Day: 01/15/2012

Fosfomycin/Tobramycin for Inhalation in Patients with Cystic Fibrosis with Pseudomonas Airway Infection .

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Fosfomycin/tobramycin for inhalation (FTI), a unique, broad-spectrum antibiotic combination, may have therapeutic potential for patients with cystic fibrosis (CF).

Objectives: To evaluate safety and efficacy of FTI (160/40 mg or 80/20 mg), administered twice daily for 28 days versus placebo, in patients greater than or equal to 18 years of age, with CF, chronic Pseudomonas aeruginosa (PA) airway infection, and FEV1 greater than or equal to 25% and less than or equal to 75% predicted.

Methods: This double-blind, placebo-controlled, multicenter study assessed whether FTI/placebo maintained FEV1 % predicted improvements achieved following a 28-day, open-label, run-in course of aztreonam for inhalation solution (AZLI).

Measurements and Main Results: A total of 119 patients were randomized to FTI (160/40 mg: n = 41; 80/20 mg: n = 38) or placebo (n = 40). Mean age was 32 years and mean FEV1 was 49% predicted at screening. Relative improvements in FEV1 % predicted achieved by the AZLI run-in were maintained in FTI groups compared with placebo (160/40 mg vs. placebo: 6.2% treatment difference favoring FTI, P = 0.002 [primary endpoint]; 80/20 mg vs. placebo: 7.5% treatment difference favoring FTI, P < 0.001). The treatment effect on mean PA sputum density was statistically significant for the FTI 80/20 mg group versus placebo (−1.04 log10 PA colony-forming units/g sputum difference, favoring FTI; P = 0.01). Adverse events, primarily cough, were consistent with CF disease. Respiratory events, including dyspnea and wheezing, were less common with FTI 80/20 mg than FTI 160/40 mg. No clinically significant differences between groups were reported for laboratory values.

Conclusions: FTI maintained the substantial improvements in FEV1 % predicted achieved during the AZLI run-in and was well tolerated. FTI is a promising antipseudomonal therapy for patients with CF.

Source:The American Journal of Respiratory medicine and critical care.

 

 

Lung Endothelial Ca2+ and Permeability Response to Platelet-Activating Factor Is Mediated by Acid Sphingomyelinase and Transient Receptor Potential Classical 6

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Platelet-activating factor (PAF) increases lung vascular permeability within minutes by activation of acid sphingomyelinase (ASM) and a subsequent nitric oxide (NO)-inhibitable and Ca2+-dependent loss in barrier function.

Objectives: To elucidate the molecular mechanisms underlying this response.

Methods: In isolated perfused rat and mouse lungs, endothelial Ca2+ concentration ([Ca2+]i) was quantified by real-time fluorescence imaging, and caveolae of endothelial cells were isolated and probed for Ca2+ entry channels. Regulation of transient receptor potential classical (TRPC) 6–mediated currents in lung endothelial cells was assessed by patch clamp technique.

Measurements and Main Results: PAF increased lung weight gain and endothelial [Ca2+]i. This response was abrogated by inhibitors of ASM or in ASM-deficient mice, and replicated by lung perfusion with exogenous ASM or C2-ceramide. PAF increased the caveolar abundance of TRPC6 channels, which was similarly blocked by ASM inhibition. PAF-induced increases in lung endothelial [Ca2+]i, vascular filtration coefficient, and edema formation were attenuated by the TRPC inhibitor SKF96365 and in TRPC6-deficient mice, whereas direct activation of TRPC6 replicated the [Ca2+]i and edema response to PAF. The exogenous NO donor PapaNONOate or the cyclic guanosine 3′,5′-monophosphate analog 8Br-cGMP blocked the endothelial [Ca2+]i and permeability response to PAF, in that they directly blocked TRPC6 channels without interfering with their PAF-induced recruitment to caveolae.

Conclusions: The present findings outline a new signaling cascade in the induction of PAF-induced lung edema, in that stimulation of ASM causes recruitment of TRPC6 channels to caveolae, thus allowing for Ca2+ influx and subsequent increases in endothelial permeability that are amplified in the absence of endothelial NO synthesis.

Source:The American Journal of Respiratory medicine and critical care.

 

How Has Stephen Hawking Lived to 70 with ALS?

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An expert on Lou Gehrig’s disease explains what we know about this debilitating condition and how Hawking has beaten the odds.

 

Stephen Hawking turns 70 on Sunday, beating the odds of a daunting diagnosis by nearly half a century.

The famous theoretical physicist has helped to bring his ideas about black holes and quantum gravity to a broad public audience. For much of his time in the public eye, though, he has been confined to a wheelchair by a form of the motor-neuron disease amyotrophic lateral sclerosis (ALS). And since 1985 he has had to speak through his trademark computer system—which he operates with his cheek—and have around-the-clock care.

