetic nephropathy (P=0.03). Meta-analysis of these data with those of the Japanese and GoKinD collections significantly improved the strength of the association (P=9.7 × 10−9). In addition, there was a significant association at the 11p15.4 locus (rs451041: P=0.02). Thus, associations identified in the GoKinD collections on chromosomes 11p15.4 (near the CARS gene) and 13q33.3 (within an intergenic region between MYO16 and IRS2) are susceptibility loci of kidney disease common to both type 1 and 2 diabetes.
Sunday, June 12, 2011
Peptidoglycan recognition proteins kill bacteria by activating protein-sensing two-component systems
Nature Medicine 17,676–683(2011) doi:10.1038/nm.2357
Mammalian peptidoglycan recognition proteins (PGRPs), similar to antimicrobial lectins, bind the bacterial cell wall and kill bacteria through an unknown mechanism. We show that PGRPs enter the Gram-positive cell wall at the site of daughter cell separation during cell division.
In Bacillus subtilis, PGRPs activate the CssR-CssS two-component system that detects and disposes of misfolded proteins that are usually exported out of bacterial cells. This activation results in membrane depolarization, cessation of intracellular peptidoglycan, protein, RNA and DNA synthesis, and production of hydroxyl radicals, which are responsible for bacterial death. PGRPs also bind the outer membrane of Escherichia coli and activate the functionally homologous CpxA-CpxR two-component system, which kills the bacteria.
We exclude other potential bactericidal mechanisms, including inhibition of extracellular peptidoglycan synthesis, hydrolysis of peptidoglycan and membrane permeabilization. Thus, we reveal a previously unknown mechanism by which innate immunity proteins that bind the cell wall or outer membrane exploit the bacterial stress defense response to kill bacteria.
Mouth-watering brown color of barbecue and baked goods is due to the non-enzymatic production of advanced glycation end products (AGEs).
Functional Glycomics (09 June 2011) | doi:10.1038/fg.2011.22
The solution structure of the RAGE V domain in complex with a glycated peptide indicates how this receptor can recognize a large variety of AGE ligands.
The mouth-watering brown color of barbecue and baked goods is due to the non-enzymatic production of advanced glycation end products (AGEs). Under stress conditions, these compounds are also produced endogenously on lysine and arginine side chains in proteins.
In particular, compounds such as Nε-carboxy-methyl-lysine (CML) and Nε-carboxy-ethyl-lysine (CEL) can cause inflammatory responses via a receptor called RAGE.
In fact, RAGE signaling has been linked to diseases such as chronic inflammation, diabetes, Alzheimer's and cancer. RAGE is a member of the immunoglobulin superfamily, with three extracellular immunoglobulin domains (V, C1 and C2), a transmembrane helix and a short cytoplasmic tail. AGE products bind exclusively to the V domain, and now Alexander Shekhtman and colleagues have made an important step in understanding this interaction at an atomic level.
The structural basis of AGE recognition by RAGE is still unclear. One obstacle for such studies has been the heterogeneity of AGE products, as glycation reactions can occur on almost any arginine or lysine residue in a protein, generating ligands with a huge diversity of primary, secondary and tertiary structures. On the other hand, it is known that free CEL and CML compounds cannot bind or activate RAGE on their own.
In a recent paper published in the journalStructure, Shekhtman and co-workers first characterize the binding of short peptides representing major glycation sites in human serum albumin, unmodified or modified with CML and CEL, to the V domain of RAGE, by monitoring the native tryptophan fluorescence. These binding experiments revealed that the CEL- or CML-containing peptides had overall similar affinities to RAGE. The authors went on to map the residues from RAGE V domain that are affected by interaction with the modified peptides, doing NMR chemical shift titrations. This analysis showed that the same residues are involved in binding to CEL and CML peptides.
