More Drugs Cited As A Risky Mix with Grapefruit

(Helen Thompson)

http://www.npr.org/blogs/health/2012/11/27/166012281/a-deadly-cocktail-some-medications-don-t-mix-well-with-grapefruit?ft=1&f=1001

NATURE | NEWS

Simulated brain scores top test marks

First computer model to produce complex behaviour performs almost as well as humans at simple number tasks.

• Ed Yong

29 November 2012

Spaun solves simple tests

Article tool

Spaun sees a series of digits: 1 2 3; 5 6 7; 3 4 ?. Its neurons fire, and it calculates the next logical number in the sequence. It scrawls out a 5, in legible if messy writing.

This is an unremarkable feat for a human, but Spaun is actually a simulated brain. It contains 2.5 million virtual neurons — many fewer than the 86 billion in the average human head, but enough to recognize lists of numbers, do simple arithmetic and solve reasoning problems. 

NATURE

• P

  Jiangxi province, China, 2009.

REUTERS

Grim picture of polar ice-sheet loss

Antarctica and Greenland are rapidly losing their ice sheets because of climate change, says a comprehensive review.

Climate policy: The Kyoto approach has failed

Emissions trading: Cap and trade finds new energy

The global energy challenge: Awash with carbon

More than ever, nations are powering themselves from abundant supplies
of fossil fuels.

Graphic

Press Release No. 966

For use of the information media
Not an official record

2012: Record Arctic Sea Ice Melt, Multiple Extremes and High Temperatures

GENEVA/DOHA, 28 November 2012 (WMO) – The years 2001–2011 were all among the  warmest on record, and, according to the World Meteorological Organization, the first ten months indicate that 2012 will most likely be no exception despite the cooling influence of La Niña early in the year.

WMO’s provisional annual statement on the state of the global climate also highlighted the unprecedented melt of the Arctic sea ice and multiple weather and climate extremes which affected many parts of the world. It was released today to inform negotiators at the United Nations Climate Change Conference in Doha, Qatar.

January-October 2012 has been the ninth warmest such period since records began in 1850. The global land and ocean surface temperature for the period was about 0.45°C (0.81°F) above the corresponding 1961–1990 average of 14.2°C, according to the statement.

...

“The extent of Arctic sea ice reached a new record low. The alarming rate of its melt this year highlighted the far-reaching changes taking place on Earth’s oceans and biosphere.  Climate change is taking place before our eyes and will continue to do so as a result of the concentrations of greenhouse gases in the atmosphere, which have risen constantly and again reached new records,” added Mr Jarraud.

The Arctic reached its lowest annual sea ice extent since the start of satellite records on 16 September at 3.41 million square kilometers. This was 18% less than the previous record low of 18 September, 2007. The 2012 minimum extent was 49 percent or nearly 3.3 million square kilometers (nearly the size of India) below the 1979–2000 average minimum. Some 11.83 million square kilometers of Arctic ice melted between March and September 2012.

WMO will release a 10-year report on the state of the climate, “2001-2010, A Decade of Extremes” on 4 December 2012. It was produced in partnership with other United Nations and international agencies and highlights the warming trend for the entire planet, its continents and oceans during the past decade, with an indication of its impacts on health, food security and socio-economic development.

Highlights of 2012 provisional statement

Temperatures:.

During the first ten months of 2012, above-average temperatures affected most of the globe’s land surface areas, most notably North America (warmest on record for contiguous United States of America), southern Europe, western and central Russia and northwestern Asia. Much of South America and Africa experienced above average temperatures during the first ten months of the year, with the most anomalous warmth across parts of northern Argentina and northern Africa. Much of Asia had above-average temperatures, with cooler-than-average conditions across parts of northern China. South Asia and the Pacific were also predominantly warmer than normal, except for Australia.

Extremes: Notable extreme events were observed worldwide, but some parts of the Northern Hemisphere were affected by multiple extremes during January–October 2012.

• Heat waves: Major heat waves impacted the Northern Hemisphere during the year, with the most notable in March–May across the continental United States of America and Europe. Warm spells during March 2012 resulted in many record-breaking temperatures in Europe and nearly 15,000 new daily records across the USA. Russia witnessed the second warmest summer on record after 2010.  Numerous temperature records were broken in Morocco in summer.