But his disease seems hardly to have slowed him down. Hawking spent 30 years as a full professor of mathematics at the University of Cambridge. And he is currently the director of research at the school’s Center for Theoretical Cosmology.

But like his mind, Hawking’s illness seems to be singular. Most patients with ALS—also known as Lou Gehrig’s disease, for the famous baseball player who succumbed to the disease—are diagnosed after the age of 50 and die within five years of their diagnosis. Hawking’s condition was first diagnosed when he was 21, and he was not expected to see his 25th birthday.

Why has Hawking lived so long with this malady when so many other people die so soon after diagnosis? We spoke with Leo McCluskey, an associate professor of neurology and medical director of the ALS Center at the University of Pennsylvania, to find out more about the disease and why it has spared Hawking and his amazing brain.
What is ALS—and is there more than one form of it?
ALS, which is also known as a motor-neuron disease—and colloquially as Lou Gehrig’s disease in the U.S.—is a neurodegenerative disease. Each muscle is controlled by motor neurons that reside in the brain in the frontal lobe. These are controlled electrically and are synaptically connected to motor neurons that reside lower down in the brain—as well as motor neurons that reside in the spinal cord. The guys in the brain are called the upper motor neurons, and the guys in the spine are called the lower motor neurons. The disease causes weakness of either upper motor neurons or lower motor neurons or both.

It’s been known for quite some time that there are variants of ALS. One is referred to as progressive muscular atrophy, or PMA. It appears to be an isolated illness of the lower motor neurons. However, pathologically, if you do an autopsy of a patient, they will have evidence of deterioration of upper motor neurons.

There is also primary lateral sclerosis—PLS—and clinically it looks like an isolated upper motor-neuron disorder. However, pathologically they also have lower motor-neuron disorder.

The other classic syndrome is called progressive baldor palsy—or progressive supranuclear palsy—which is weakening of cranial muscles, like the tongue, face and swallowing muscles. But it pretty much always spreads to limb muscles.

Those are the four classic motor-neuron disorders that have been described. And it was thought for quite some time that these disorders were limited to motor neurons. It’s now clear that that’s not true. It’s now well recognized that 10 percent of these patients can develop degeneration in another part of the brain, such as other parts of the frontal lobe that don’t contain the motor neurons or the temporal lobe. So some of these patients can actually develop dementia, called frontal-temporal lobe dementia.

One of the misconceptions about ALS is that it’s only a, and that’s not true.

What has Stephen Hawking’s case shown about the disease?
One thing that is highlighted by this man’s course is that this is an incredibly variable disorder in many ways. On average people live two to three years after diagnosis. But that means that half the people live longer, and there are people who live for a long, long time.

Life expectancy turns on two things: the motor neurons running the diaphragm—the breathing muscles. So the common way people die is of respiratory failure. And the other thing is the deterioration of swallowing muscles, and that can lead to malnutrition and dehydration. If you don’t have these two things, you could potentially live for a long time—even though you’re getting worse. What’s happened to him is just astounding. He’s certainly an outlier.

Has he lived so long because he got the disease when he was young and had the juvenile-onset type?
Juvenile-onset is diagnosed in the teenage years, and I don’t know enough about his course to say. But it’s probably something similar to juvenile-onset disorder, which is something that progresses very, very, very slowly. I have patients in my clinic who were diagnosed in their teens and are still alive in their 40s, 50s or 60s. But not having ever examined him or taken a history, it’s a little hard for me to say.

He’s a very good example of the sparing of the non-motor parts of the brain that can occur.

How frequent are these cases of very slow-progressing forms of ALS?
I would say probably less than a few percent.

How much do you think Stephen Hawking’s longevity has been due to the excellent care that he has received versus the biology of his particular form of ALS?
It’s probably a little bit of both. I just know him from television, so I don’t know what kind of interventions he’s had. If he really isn’t on a ventilator, then it’s his biology—it’s the biology of his form of the neurodegenerative disease that determines how long he will live. For trouble swallowing you can elect to have a feeding tube placed, which basically takes malnutrition and dehydration off the table. But mostly it’s about the biology of the disease.

Hawking obviously has quite the active mind, and previous statements that he has made seem to indicate he has a pretty positive mental outlook, despite his condition. Is there any evidence that lifestyle and psychological well-being do much to help with patients’ outcomes? Or is the disease usually too quick for that to make a difference?
I don’t believe that adds to longevity.

ALS still doesn’t have a cure. What have we learned about the disease recently that might help us find one—or at least better treatments?
Beginning in 2006 it became clear that like a lot of other neurodegenerative diseases, ALS was determined by the accumulation of abnormal proteins in the brain. Ten percent of ALS is genetic and based on a gene mutation. I’m sure there are also at-risk genes for ALS, but there are now multiple genes that have been identified as potentially causing the disease. Each one of them are interesting in that they lead to the accumulation of different proteins in the brain. Knowing specific genes gives us particular mechanisms in the brain, and would potentially give us targets for therapies. But none of this has given us any robust therapies yet.