The authors solved the solution structure of the V domain in complex with a peptide containing CEL. The structure revealed that the CEL peptide–binding site is relatively flat, which explains the ability of RAGE to recognize AGEs in different amino acid sequences, and it sits on a positively charged groove, consistent with its binding to negatively charged CEL or CML. The CEL moiety appears in an extended conformation and makes the most contacts with the receptor. The methyl group of CEL does not seem to contribute to the binding, as it points away from the binding site; CML lacks this methyl group and, indeed, exhibits a similar binding affinity for the V domain. The structure also shows that V domain residues Lys52 and Arg98 have an important role in ligand binding, an observation confirmed by mutagenesis. Finally, the authors show that the peptide backbone is necessary to provide stable binding with the V domain, with contacts made with the residue right beside CEL.
In summary, the functional and structural data presented provide insight into how RAGE can recognize such a wide array of modified proteins. In addition, the work opens a potential avenue for therapeutic intervention, as blocking ligand binding may be used to reduce or prevent RAGE signaling and inflammation.
Author:Inês Chen
Original research paper
- Xue, J. et al. Advanced glycation end product recognition by the receptor for AGEs. Structure 19, 722–732 (2011). | Article
Saturday, June 11, 2011
Migraine is among the most debilitating conditions in medicine
WSJ, June, 6, 2011
A migraine is among the most debilitating conditions in medicine—a blinding, throbbing pain that typically lasts between four and 72 hours. There is no cure.
Yet, a few hours or days before the dreaded headache sets in, subtle symptoms emerge: Some people feel unusually fatigued, cranky or anxious. Some have yawning jags. Others have food cravings or excessive thirst.
If migraine sufferers can learn to identify their particular warning signs, they may be able to head off the headache pain with medication or lifestyle changes before it begins, experts say.
"The holy grail of migraine treatment would be to have something you could take tonight to ward off an attack tomorrow," says neurologist Peter Goadsby, director of the headache program at the University of California-San Francisco. At a conference of the American Headache Society last week, he and other experts said these early symptoms may hold clues to what causes migraines in the first place.
Scientists have long known about this so-called premonitory phase, which occurs well before the better-known aura, the flashing lights and wavy lines that about 30% of migraine sufferers see shortly before the headache begins. Yet there have been only a handful of clinical trials treating patients in the premonitory stage—in part because the symptoms are so vague. Still, once patients know what to look for, many can identify some early warning signs.
"If you ask the average migraine sufferer, 'Do you have any symptoms a few hours before the headache starts?' about 30% will say yes," says Werner Becker, professor of neuroscience at the University of Calgary in Alberta. But given a list of 20 common signs, from changes in mood, appetite or energy to urinating frequently or yawning excessively, about 80% of patients will say, "Oh yes, I've noticed that," he says.
Dr. Becker says one of his patients frequently feels dizzy and loses her appetite about 6 p.m. and knows that an attack is imminent. She finds that taking the migraine drug rizatriptan—usually taken only after the headache starts—can ward it off. "If she doesn't take it, then the next morning, she wakes up with a full-blown migraine," Dr. Becker says.
Sheena Selvey, a 28-year old special-education teacher in Northbrook, Ill., says she knows a migraine is coming when co-workers say her neck muscles have tightened up. She rubs her neck with an essential peppermint oil until she can inject herself with Imitrex, another medication usually used to stop rather than prevent headache pain. She says such steps have helped reduce attacks to two or three times a month from three or four times a week.
Ben McKeeb, a 35-year-old nursing student in Bellingham, Wash., says his wife noticed that his forehead muscles tense up in the shape of a "V" a few hours before his headaches begin. "I can almost always catch that feeling, and if I do all the right things—stay hydrated, stay out of the sun, get plenty of sleep, don't work too hard—I probably won't get one," he says.
Nationwide, about 36 million Americans suffer from migraines. Although some people use the word very loosely, migraines are far more severe than a typical headache, last longer and tend to involve nausea, vomiting and sensitivity to light. Women are three times as likely as men to get migraines, and they've been diagnosed in children as young as 6 months. Migraines cost the country more than $20 billion a year in lost wages, disability payments and health-care bills, according to the American Headache Society, an organization of health-care professionals who specialize in headaches.