• Drought:  According to the U.S. Drought Monitor, nearly two-thirds of the continental United States (65.5 percent) was considered to be in moderate to exceptional drought on 25 September  2012. Drought conditions impacted parts of western Russia and western Siberia during June and July, and Southeast Europe, the Balkans and some Mediterranean countries during summer. In China, the Yunnan and southwestern Sichuan province experienced severe drought during winter and spring. Northern Brazil witnessed the worst drought in 50 years. The April–October precipitation total, in Australia was 31 percent below normal.

• Floods: Many parts of western Africa and the Sahel, including Niger and Chad, suffered serious flooding between July and September because of a very active monsoon. Heavy rainfall from the end of July through early October prompted exceptional floods across Nigeria. Parts of southern China experienced their heaviest rainfall in the last 32 years in April and May. Devastating monsoonal floods impacted Pakistan during September.  Central and parts of northern Argentina suffered from record rainfall and flooding in August, and parts of Colombia were affected by heavy precipitation for most of the year.

• Snow and Extreme Cold:  A cold spell on the Eurasian continent from late January to mid-February was notable for its intensity, duration, and impact. Across eastern Russia, temperatures ranged between -45°C to -50°C during the end of January. Several areas of eastern Europe reported minimum temperatures as low as -30°C, with some areas across northern Europe and central Russia experiencing temperatures below -40°C.

Tropical Cyclones: Global tropical cyclone activity for the first ten months was near the 1981–2010 average of 85 storms, with a total of 81 storms (wind speeds greater or equal than 34 knots, or 63 kilometers per hour).  The Atlantic basin experienced an above-average hurricane season for a third consecutive year with a total of 19 storms, with ten reaching hurricane status, the most notably being Sandy, which wreaked havoc across the Caribbean and the USA East Coast. Throughout the year, East Asia was severely impacted by powerful typhoons. Typhoon Sanba was the strongest cyclone, globally, to have formed in 2012. Sanba impacted the Philippines, Japan, and the Korean Peninsula, dumping torrential rain and triggering floods and landslides that affected thousands of people and caused millions in U.S. dollars in damage.

Undisclosed Finding by Mars Rover Fuels Intrigue

The Mars rover Curiosity has found something — something noteworthy, in a pinch of Martian sand. But what is it?

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NASA/JPL-Caltech, via Malin Space Science Systems, via EPA

The Curiosity rover in a self-portrait stitched together from 55 images taken by a camera at the end of one of its arms. Data from the rover’s first soil sample is now being analyzed by scientists.

The scientists working on the mission who know are not saying. Outside of that team, lots of people are guessing.

The intrigue started last week when John P. Grotzinger, the Mars mission’s project scientist, told National Public Radio: “This data is going to be one for the history books. It’s looking really good.”

And then he declined to say anything more.

Fossils? Living microbial Martians? Maybe the carbon-based molecules known as organics, which are the building blocks of life? That so much excitement could be set off by a passing hint reflects the enduring fascination of both scientists and nonscientists with Mars.

“It could be all kinds of things,” said Peter H. Smith, a planetary scientist at the University of Arizona who was the principal investigator for NASA’s earlier Phoenix Mars mission but is not involved with Curiosity. “If it’s historic, I think it’s organics. That would be historic in my book.”

Dr. Grotzinger and other Curiosity scientists will announce their latest findings on Monday in San Francisco at a meeting of the American Geophysical Union.

Do not expect pictures of Martians, though.

Guy Webster, a spokesman for NASA’s Jet Propulsion Laboratory in Pasadena, Calif., which operates Curiosity, said the findings would be “interesting” rather than “earthshaking.”

Mr. Webster noted that “a really big announcement,” if one should occur, would most likely be made at NASA headquarters in Washington and not at an academic conference.

Whatever is revealed will be linked to the work of Curiosity’s sophisticated chemistry laboratory instrument, Sample Analysis at Mars — SAM, for short. The rover’s robotic arm dropped the first bit of sand and dust into the instrument on Nov. 9, and the scientists have been analyzing and contemplating ever since.

One of the main goals of SAM is to identify organic molecules, but it would be a big surprise for organics to show up in a first look at a sand sample selected more as a test exercise than with the expectation of a breakthrough discovery.

Curiosity will be headed toward layers of clays, which could be rich in organics and are believed to have formed during a warm and wet era early in the planet’s history. But Curiosity has months to drive before arriving at those locations.