What does Stephen Hawking’s case mean for people who have the disease?
It’s just an incredible, incredible example of the variability of the disease—and the hope for patients who have it that they could also live a long life. Unfortunately, it’s a small percentage of people for whom that actually happens.

Source:Scientific American.

Biggest Map Yet of Universe’s Invisible Dark Matter Unveiled.

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Scientists hope that by plotting out the distribution of dark matter throughout space, they will come closer to understanding what it is..

The hidden side of the universe is now a bit more illuminated thanks to the largest map yet of dark matter, the strange substance thought to inhabit much of space.

Scientists have created the largest scale rendering of dark matter across the universe, revealing a picture of the invisible stuff thought to represent 98 percent of all matter in the universe.

Dark matter has never been directly detected, but its presence is felt through its gravitational pull on normal matter. Scientists suspect dark matter is made of some exotic particle that doesn’t interact with regular atoms.

“We know very little about the dark universe,” said co-leader of the study, Catherine Heymans of the University of Edinburgh’s School of Physics and Astronomy, during a press conference announcing the findings here at the 219th meeting of the American Astronomical Society.”We don’t know what the dark matter particle is. It’s very widely believed that the final understanding of the dark universe is going to have to invoke some new physics.”

The new map reveals the distribution of dark matter over a larger swath of space than ever before. It covers more than 1 billion light-years. One light-year is the distance light travels in a year, about 6 trillion miles (10 trillion kilometers). [See the new giant dark matter map]

Warping light
To trace invisible dark matter, the researchers searched for signs of its gravitational tug on other matter. They measured an effect called gravitational lensing, which occurs when gravity from a massive body bends space-time, causing light to travel along a curved path through space and appear distorted when it reaches Earth.

The scientists measured warped light from 10 million distant galaxies in four different regions of the sky, caused when those galaxies’ light passed by large bundles of dark matter that bent its path.

“It is fascinating to be able to ‘see’ the dark matter using space-time distortion,” another co-author of the study, Ludovic Van Waerbeke of the University of British Columbia, said in a statement. “It gives us privileged access to this mysterious mass in the universe which cannot be observed otherwise. Knowing how dark matter is distributed is the very first step towards understanding its nature and how it fits within our current knowledge of physics.”

Scientists hope that by plotting out the distribution of dark matter throughout space, they will come closer to understanding what it is.

“By analyzing light from the distant universe, we can learn about what it has travelled through on its journey to reach us,” Heymans said. “We hope that by mapping more dark matter than has been studied before, we are a step closer to understanding this material and its relationship with the galaxies in our universe.”

A close match
The new maps represent the first direct evidence of dark matter on such large scales.

“What we see here is very similar to the simulation,” Van Waerbeke said. “Dark matter is concentrated in lumps and the rest stretches in filaments.”

The web of dark matter throughout the universe revealed by the map agreed well with predictions made by computer simulations based on scientists’ best theory of dark matter.

“So far we haven’t seen any off things, or any deviation from what we expect,” Van Waerbeke told SPACE.com.

To create the map, the astronomers used data collected by the Canada-France-Hawaii Telescope in Hawaii during a five-year project called the Canada-France-Hawaii Telescope Lensing Survey.

“These lensing maps are very important tests of our cosmological paradigm,” said astronomer Rachel Mandelbaum of Carnegie Mellon University and Princeton University, who was not involved in the new study. “These results could be used as a test of dark matter, dark energy and even the theory of gravity.”

Smaller scales
In a separate study also presented today at the American Astronomical Society meeting in Austin, Sukanya Chakrabarti of Florida Atlantic University developed a new method of mapping the dark matter in individual galaxies.

Chakrabarti studied ripples on the outskirts of spiral galaxies to trace the shape of the dark matter within and surrounding the galaxies.

This research, targeting the invisible stuff on a much smaller scale than the first study, also helps astronomers hone in on an understanding of dark matter.

“These results with spiral galaxies allow the study of matter in a regime of individual galaxies, which has not been possible with weak lensing,” Mandelbaum said. “Both of these results represent two important ways of studying the dark mater, but they’re in two very different regimes.”

Source:Space

 

 

 

Radio Array Starts Work to Detect Whispers from Universe.

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Giant low-frequency sensor system on track to probe the birth of the first stars.

The Netherlands, one of the most densely populated countries in Europe, would seem to be an inauspicious place to detect radio whispers from the distant Universe. Mobile-phone towers, television transmissions, planes overhead and even the odd burst of noise from a windmill create a background din in the radio sky.