As many as half of all sufferers don't seek treatment, in part because they think there is little doctors can do for them. In fact, treatments are proliferating, including over-the-counter pain relievers for mild cases and a class of drugs called triptans typically used to stop migraine pain. For chronic migraines, doctors also prescribe beta blockers, antiseizure medications and antidepressants, but they have significant side effects and help only about 50% of patients about 50% of the time. More drugs are in clinical trials, and non-drug treatments such as acupuncture, massage, biofeedback and transcranial-magnetic stimulation are also showing some promise at alleviating migraine pain.
Doctors used to tell patients to wait until their headache pain was severe to moderate before taking medication. But that's changing. "Now we know the closer we can get to the beginning of the attack, the better the outcome will be," says David Dodick, president of the American Headache Society and neurologist at the Mayo Clinic in Phoenix.
Experts also think that they can learn a lot about the origin of migraines by studying how the body changes in the premonitory phase.
For example, "Many people tell us that they vomit yesterday's food," says Joel Saper, director of the Michigan Head-Pain and Neurological Institute in Ann Arbor. That's a sign, he notes, that their digestion slowed long before they knew a migraine was coming.
Some experts are also re-examining the role of common migraine triggers such as alcohol, chocolate, red wine, aged cheese and caffeine. It could be that physiological changes in the premonitory phase trigger a sensitivity to such foods, rather than the other way around.
"For years, patients would say they got a migraine because they ate chocolate or pizza or a hot dog," says Dr. Saper. "But when you ask why they ate those things, they say, 'I had this insatiable craving....' We need to understand where that craving came from."
Functional-imaging studies of the brain have revealed another tantalizing clue: During the aura phase, a wave of electrical activity sweeps over the outer, furrowed layer of the brain known as the cortex, at a pace of 2 to 3 millimeters per minute. This wave—known as "cortical spreading depression"—activates nerve cells as it goes, and the symptoms sufferers report typically correspond to the area of the brain the wave is passing over. For example, the patient sees flashing lights and wavy lines when the wave is over the visual cortex, and tingling in the hands and feet when the wave is in the motor cortex. Once the wave passes by, the nerve cells become quiet and spent.
Dr. Goadsby and colleagues at UCSF are conducting more imaging studies to determine what brain activity occurs during the premonitory phase.
Experts say migraine sufferers can help themselves and their physicians by keeping a careful log of when their headaches occur, what they ate, drank and did several days in advance, as well as any early symptoms they experienced. They may notice patterns and find their own warning signs.
And even though there is no scientific evidence that taking medication at that early stage will stave off migraine headaches, some experts say it makes sense for patients to avoid their known triggers if a migraine seems imminent.
"If stress seems to be a trigger, cut back on your schedule, try a relaxation technique, don't plan a 12-hour day," says Dr. Becker. "You could potentially stop an attack."
Thursday, June 9, 2011
Improving fluid intelligence with training on working memory
Published online before print April 28, 2008, doi:10.1073/pnas.0801268105
Fluid intelligence Gf refers to the ability to reason and to solve new problems independently of previously acquired knowledge. Gf is critical for a wide variety of cognitive tasks, and it is considered one of the most important factors in learning. More over, Gf is closely related to professional and educational success, especially in complex and demanding environments. Although performance on tests of Gf can be improved through direct practice on the tests themselves, there is no evidence that training on any other regimen yields increased Gf in adults. Furthermore, there is a long history of research into cognitive training showing that, although performance on trained tasks can increase dramatically, transfer of this learning to other tasks remains poor. Here, we present evidence for transfer from training on a demanding working memory task to measures of Gf. This tranfer results even though the trained task is entirely different from the intelligence test itself. Furthermore, we demonstrate that the extent of gain in intelligence critically depends on the amount of training: the more training, the more improvement in Gf. That is, the training effect is dosage-dependent. Thus, in contrast to many previous studies, we conclude that it is possible to improve Gf without practicing the testing tasks themselves, opening a wide range of applications.
The most influential Journals: Impact factor and Eigenactor
Published online before print April 20, 2009, doi:10.1073/pnas.0903307106
Progress in science is driven by the publication of novel ideas and experiments, most usually in peer reviewed journals, but now days increasingly just on the internet. We all have our own ideas of which are the most influential journals, but is there a simple statistical metric of the influence of a journal? Most scientists would immediately say Impact Factor-IF, which is published online in Journal Citation Reports as part of the ISI Web Of Knowledge.