And the Curiosity scientists have learned through experience that it pays to double-check their results before trumpeting them. An initial test of the Martian atmosphere by the same instrument showed the presence of methane, which would have been a major discovery, possibly indicating the presence of methane-generating microbes living on Mars today. But when the scientists ran the experiment again, the signs of methane disappeared, leading them to conclude that the methane found in the first test had come from air that the spacecraft had carried to Mars from its launching spot in Florida.

Mr. Webster, who was present during the interview with NPR, said Dr. Grotzinger had been talking more generally about the quality of data coming back from Curiosity and was not suggesting that the data contained a breakthrough surprise. “I don’t think he had in mind, ‘Here’s some particular chemical that’s been found,’ ” Mr. Webster said. “That’s not my impression of the conversation.”

On Twitter, Curiosity chimed in: “What did I discover on Mars? That rumors spread fast online. My team considers this whole mission ‘one for the history books.’ ” (The public information staff at the Jet Propulsion Laboratory writes the posts for the rover.)

Stores of ice confirmed on Sun-scorched Mercury

MESSENGER finds evidence of pure water ice near planet's north pole.

• Maggie McKee

29 November 2012

Water ice is abundant in Mercury's dark polar craters.

NASA/JOHNS HOPKINS UNI APPLIED PHYS LAB/CARNEGIE INST OF WASHINGTON

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Talk about a land of fire and ice. The surface of Mercury is hot enough in some places to melt lead, but it is a winter wonderland at its poles — with perhaps a trillion tonnes of water ice trapped inside craters — enough to fill 20 billion Olympic skating rinks.

The ice — whose long-suspected presence¹ has now been confirmed by NASA's orbiting MESSENGER probe — seems to be much purer than ice inside similar craters on Earth's Moon, suggesting that the closest planet to the Sun could be a better trap for icy materials delivered by comets and asteroids. Three papers detailing the findings are published today in Science^2, 3, 4.

Despite Mercury’s blistering 400 °C temperatures, the floors of many of its polar craters are in permanent shadow, because the planet's rotational axis is perpendicular to its orbital plane, so its poles never tip towards the star. Indeed, radar pinged to the planet from Earth in the past 20 years has revealed bright regions¹ near the poles consistent with metres-thick slabs of pure water ice.

Now, three different lines of evidence back the water-ice interpretation. Infrared laser pulses fired at the planet by MESSENGER's Mercury Laser Altimeter have revealed bright regions inside nine darkened craters near the planet's north pole². These bright regions, thought to be water ice, line up perfectly with ultra-cold spots that, according to a thermal model of the planet that takes into account Mercury's topography, should never be warmer than –170 °C³.But “radar does not uniquely identify water ice,” says David Lawrence, a planetary scientist at the Johns Hopkins University Applied Physics Laboratory in Laurel, Maryland. Sulphur, for example, could have produced a similar radar signature.

A third team, using MESSENGER's Neutron Spectrometer, has spotted the telltale signature of hydrogen — which they think is locked up in water ice — in those same regions⁴. "Not only is water the best explanation, we do not see any other explanation that can tie all the data together," says Lawrence, lead author of the spectrometer study.

So where did the water come from? The bright icy spots identified by MESSENGER's laser are surrounded by darker terrain which receives a bit more sunlight and heat. The neutron measurements suggest that this darker area is a layer of material about 10 centimetres thick that lies on top of more ice, insulating it.

Dark materials

This darker material around the bright spots may be made up of complex hydrocarbons expelled from comet or asteroid impacts, says David Paige, a planetary scientist at the University of California, Los Angeles, and first author of  the thermal-model paper³.

Paige and his colleagues suggest that when these icy bodies slam into Mercury, their components migrate over time — by repeatedly vaporizing and precipitating — to the cooler poles, where they get stuck in the frigid polar craters.

But even there, sunlight will sometimes hit parts of the craters' interiors, vaporizing the water ice and leaving behind ‘lag deposits’ of hydrocarbons that gradually become thicker and darker as they are chemically altered by sunlight.

Small impacts should have buried the surface if the ice were a billion years old, and the MESSENGER researchers believe it might be much younger than that, perhaps 50 million years old.

"The ice deposits we are looking at are not ancient," says Paige.

