Researchers find antibiotic-resistant bacteria deep in one of the largest, unspoiled underground caves.


McMaster University and University of Akron researchers are leading the way in understanding the origins of antibiotic resistance, a global challenge that is creating a serious threat to the treatment of infectious diseases.

Gerry Wright, scientific director of the Michael G. DeGroote Institute for Infectious Disease Research (IIDR) at McMaster University, and Hazel Barton, associate professor of biology at the University of Akron, discovered a remarkable prevalence of antibiotic resistance bacteria isolated from Lechuguilla Cave in New Mexico, one of the deepest and largest caves in the world and a place isolated from human contact for more than four million years.

The research was published today in the Journal PLoS ONE.

 

“Our study shows that antibiotic resistance is hard-wired into bacteria, it could be billions of years old, but we have only been trying to understand it for the last 70 years,” says Wright. “This has important clinical implications. It suggests that there are far more antibiotics in the environment that could be found and used to treat currently untreatable infections.”

Amid the rare beauty of the Lechuguilla Cave, in Carlsbad Cavern National Park, researchers collected strains of bacteria from its deep and isolated recesses. They then examined these bacteria for antibiotic resistance. They found that while none of the bacteria are capable of causing human disease nor have they ever been exposed to human sources of antibiotics, almost all were resistant to at least one antibiotic, and some were resistant to as many as 14 different antibiotics. In all, resistance was found to virtually every antibiotic that doctors currently use to treat patients.

For instance, the researchers were able to identify a type of resistance that has yet to emerge in the clinic in a group of bacteria distantly related to the bacterium that causes anthrax.

Says Barton: “We can say to doctors, ‘while this isn’t a problem right now, it could be in the future so you need be aware of this pre-existing resistance and be prepared if it emerges in the clinic. Or you are going to have a problem’.”

The development of antibiotic resistant bacteria is becoming an increasing health concern. With the emergence of bacteria, such as multi-drug resistant Staphylococcus and the global spread of resisance to all clinically used drugs, where and how these organisms acquire resistance is an important question, says Wright.

“Most practitioners believe that bacteria acquire antibiotic resistance in the clinic,” he says. “As doctors prescribe antibiotics, they select for members of the community that are resistant to these drugs. Over time, these organisms spread and eventually the bacteria that commonly cause these infections are all resistant. In extreme cases these organisms are resistant to seven or more drugs and are untreatable using traditional treatment, and ¬ doctors must resort to surgery to remove infected tissue. The actual source of much of this resistance are harmless bacteria that live in the environment.”

Because antibiotics are heavily prescribed and used in agriculture, it is difficult to find an environment where antibiotics do not exert some kind of influence, adds Barton, noting this is why Lechuguilla Cave was the perfect environment to look at the pre-existing reservoir of antibiotic resistance in nature. Discovered in 1986, access to the cave has been limited to a few expert cavers and researchers each year. It is also surrounded by an impermeable layer of rock, meaning infiltration of water into the cave can take up to 10,000 years to reach its deepest recesses, an age well beyond the discovery of antibiotics. The researchers sampled bacteria from so far deep into the cave that Barton and some other researchers involved in the study camped in the cave during the collection process.

Their findings support recent studies at McMaster that suggest antibiotic resistance has a long evolutionary past.

Source:  McMaster University .

 

 

Scientists find how plants grow to escape shade.


Mild mannered though they seem, plants are extremely competitive, especially when it comes to getting their fair share of sunlight. Whether a forest or a farm, where plants grow a battle wages for the sun’s rays.

 

A plant’s primary weapon in this fight is the ability to grow towards the light, getting just the amount it needs and shadowing its competition. Now, scientists at the Salk Institute for Biological Studies have determined precisely how leaves tell stems to grow when a plant is caught in a shady place.

In a paper published April 15 in Genes and Development, the researchers report that a protein known as phytochrome interacting factor 7 (PIF7) serves as the key messenger between a plant’s cellular light sensors and the production of auxins, hormones that stimulate stem growth.

“We knew how leaves sensed light and that auxins drove growth, but we didn’t understand the pathway that connected these two fundamental systems,” says Joanne Chory, professor and director of the Salk’s Plant Biology Laboratory and a Howard Hughes Medical Institute investigator. “Now that we know PIF7 is the relay, we have a new tool to develop crops that optimize field space and thus produce more food or feedstock for biofuels and biorenewable chemicals.”

Plants gather intelligence about their light situation —- including whether they are surrounded by other light-thieving plants —- through photosensitive molecules in their leaves. These sensors determine whether a plant is in full sunlight or in the shade of other plants, based on the wavelength of red light striking the leaves.