The Impact factor is the average number of citations in a year given to those papers in a journal published in the previous 2 years. But what, for example, is the most influential of the 3 following journals: A, which published just 1 paper a year and has a stellar IF of 100; B, which published 1,000,000 papers per years and has a dismal IF of 0.1 but 100,000 citations; or C which publishes 5,000 papers a year with an IF of 10? Unless there is a very odd distribution of citations in B, A has a paradigm shifting paper like the Waston and Crick DNA structure, C is likely to be the most influential journal. Clearly neither IF nor total number of citations is, per se, the metric of the overall influence of a journal.
Bibliometricians have introduced various scales of ranking journals; some based on publications, some based on usage as well, including the internet, using social networking analysis. Bollen et al. recently concluded that no single indicator adequately measures impact and IF is at the periphery of 39 scales analyzed. But there is a new parameter, the Eigenfactor, which attempts to rate the influence of journals. The Eigenfactor ranks journals in a manner similar to that used by Google for ranking the importance of Web sites in a search. To quote from www.eigenfactor.org/methods.htm:-
The Eignefactor algorithm corresponds to a simple model of research in which readers follow chains of citations as they move from journal to journal. Imagine that a researcher goes to the library and selects a journal article at random. After reading the article, the researcher selects at random one of the citation from the article. She then proceeds to the journal that was cited, reads a random article there, and selects a citation to direct her to her next journal volume. the researcher does this ad infinitum.
The Eigenfactor is now listed by Journal Citation Reports. In practice, there is strong correlation between Eigenfactors and the total number of citations received by a journal. A plot of the 2007 Eigenfactors for the top 200 cited journals against the total number of citations shows some startling results.:
Three journals have by far and away the most overall influence on science: Nature, PNAS and Science, closely followed by the Journal of Biological Chemistry.
The terrible legacy of IF is that it is being used to evaluate scientists, rather than journals, which has become of increasing concern to many of us. Judgment of individuals is, of course, best done by in depth analysis by expert scholars in the subject area. But, some bureaucrats want a simple metric. My experience of being on international review committees is that more notice is taken of IF when they do not have the knowledge to evaluate the science independently.
An extreme example of such behavior is an institute in the heart of the European Union that evaluates papers from its staff by having a weighting factor of 0 for all papers published in journals with IF<5 and just a small one for 5<IF<10. So, publishing in the Journal of Molecular biology counts for naught, despite its being at the top of areas such as protein folding.
All journals have a spread of citations, and even the best have some papers that are never cited plus some fraudulent papers and some excruciatingly bad ones. So, it is ludicrous to judge an individual paper solely on the IF of the journal in which it is published.
Fortunately, PNAS has both a good IF and a high reliability because of its access to so many expert National Academy of Sciences member- Editors. If a paper has to be judged by a metric, then it should by the citations to it and not to the journal. The least evil of the metrics for individual scientists is the h-index, which ranks the influence of a scientist by the number of citations to a significant number of his or her papers; an h of 100 would mean that 100 of their publication have been cited at least 100 times each. In terms of a “usage metric, Hirsch’s h-index paper is exceptional in its number of downloads( 111,126 downloads versus 262 citations since it was published in November 2005).
While new and emerging measure of scientific impact are developed, it is important not to rely solely on one standard. After all, science is about progress, which is ultimately assessed by human judgment.
Structural insights into a unique cellulase fold and mechanism of cellulose hydrolysis
Published online before print March 10, 2011, doi:10.1073/pnas.1015006108
Clostridium thermocellum is a well characterized cellulose degrading microorganism. The genome sequence of C.thermocellum encodes a number of proteins that contain type I dockerin domains, which implies that they are components of the cellulose degrading apparatus, but display no significant sequence similarity to known plant cell wall degrading enzymes. Here, we report the biochemical properties and crystal structure of one of these proteins, designated CtCel124. The protein was shown to be an endo-acting cellulase that displays a single displacement mechanism and acts in synergy with Cel485, the major cellulosomal exo-cellulase. The crystal structure of CtCel124 in complex with two cellotriose molecules, determined to 1.5 Angastrom, displays a superhelical fold in which a constellation of alpha-helices encircle a central helix that houses the catalytic apparatus. The catalytic acid, Glu96, is located at the C-terminus of the central helix, but there is no candidate catalytic base. The substrate binding cleft can be divided into two discrete topographical domains in which the bound cellotriose molecules display twisted and linear conformations, respectively,suggesting that the enzyme may target the interface between crystalline and disordered regions of cellulose.