ATHLETE CONNECTED WITH PEDS

By Boston.com Staff 

Jermaine Cunningham has become the latest Boston athlete to be suspended for violating a performance-enhancing drug policy. The defensive end reportedly tested positive for Adderall, a drug commonly prescribed for patients with attention disorders.

Cunningham joined a list of prominent athletes, many from Boston, who have been accused or convicted of using substances banned by their various leagues

Scientist takes inspiration from natural world to create self-filling water bottle | PRI.ORG

Scientist takes inspiration from natural world to create self-filling water bottle | PRI.ORG

United Nations Environmental Progamme

Bridging the Global Emissions Gap 

Executive Summary

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• Science 

Two Interesting Proteins Discovered

SLEEP

Modulation of Vigilance in the Primary Hypersomnias by Endogenous Enhancement of GABA_A Receptors

ABSTRACT

The biology underlying excessive daytime sleepiness (hypersomnolence) is incompletely understood. After excluding known causes of sleepiness in 32 hypersomnolent patients, we showed that, in the presence of 10 μM γ-aminobutyric acid (GABA), cerebrospinal fluid (CSF) from these subjects stimulated GABA_A receptor function in vitro by 84.0 ± 40.7% (SD) relative to the 35.8 ± 7.5% (SD) stimulation obtained with CSF from control subjects (Student’s t test, t = 6.47, P < 0.0001); CSF alone had no effect on GABA_A signaling. The bioactive CSF component had a mass of 500 to 3000 daltons and was neutralized by trypsin. Enhancement was greater for α2 subunit– versus α1 subunit–containing GABA_A receptors and negligible for α4 subunit–containing ones. CSF samples from hypersomnolent patients also modestly enhanced benzodiazepine (BZD)–insensitive GABA_A receptors and did not competitively displace BZDs from human brain tissue. Flumazenil—a drug that is generally believed to antagonize the sedative-hypnotic actions of BZDs only at the classical BZD-binding domain in GABA_A receptors and to lack intrinsic activity—nevertheless reversed enhancement of GABA_A signaling by hypersomnolent CSF in vitro. Furthermore, flumazenil normalized vigilance in seven hypersomnolent patients. We conclude that a naturally occurring substance in CSF augments inhibitory GABA signaling, thus revealing a new pathophysiology associated with excessive daytime sleepiness.

EAT

GPRC5B Activates Obesity-Associated Inflammatory Signaling in Adipocytes

Abstract: A genome-wide association study identified a strong correlation between body mass index and the presence of a 21-kb copy number variation upstream of the human GPRC5B gene; however, the functional role of GPRC5B in obesity remains unknown. We report that GPRC5B-deficient mice were protected from diet-induced obesity and insulin resistance because of reduced inflammation in their white adipose tissue. GPRC5B is a lipid raft–associated transmembrane protein that contains multiple phosphorylated residues in its carboxyl terminus. Phosphorylation of GPRC5B by the tyrosine kinase Fyn and the subsequent direct interaction with Fyn through the Fyn Src homology 2 (SH2) domain were critical for the initiation and progression of inflammatory signaling in adipose tissue. We demonstrated that a GPRC5B mutant lacking the direct binding site for Fyn failed to activate a positive feedback loop of nuclear factor B–inhibitor of B kinase  signaling. These findings suggest that GPRC5B may be a major node in adipose signaling systems linking diet-induced obesity to type 2 diabetes and may open new avenues for therapeutic approaches to diabetic progression.

NEJM

Effect of Three Decades of Screening Mammography on Breast-Cancer Incidence

Benefit and Harm with Screening Mammography and Use of Aspirin over 10 Years.
Use of Screening Mammography and Incidence of Stage-Specific Breast Cancer in the United States, 1976–2008.

RESULTS

The introduction of screening mammography in the United States has been associated with a doubling in the number of cases of early-stage breast cancer that are detected each year, from 112 to 234 cases per 100,000 women — an absolute increase of 122 cases per 100,000 women. Concomitantly, the rate at which women present with late-stage cancer has decreased by 8%, from 102 to 94 cases per 100,000 women — an absolute decrease of 8 cases per 100,000 women. With the assumption of a constant underlying disease burden, only 8 of the 122 additional early-stage cancers diagnosed were expected to progress to advanced disease. After excluding the transient excess incidence associated with hormone-replacement therapy and adjusting for trends in the incidence of breast cancer among women younger than 40 years of age, we estimated that breast cancer was overdiagnosed (i.e., tumors were detected on screening that would never have led to clinical symptoms) in 1.3 million U.S. women in the past 30 years. We estimated that in 2008, breast cancer was overdiagnosed in more than 70,000 women; this accounted for 31% of all breast cancers diagnosed.