But the builders of LOFAR, the Low-Frequency Array of radio receivers centred around the tiny village of Exloo, say that they have found ways to ignore the noise. In doing so, Dutch astronomers at ASTRON, the Netherlands Institute for Radio Astronomy in Dwingeloo, are opening up a region of the electro­magnetic spectrum that should hold clues to one of the earliest phases of cosmic history, when the first stars formed–an era beyond the ken of even the biggest optical telescopes.

“Many of the radio astronomers said this couldn’t be done,” says Heino Falcke, an astronomer at Radboud University in Nijmegen and chairman of the International LOFAR Telescope Board, the five-nation foundation that governs the €150-million ($192-million) project. Yet Falcke and his colleagues defied the doubters by presenting their first results on 9 January at a meeting of the American Astronomical Society in Austin, Texas. “The message today is: the basic things all work. We can do this,” he said.

Mapping the low-frequency sky requires an expansive telescope as well as the ability to tune out noise. When completed later this year, the array will contain 2,700 slender dipole antennas tuned to 30-80 megahertz, and 43,000 antennas embedded in flat tiles a few metres square that are sensitive to 120-240 megahertz. The antennas will be concentrated in 40 stations across the Netherlands; 8 other stations in the United Kingdom, France, Germany and Sweden give the array extra angular resolution for fine-scale imaging. The fiber-optic data network that links the LOFAR antennas will also support sensor webs for geoscience and agricultural monitoring (see `A multi-purpose array‘).

LOFAR has already turned up surprises. Its observations of four pulsars–spinning neutron stars that emit regular radio pulses–show that the emissions at a wide range of frequencies are bunched together in time, implying that they emanate from a narrow region near the pulsar. The finding challenges a common picture in which pulsars generate their radio signal in a much wider region, says ASTRON’s Jason Hessels, co-principal investigator of LOFAR’s pulsar working group.

But the real prize would be the detection of a signal from the epoch of re-ionization. That was roughly 400 million to 800 million years after the Big Bang, when radiation from the first stars and galaxies ionized the primordial hydrogen gas that filled the newborn Universe, creating bubbles of ionized gas like the holes in a Swiss cheese. By mapping the gradual disappearance of the faint 21-centimeter emission line from the primordial hydrogen, LOFAR astronomers hope to distinguish between two re-ionization mechanisms: one driven by the stars’ ultraviolet light and one by X-rays from super-massive black holes in newborn galaxies. That would allow the astronomers to watch the first stars and galaxies being born.

Based on an initial run of ten hours spent staring at several quiet corners of the radio sky, ASTRON’s Ger de Bruyn suspects that the re-ionization signal could be detected with 400 hours of devoted observing time — a campaign he plans to begin by the end of the year.

That schedule would put LOFAR ahead of rival re-ionization projects in remote parts of Australia, South Africa and New Mexico, locations chosen partly for their lack of radio noise. Greg Taylor, an astronomer at the University of New Mexico in Albuquerque and director of the Long Wavelength Array being built in New Mexico, acknowledges that LOFAR is the array to beat in the race to detect re-ionization–but says that would be just the beginning. “If you make the discovery, then it’s a Nobel prize for somebody,” he says. But afterwards, “it has the potential to explode into a field of study”.

Source:Nature.

 

 

 

 

 

Rare Chinese white dolphin gets DNA bank.

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A Hong Kong conservation group said Saturday it has set up a DNA bank for the rare Chinese white dolphin, also known as the pink dolphin, in a bid to save the mammals facing a sharp population decline.

There are about 2,500 Chinese white dolphins in the Pearl River Delta region, the body of water between Macau and Hong Kong, with the majority of the mammals in Chinese waters and the rest in Hong Kong.

But experts say their number has dropped significantly in the past few years due to overfishing, an increase in maritime traffic, water pollution, habitat loss and coastal development.

In a bid to save the dwindling population, the Ocean Park Conservation Foundation Hong Kong said it had joined hands with a Chinese university to set up a DNA bank, which will also spearhead a genetic research project.

“We hope to offer the scientific community a standardised genetic analysis platform to assess the sustainability of Chinese white dolphin populations,” Judy Chen, the foundation chairwoman said in a statement.

“The collected data will provide important reference to governments in the region for developing critical strategies of Chinese white dolphin conservation,” she added.

The biological samples of these dolphins will be sent to the DNA bank to investigate the environmental impacts on the mammal, the statement said.

The Chinese white dolphins, a sub-species of the Indo-Pacific humpbackdolphins, are unique for their pink skin. They are listed as “near threatened” by the International Union for Conservation of Nature.

The mammal was the official mascot at the handover ceremony when the former British colony returned to Chinese rule in 1997, while dolphin watching is a favourite tourist attraction in Hong Kong.

Its population in Hong Kong has dropped from an estimated 158 in 2003 to only 75 in 2010, according to the Hong Kong Dolphin Conservation Society.

Source: Greenpeace International.