Intrinsic functional architecture predicts electrically evoked responses in the human brain
Published online before print June 2, 2011, doi:10.1073/pnas.1019750108
Adaptive brain function is characterized by dynamic interactions within and between neuronal circuits, often occurring at the time scale of milliseconds. These complex interactions between adjacent and noncontiguous brain areas depend on a functional architecture that is maintained even in the absence of input. Functional MRI studies carried out during rest (R-fMRI) suggest that this architecture is represented in low frequency (<0.1 Hz) spontaneous fluctuations in the blood oxygen level dependent signal that are correlated within spatially distributed networks of brain areas. These networks, collectively referred to as the brain’s intrinsic functional architecture, exhibit a remarkable correspondence with patterns of task evoked coactivation as well as maps of anatomical connectivity. Despite this striking correspondence, there is no direct evidence that this intrinsic architecture forms the scaffold that gives rise to faster processes relevant to information processing and seizure spread. Here, we demonstrate that the spatial distribution and magnitude of temporally correlated low frequency fluctuations observed with R-fMRI during rest predict the pattern and magnitude of corticocortical evoked potential elicited within 500 ms after single pulse electrical stimulation of the cerebral cortex with intracranial electrodes. Across individuals, this relationship was found to be independent of the specific regions and functional systems probed. Our findings bridge the immense divide between the temporal resolutions of these distinct measure of brain function and provide strong support for the idea that the low frequency signal fluctuations observed with R-fMRI maintain and update the intrinsic architecture underlying the brain’s repertoire of functional responses.
Wednesday, June 8, 2011
Skin Wrinkles May Provide a Glimpse Into Bone Health
Medscape Medical News, June 6, 2011
A close look at the skin of early postmenopausal women might provide a glimpse into their skeletal health, according to a study presented here at ENDO 2011: The Endocrine Society 93rd Annual Meeting, Boston, MA, USA.
The study found a significant inverse association between skin wrinkles and bone mineral density(BMD) in a population of women within 3 years of menopause who were not on any hormone therapy and who had not had any cosmetic skin procedures.
“it’s a unique population when changes are happening in a dynamic fashion.” This is a relation “not previously described,” said study presenter Lubna Pal, associate professor at Yale School of Medicine in New Haven Connecticut.
The architecture of the skeleton and the skin share a common building block: Collagen. Age related changes in collagen contribute to age-related skin changes like wrinkles and sagging and might also contribute to reduced BMD.
“When I am seeing an older patient, her bigger concern is what is happening to her skin; the clinician’s concern is what is happening to her bones,” Dr. Pal said. “ So part of the question was: Can I fine tune to the patient’s concern and get a sense of the bone health?”
Dr. Pal and colleagues performed a cross sectional analysis of baseline data on 114 early postmenopausal women (70% white) enrolled in the longitudinal Kronos Early Estrogen Prevention Study (KEEPS).
As part of an ancillary study of the skin, the distribution and depth of skin wrinkles were assessed at 11 sites on the face and neck using the Lemperle wrinkle scale. Skin firmness was assessed at the forehead and cheek using a durometer, which has been validated in patients with scleroderma, and bone density was assessed with dual x-ray absorptiometry at the lumbar spine, hip and total body.
The researchers observed a clear inverse correlation between skin wrinkling and Bone mass density at the spine (r,-0.27; P<0.01), femoral neck (r, –0.29; P< 0.01) and total body (r, –0.26; P=0.01), independent of age, body composition, other factors known to influence Bone mass density.