Full Text of Results...

CONCLUSIONS

Despite substantial increases in the number of cases of early-stage breast cancer detected, screening mammography has only marginally reduced the rate at which women present with advanced cancer. Although it is not certain which women have been affected, the imbalance suggests that there is substantial overdiagnosis, accounting for nearly a third of all newly diagnosed breast cancers, and that screening is having, at best, only a small effect on the rate of death from breast cancer.

NEJM

Medication for Attention Deficit–Hyperactivity Disorder and Criminality

FIGURE 1
Extended Kaplan–Meier Curves for Patients in the Swedish Patient Register with a Diagnosis of ADHD Who Were Born No Later Than 1990, According to Sex and Medication Status.

BACKGROUND
Attention deficit–hyperactivity disorder (ADHD) is a common disorder that has been associated with criminal behavior in some studies. Pharmacologic treatment is available for ADHD and may reduce the risk of criminality.

METHODS

Using Swedish national registers, we gathered information on 25,656 patients with a diagnosis of ADHD, their pharmacologic treatment, and subsequent criminal convictions in Sweden from 2006 through 2009. We used stratified Cox regression analyses to compare the rate of criminality while the patients were receiving ADHD medication, as compared with the rate for the same patients while not receiving medication.

RESULTS

As compared with nonmedication periods, among patients receiving ADHD medication, there was a significant reduction of 32% in the criminality rate for men (adjusted hazard ratio, 0.68; 95% confidence interval [CI], 0.63 to 0.73) and 41% for women (hazard ratio, 0.59; 95% CI, 0.50 to 0.70). The rate reduction remained between 17% and 46% in sensitivity analyses among men, with factors that included different types of drugs (e.g., stimulant vs. nonstimulant) and outcomes (e.g., type of crime).

CONCLUSIONS

Among patients with ADHD, rates of criminality were lower during periods when they were receiving ADHD medication. These findings raise the possibility that the use of medication reduces the risk of criminality among patients with ADHD. (Funded by the Swedish Research Council and others.)

NATURE 

Misfolded protein transmits Parkinson’s from cell to cell

Link between cell death and protein clumps opens pathway to possible treatment.

• Virginia Hughes

15 November 2012

Protein clumps called Lewy bodies (centre) found in Parkinson’s disease are caused as misfolded α-synuclein moves from cell to cell.

KELVIN LUK/UNIV. PENNSYLVANIA/SCIENCE AAAS

Article toolThe catastrophic damage wreaked by a rogue protein involved in Parkinsons' disease has been tracked by researchers, in work that might help to reinvigorate an old treatment strategy to slow the condition.

A team led by Virginia Lee, a neurobiologist at the University of Pennsylvania in Philadelphia, injected a misfolded synthetic version of the protein α-synuclein into the brains of normal mice and saw the key characteristics of Parkinson’s disease develop and progressively worsen. The study, published today in Science¹, suggests that the disease is spread from one nerve cell to another by the malformed protein, rather than arising spontaneously in the cells.

The finding raises the possibility that an antibody that binds the misfolded α-synuclein could be used to intercept the protein as it passes between nerve cells. “It’s very hard to ask antibodies not only to get inside the brain, but to get inside cells,” says Lee. “But now you have the possibility of stopping the spreading. And if you stop the spreading, perhaps you can slow the progression of the disease.”

The idea that Parkinson’s might be spread from neuron to neuron by a rogue protein took off in 2008, when transplants of fetal nerve tissue given to patients with the disease developed the characteristic clumps associated with the condition^2, 3. This indicated that the nearby diseased cells had somehow infected the transplanted tissue. Subsequent studies showed that misfolded α-synuclein can spread between neighbouring cells⁴ and can cause cell death⁵.

But the question remained as to whether the misfolded α-synuclein was responsible for the cascade of damage seen in Parkinson’s. Lee says that her team has now captured the full consequences of runaway α-synuclein in the brain.