If a sun-loving plant, such as thale cress (Arabidopsis thaliana), the species Chory studies, finds itself in a shady place, the sensors will tell cells in the stem to elongate, causing the plant to grow upwards towards sunlight.

When a plant remains in the shade for a prolonged period, however, it may flower early and produce fewer seeds in a last ditch effort to help its offspring spread to sunnier real estate. In agriculture, this response, known as shade avoidance syndrome, results in loss of crop yield due to closely planted rows of plants that block each other’s light.

 

Scientists knew that a pigment found in leaves of thale cress plants, phytochrome B (PHYB), is excited by both the red wavelengths of light that drive photosynthesis, as well as the near infrared light that is enriched in shady spots. But no one had found a direct link between this response to light and the hormone-driven growth response to shade.

In their study, Chory and her colleagues, including Joseph R. Ecker, a professor in Salk’s Plant Molecular and Cellular Biology Laboratory, used biochemical and genomic analyses to identify PIF7, as the key molecular link between a plant’s light sensors and production of auxins.

They showed that when a thale cress plant is placed in shade, a cascade of molecular changes occurs in the cells of the leaves: the PHYB photoreceptor causes chemical changes in PIF7, which then activates genes that direct the cell to produce auxin.

 

“We already knew that auxin is made in the leaves and travels to the stem to stimulate growth,” says Chory. “Now we know how shade stimulates the leaves to produce auxin, and it turns out that it’s a remarkably simple pathway to control such an important function.”

She added that the findings may offer new avenues for developing crops with stem architectures better suited to tightly planted field rows, making them less prone to shade avoidance syndrome. If successful, such crops would produce higher yields of foods and biofuels than existing strains.

Source: Salk Institute

 

Nanoparticles home in on brain tumors, boost accuracy of surgical removal.


Like special-forces troops laser-tagging targets for a bomber pilot, tiny particles that can be imaged three different ways at once have enabled Stanford University School of Medicine scientists to remove brain tumors from mice with unprecedented accuracy.

In a study to be published online April 15 in Nature Medicine, a team led by Sam Gambhir, MD, PhD, professor and chair of radiology, showed that the minuscule nanoparticles engineered in his lab homed in on and highlighted brain tumors, precisely delineating their boundaries and greatly easing their complete removal. The new technique could someday help improve the prognosis of patients with deadly brain cancers.

About 14,000 people are diagnosed annually with brain cancer in the United States. Of those cases, about 3,000 are glioblastomas, the most aggressive form of brain tumor. The prognosis for glioblastoma is bleak: the median survival time without treatment is three months. Surgical removal of such tumors — a virtual imperative whenever possible — prolongs the typical patient’s survival by less than a year. One big reason for this is that it is almost impossible for even the most skilled neurosurgeon to remove the entire tumor while sparing normal brain.

“With brain tumors, surgeons don’t have the luxury of removing large amounts of surrounding normal brain tissue to be sure no cancer cells are left,” said Gambhir, who is the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research and director of the Molecular Imaging Program at Stanford. “You clearly have to leave as much of the healthy brain intact as you possibly can.”

This is a real problem for glioblastomas, which are particularly rough-edged tumors. In these tumors, tiny fingerlike projections commonly infiltrate healthy tissues, following the paths of blood vessels and nerve tracts. An additional challenge is posed by micrometastases: minuscule tumor patches caused by the migration and replication of cells from the primary tumor. Micrometastases dotting otherwise healthy nearby tissue but invisible to the surgeon’s naked eye can burgeon into new tumors.

Although brain surgery today tends to be guided by the surgeon’s naked eye, new molecular imaging methods could change that, and this study demonstrates the potential of using high-technology nanoparticles to highlight tumor tissue before and during brain surgery.

The nanoparticles used in the study are essentially tiny gold balls coated with imaging reagents. Each nanoparticle measures less than five one-millionths of an inch in diameter — about one-sixtieth that of a human red blood cell.

“We hypothesized that these particles, injected intravenously, would preferentially home in on tumors but not healthy brain tissue,” said Gambhir, who is also a member of the Stanford Cancer Institute. “The tiny blood vessels that feed a brain tumor are leaky, so we hoped that the spheres would bleed out of these vessels and lodge in nearby tumor material.” The particles’ gold cores, enhanced as they are by specialized coatings, would then render the particles simultaneously visible to three distinct methods of imaging, each contributing uniquely to an improved surgical outcome.