“Basically, what we found was that the higher the wrinkle score, the worse the bone mineral density,” Dr. Pal said, “so our hypothesis was substantiated by these associations.”
Firmer skin of the face and forehead was associated with higher BMD.
Tuesday, June 7, 2011
Super Toxic Bug
Medscape Medical News, June 3, 2011
Be on alert for ‘Super Toxic’ Bug in Travelers, CDC says:
As health officials in Germany continued to seek the source of a uniquely toxic enterohemorrhagic Escherichia coli outbreak that has claimed the lives of at least 18 people, the Centre for Disease Control and Prevention issued a notice to healthcare providers to be on alert for the Shiga toxin producing E.coli O104:H4(STEC O104:H4) infections among travelers returning from Germany.
While there are some reports of the outbreak stabilizing the World Health Organization confirms that a total of 1823 cases of STEC O104:H4 have been reported, including 520 cases of hemolytic uremic syndrome, a potentially life threatening complication of the infection that can cause kidney failure. Twelve HUS cases were fatal and 6 deaths were reported among non-HUS cases.
The number of countries reporting cases of the STEC O 104:H4 poisoning had increased to 11 on Friday. However, all but 1 of the deaths since the outbreak emerged in May have occurred in Germany. The 18th death was reportedly in Sweden and involved a person who had recently returned from Germany.
Symptoms of the strain, which European authorities have called “super toxic”, are notably severe, including stomach cramps, bloody diarrhea, vomiting and fever. However, fever is not usually high.
Four suspected cases of the infection have been reported in United States, all involving people who had recently traveled to Hamburg, Germany, said Chris Braden MD, Director of Foodborne, Waterborne and Environmental Diseases for the CDC, at a press briefing today.
Three of the four cases in the US involved HUS and the patients were hospitalized. “The fourth case did not develop HUS but had bloody diarrhea, and we know there was a Shiga toxin producing organism involved,” he said.
Dr.Braden described the STEC O 104:H4 strain as “very rare” but not entirely unfamiliar.
“The CDC is not aware of any confirmed cases of this infection ever reported in the US. However, we have become aware of similar strains in other countries in the past,” he said.
The strain attacks the body in a manner unlike other strains of Shiga producing E.coli.
“The strain is different in its genetic markers and in the way it attaches to the lining of the intestine,” Dr. Braden added.
In addition to causing particularly severe symptoms, the strain is usual in that most of its victims appear to be women and people over the age of 20.
“It is true that in Germany 60% of the enterohemorrhagic E.coli cases and 71% of the HUS cases are female,” the WHO confirmed.
The unusual patterns underscore that little is known about the strain’s unusual nature, but they could also suggest the source that may be somehow related to the adult female demographic, Dr. Braden said.
“We have a lot to learn about this particular organism. It’s possible this organism had a predilection for adults over children, but it’s also possible the type of food or produce is being eaten by adult women than others.”
Dr. Braden also noted that the duration time from exposure to onset of symptoms is also unique, with incubation times of more than a week upto 12 days, compared to as little as 5 days commonly seen with other E.coli infections.
Most patients’ symptoms resolve within 5 to 7 days. However, HUS can develop a week after diarrhea begins. “The classic triad of findings in HUS is acute renal damage, microangiopathic hemolytic anemia( evidence of schistocytes and helmet cells on peripheral blood smear) and thrombocytopenia,” the CDC explained in a statement.
After backtracking on an earlier suggestion that the source of E.coli strain could be linked to organic Spanish cucumbers, German officials maintain that cucumbers, tomatoes and the lettuce are top suspects.
In addition, the Robert Koch Institute, Germany’s national disease control agency, has advised consumers, particularly those in the northern Germany region around Hamburg to avoid those vegetables.
In treating suspected STEC cases, some research has shown that administering antibiotics may in fact increase their risk of developing HUS, but the CDC recommended that clinicians ultimately determine treatment according to each individual patient. “There may be indications for antibiotics in patients with severe intestinal inflammation if perforation is of concern”, the agency said. “Of note, isolates of STEC O104:H4 from patients in Germany have demonstrated resistance to multiple antibiotics.”
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