Related stories

• Prions and chaperones: Outside the fold
• Neuroscience: While you were sleeping
• Parkinson's vaccine thwarts suspect proteins

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“We knew this transfer from one cell to another can happen, but whether it could play a significant role in the disease was still open,” says Tim Greenamyre, director of the Pittsburgh Institute for Neurodegenerative Diseases in Pennsylvania, who was not involved in the latest work.

Insidious spread

Parkinson’s disease has two distinct features: clumps of protein called Lewy bodies and a dramatic loss of nerve cells that produce the chemical messenger dopamine. When Lee’s team injected the misfolded α-synuclein into a part of the mouse brain rich in dopamine-producing cells, Lewy bodies began to form. This was followed by the death of dopamine neurons. Nerve cells that linked to those near the injection site also developed Lewy bodies, a sign that cell-to-cell transmission was taking place, say the researchers.

Greenamyre says that that is possible, but hasn’t yet been proved. “All of the cells affected in this paper were those directly in contact with the injection site,” he says.

Nevertheless, within six months of the injection, coordination of movement, grip strength and balance had all deteriorated in the mice, echoing what happens in people with Parkinson’s disease.

“It’s really pretty extraordinary,” says Eliezer Masliah, a neuroscientist at the University of California, San Diego. “We have been trying that experiment for a long time in the lab and we have not seen such dramatic effects.” The study lends theoretical support to the handful of biotechnology companies that are sponsoring clinical trials of α-synuclein antibodies for Parksinson’s, Masliah says. It should also spur research on how the protein gets in and out of cells, he adds.

At least one mystery still remains: why do the Lewy bodies appear in the first place? “Parkinson’s disease is not a disorder in which somebody injects synuclein into your brain,” notes Ted Dawson, director of the Institute for Cell Engineering at Johns Hopkins University in Baltimore, Maryland. “So what sets it in motion?”

E.P.A. Upholds Federal Mandate for Ethanol in Gasoline

The Environmental Protection Agency declined on Friday to relax its requirement on the use of corn ethanol in gasoline, rejecting a request from several states related to a steep decline in the nation’s corn production.

A blog about energy and the environment.

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A summer drought that withered crops led to a spike in prices, hurting the livestock industry and others that depend on corn for food. Estimates indicate that as much as half of the nation’s crop will be used to produce ethanol this year to meet the federal renewable energy standard for transportation fuel.

“We recognize that this year’s drought has created hardship in some sectors of the economy, particularly for livestock producers,” Gina McCarthy, an E.P.A. assistant administrator, said in a statement. “But our extensive analysis makes clear that Congressional requirements for a waiver have not been met.”

A coalition of livestock groups expressed frustration with the decision, as did the National Council of Chain Restaurants, which says its costs have also risen because of the use of corn in ethanol production.

Several environmental groups are also opposed to the ethanol requirement, saying that corn ethanol production is not clean energy. “If the worst U.S. drought in more than 50 years and skyrocketing food prices are not enough to make E.P.A. act, it falls to Congress to provide relief from our senseless federal support for corn ethanol,” Michal Rosenoer, abiofuels specialist at Friends of the Earth, said in a statement. She said the mandate was “exacerbating our economic and environmental problems.”

That would put some environmentalists in rare alignment with the oil industry, which is required to use an increasing amount of ethanol in its fuel production but complains that its system is glutted with the substance.

Since Congress specified a year-by-year gallon quota for biofuels in 2007, total fuel demand in the United States has dropped, so the percentage of ethanol fuel in gasoline has reached unexpected highs.

Farm groups and trade associations for companies seeking to make ethanol from nonfood sources like wood chips or crop residues have applauded the mandate, however. They say that if the corn ethanol mandate is reduced, there will be less demand for their biofuels products as well.

At the Advanced Ethanol Council, Brooke Coleman, the executive director, pointed out that the quota rules include a provision that allows the oil industry to postpone up to 20 percent of its obligation to a future year “if there is a good year one year and a less good year the next.”

At Novozymes, which supplies enzymes to ethanol manufacturers, Adam Monroe, president of the company’s North American division, said the biofuels mandate “has generated 400,000 careers, billions in private investment, and domestic, renewable fuel for America.”

In the longer term, Congress anticipates substantial production of biofuels from nonfood sources, but so far that has not developed.