One of those methods, magnetic resonance imaging, is already frequently used to give surgeons an idea of where in the brain the tumor resides before they operate. MRI is well-equipped to determine a tumor’s boundaries, but when used preoperatively it can’t perfectly describe an aggressively growing tumor’s position within a subtly dynamic brain at the time the operation itself takes place.

The Gambhir team’s nanoparticles are coated with gadolinium, an MRI contrast agent, in a way that keeps them stably attached to the relatively inert spheres in a blood-like environment. (In a 2011 study published in Science Translational Medicine, Gambhir and his colleagues showed in small animal models that nanoparticles similar to those used in this new study, but not containing gadolinium, were nontoxic.)

A second, newer method is photoacoustic imaging, in which pulses of light are absorbed by materials such as the nanoparticles’ gold cores. The particles heat up slightly, producing detectable ultrasound signals from which a three-dimensional image of the tumor can be computed. Because this mode of imaging has high depth penetration and is highly sensitive to the presence of the gold particles, it can be useful in guiding removal of the bulk of a tumor during surgery.

The third method, called Raman imaging, leverages the capacity of certain materials (included in a layer coating the gold spheres) to give off almost undetectable amounts of light in a signature pattern consisting of several distinct wavelengths. The gold cores’ surfaces amplify the feeble Raman signals so they can be captured by a special microscope.

To demonstrate the utility of their approach, the investigators first showed via various methods that the lab’s nanoparticles specifically targeted tumor tissue, and only tumor tissue.

Next, they implanted several different types of human glioblastoma cells deep into the brains of laboratory mice. After injecting the imaging-enhancing nanoparticles into the mice’s tail veins, they were able to visualize, with all three imaging modes, the tumors that the glioblastoma cells had spawned.

The MRI scans provided good preoperative images of tumors’ general shapes and locations. And during the operation itself, photoacoustic imaging permitted accurate, real-time visualization of tumors’ edges, enhancing surgical precision.

But neither MRI nor photoacoustic imaging by themselves can distinguish healthy from cancerous tissue at a sufficiently minute level to identify every last bit of a tumor. Here, the third method, Raman imaging, proved crucial. In the study, Raman signals emanated only from tumor-ensconced nanoparticles, never from nanoparticle-free healthy tissue. So, after the bulk of an animal’s tumor had been cleared, the highly sensitive Raman-imaging technique was extremely accurate in flagging residual micrometastases and tiny fingerlike tumor projections still holed up in adjacent normal tissue that had been missed on visual inspection. This, in turn, enabled these dangerous remnants’ removal.

“Now we can learn the tumor’s extent before we go into the operating room, be guided with molecular precision during the excision procedure itself and then immediately afterward be able to ‘see’ once-invisible residual tumor material and take that out, too,” said Gambhir, who suggested that the nanoparticles’ propensity to heat up on photoacoustic stimulation, combined with their tumor specificity, might also make it possible for them to be used to selectively destroy tumors. He also expressed optimism that this kind of precision could eventually be brought to bear on other tumor types.

Source: Stanford University Medical Center

 

Low birth weight is associated with earlier onset of end-stage renal disease in Danish patients with autosomal dominant polycystic kidney disease.


Low-birth-weight individuals have a higher risk of hypertension and end-stage renal disease (ESRD). Here we investigated whether low birth weight was associated with earlier onset of ESRD in patients with autosomal dominant polycystic kidney disease (ADPKD). In collaboration with all Danish departments of nephrology, 307 of 357 patients with ADPKD and ESRD born and living in Denmark were recruited. We were able to analyze complete data of 284 patients obtained from both hospital medical files and midwife protocols in the Danish State Archives. Multivariable linear regression adjusted for birth weight, adult height, mean arterial pressure, gender, birth decade, and type of antihypertensive treatment showed that for every kilogram increase in birth weight, the age at onset of ESRD significantly increased by 1.7 years. Male gender and increased mean arterial pressure were both associated with earlier onset of ESRD. Patients treated with renin–angiotensin system blockade or calcium channel blockers during follow-up had significantly later onset of ESRD by 4.3 years and 2.1 years, respectively. Treatment with beta-blockade or a diuretic was not associated with the age at onset of ESRD. Thus, low birth weight may contribute to considerable phenotypic variability in the progression of renal disease between individuals with ADPKD.

Source: Kidney International

 

 

 

 

Erythropoietin, but not the correction of anemia alone, protects from chronic kidney allograft injury.


Anemia can contribute to chronic allograft injury by limiting oxygen delivery to tissues, particularly in the tubulointerstitium. To determine mechanisms by which erythropoietin (EPO) prevents chronic allograft injury we utilized a rat model of full MHC-mismatched kidney transplantation (Wistar Furth donor and Lewis recipients) with removal of the native kidneys. EPO treatment entirely corrected post-transplant anemia. Control rats developed progressive proteinuria and graft dysfunction, tubulointerstitial damage, inflammatory cell infiltration, and glomerulosclerosis, all prevented by EPO. Normalization of post-transplant hemoglobin levels by blood transfusions, however, had no impact on chronic allograft injury, indicating that EPO-mediated graft protection went beyond the correction of anemia. Compared to syngeneic grafts, control allografts had loss of peritubular capillaries, higher tubular apoptosis, tubular and glomerular oxidative injury, and reduced expression of podocyte nephrin; all prevented by EPO treatment. The effects of EPO were associated with preservation of intragraft expression of angiogenic factors, upregulation of the anti-apoptotic factor p-Akt in tubuli, and increased expression of Bcl-2. Inhibition of p-Akt by Wortmannin partially antagonized the effect of EPO on allograft injury and tubular apoptosis, and prevented EPO-induced Bcl-2 upregulation. Thus non-erythropoietic derivatives of EPO may be useful to prevent chronic renal allograft injury.

Source: Kidney International

 

 

 

Lipopolysaccharide-pretreated plasmacytoid dendritic cells ameliorate experimental chronic kidney disease.


Plasmacytoid dendritic cells play important roles in inducing immune tolerance, preventing allograft rejection, and regulating immune responses in both autoimmune disease and graft-versus-host disease. In order to evaluate a possible protective effect of plasmacytoid dendritic cells against renal inflammation and injury, we purified these cells from mouse spleens and adoptively transferred lipopolysaccharide (LPS)-treated cells, modified ex vivo, into mice with adriamycin nephropathy. These LPS-treated cells localized to the kidney cortex and the lymph nodes draining the kidney, and protected the kidney from injury during adriamycin nephropathy. Glomerulosclerosis, tubular atrophy, interstitial expansion, proteinuria, and creatinine clearance were significantly reduced in mice with adriamycin nephropathy subsequently treated with LPS-activated plasmacytoid dendritic cells as compared to the kidney injury in mice given naive plasmacytoid dendritic cells. In addition, LPS-pretreated cells, but not naive plasmacytoid dendritic cells, convert CD4+CD25− T cells into Foxp3+ regulatory T cells and suppress the proinflammatory cytokine production of endogenous renal macrophages. This may explain their ability to protect against renal injury in adriamycin nephropathy.

Source: Kidney International

 

 

 

Transforming growth factor-β induces vascular endothelial growth factor-C expression leading to lymphangiogenesis in rat unilateral ureteral obstruction.


Inflammation is recognized as an important contributor to lymphangiogenesis; however, in tubulointerstitial lesions in human chronic kidney diseases, this process is better correlated with the presence of myofibroblasts rather than macrophages. As little is known about the interaction between lymphangiogenesis and renal fibrosis, we utilized the rat unilateral ureteral obstruction model to analyze inflammation, fibrosis, lymphangiogenesis, and growth factor expression. Additionally, we determined the relationship between vascular endothelial growth factor-C (VEGF-C), an inducer of lymphangiogenesis, and the profibrotic factor, transforming growth factor-β1 (TGF-β1). The expression of both TGF-β1 and VEGF-C was detected in tubular epithelial and mononuclear cells, and gradually increased, peaking 14 days after ureteral obstruction. The kinetics and localization of VEGF-C were similar to those of TGF-β1, and the expression of these growth factors and lymphangiogenesis were linked with the progression of fibrosis. VEGF-C expression was upregulated by TGF-β1 in cultured proximal tubular epithelial cells, collecting duct cells, and macrophages. Both in vitro and in vivo, the induction of VEGF-C along with the overall appearance of lymphatics in vivo was specifically suppressed by the TGF-β type I receptor inhibitor LY364947. Thus, TGF-β1 induces VEGF-C expression, which leads to lymphangiogenesis.

Source: Kidney International

 

 

Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.


Retinoic acid decreases proteinuria and glomerulosclerosis in several animal models of kidney disease by protecting podocytes from injury. Our recent in vitro studies suggest that all-trans retinoic acid induces podocyte differentiation by activating the retinoic acid receptor-α (RARα)/cAMP/PKA/CREB pathway. When used in combination with all-trans retinoic acid, an inhibitor of phosphodiesterase 4 further enhanced podocyte differentiation by increasing intracellular cAMP. Additionally, we found that Am580, a specific RARα agonist, has similar renal protective effects as all-trans retinoic acid in a rederived colony of HIV-1 transgenic mice with rapidly progressive renal failure (HIV-Tg) that mimics human HIV-associated nephropathy. Treatment with either the inhibitor of phosphodiesterase 4, roflumilast, or Am580 significantly reduced proteinuria, attenuated kidney injury, and improved podocyte differentiation in these HIV-Tg mice. Additional renal protective effects were found when roflumilast was combined with Am580. Consistent with the in vitro data, glomeruli from HIV-Tg mice treated with both Am580 and roflumilast had more active phosphorylated CREB than with either agent alone. Thus, phosphodiesterase 4 inhibitors could be used in combination with RARα agonists to provide additional renal protection.

Source: Kidney International

 

 

 

Toll-like receptors in transplantation: sensing and reacting to injury.


Toll-like receptors (TLRs) are a family of transmembrane proteins that have a major role in pathogen-induced inflammation and orchestrating an organism’s defense against infection. Data are emerging that the TLRs play an important role as a first response to tissue injury linking the innate with the adaptive immune system. The recognition that TLRs are expressed on nonimmune cells including renal and liver cells, and that endogenous, cell-derived ligands (damage-associated molecular patterns) can signal through specific TLRs has expanded the understanding of how these receptors impact a variety of diseases. This review focuses on recent findings elucidating the ability of TLRs to affect transplant outcomes. Specifically, observations demonstrating the link between endogenous TLR ligands and IR injury, how this can affect alloimmunity and transplant tolerance, and therapeutic implications will be discussed.

Source: Kidney International

 

 

 

Some Asian glaciers ‘putting on mass’.


Some glaciers on Asia’s Karakoram mountains are defying the global trend and getting thicker, say researchers.

A French team used satellite data to show that glaciers in part of the Karakoram range, to the west of the Himalayan region, are putting on mass.

The reason is unclear, as glaciers in other parts of the Himalayas are losing mass – which also is the global trend.

The region’s glaciers are poorly studied, yet provide a vital water source for more than a billion people.

The response of Himalayan glaciers to global warming has been a hot topic ever since the 2007 report of the Intergovernmental Panel on Climate Change (IPCC), which contained the erroneous claim that ice from most of the region could disappear by 2035.

Although often regarded as part of the Himalayas, the Karakoram range is technically a separate chain that includes K2, the world’s second-highest peak.

Much of the region is inaccessible, and there has been a general recognition that observations need to be stepped up in order to clarify what is going on.

The French scientists, from the National Centre for Scientific Research and the University of Grenoble, compared two models of land surface elevation derived from satellite observations, for 1999 and 2008, and report their findings in the Nature Geoscience journal.

The method has been used before in other mountain ranges, but it is not as straightforward as it might sound.

“It’s not been used more because these elevation models are quite difficult to acquire – you need clear sky conditions and reduced snow cover,” said lead researcher Julie Gardelle.

Other factors that can change the height of the ice surface, other than changes to the ice itself, also need to be accounted for.

Having done all these calculations, the team found that between 1999 and 2008 the mass of the glaciers in this 5,615 sq km (2,168 sq miles) region of the Karakoram increased marginally, although there were wide variations between individual glaciers.

Why this should be is not clear, though it is well known from studies in other parts of the world that climate change can cause extra precipitation into cold regions which, if they are cold enough, gets added to the existing mass of ice.

“We don’t really know the reason,” Ms Gardelle told BBC News.

“Right now we believe that it could be due to a very specific regional climate over Karakoram because there have been meteorological measurements showing increased winter precipitation; but that’s just a guess at this stage.”

Whatever the region, it is clear that the trend contrasts with other parts of the wider Himalayas-Hindu Kush region, home to an estimated 210 million people and where glaciers act as fresh water stores for about 1.3 billion living in river basins below.

Late last year, the Kathmandu-based International Centre for Integrated Mountain Development (Icimod) released data showing that across 10 regularly studied glaciers, the rate of ice loss had doubled since the 1980s.

However, it also made clear just how sparse data is from the region, finding only these 10 intensively studied glaciers among a total of more than 54,000.

Measurements by the GRACE satellite mission, which detects minuscule variations in the Earth’s gravitational pull, have also shown a net loss of mass across the whole region.

Graham Cogley, the scientist from Trent University in Ontario, Canada, who first publicly questioned the IPCC’s 2035 figure, comments in Nature that reconciling the different mass loss figures found by different methods of study “will keep glaciologists busy for some time”.

Source:BBC