Posted by Zack Lynch
Jonathan Moreno writes another insightful piece, Intelligence on the Brain which discusses the need for a new dialogue on neuroresearch and national security.
Posted by Zack Lynch
Jonathan Moreno writes another insightful piece, Intelligence on the Brain which discusses the need for a new dialogue on neuroresearch and national security.
Dr Andrew Whitten, Dr Cy Jeffries and Professor Jill Trewhella, from the School of Molecular and Microbial Biosciences, University of Sydney, with Samantha Harris, from the University of California, USA, have the first data showing how a protein in heart muscle cells works to maintain regular heart function.
The research, published in the Proceedings of the National Academy of Sciences, USA, on 25 November 2008, shows how this cardiac protein interacts with actin - one of the two filament-forming muscle proteins (the other is myosin) that slide past each other to create the rhythmic contraction and relaxation that causes our heart to beat.
"Understanding the structure of this heart protein - called cardiac myosin-binding protein C - and how it attaches to actin, gives us an insight into how it actually works to modulate heart contractions," explained Professor Jill Trewhella.
"There's a lot of interest in cardiac myosin-binding protein C, because of its influence on fine-tuning heart muscle contractions and its links to familial hypertrophic cardiomyopathy - an inherited cardiac disorder that affects one in 500 adolescents and young adults.
"Young people with familial hypertrophic cardiomyopathy have a gradual thickening of the ventricle walls of their hearts and a correlated increase in the risk of heart failure," said Professor Trewhella.
However, the precise molecular mechanisms by which cardiac myosin-binding protein C influences actin and myosin interactions have not been fully understood.
Cardiac myosin-binding protein C, known as an 'accessory protein' in the muscle cells that keep our hearts beating, is a long molecule made up of eleven segments, called domains, arranged like beads on a string.
Using neutron scattering to examine the structure of cardiac myosin-binding protein C when bound to actin, the team found the specific domains of the protein that bind to and stabilise actin filaments.
"It turns out there are two domains of cardiac myosin-binding protein C that bind to actin - the C0 and C1 domains that are at one end of the molecule. Domains at the opposite end are attached to myosin," explained Professor Trewhella.
"This is a real first - it's the first direct structural evidence that clearly shows how cardiac myosin-binding protein C stabilises actin filaments. We've not only found the particular domains of the protein that bind to actin, but where they bind and how they are positioned to modulate the interactions between actin and myosin and hence the contractile cycle," said Professor Trewhella.
"Dr Andrew Whitten and Dr Cy Jeffries, two postdoctoral research fellows in the School of Molecular and Microbial Biosciences, University of Sydney, performed the research and analysed the data from experiments which the team had designed. Andrew also developed a new 2D atom modeling program - a new analytic tool to examine the data.
"It's great to see two young scientists early in their career produce this successful and exciting research that will help inform us of the molecular basis for a devastating disease," said Professor Trewhella.
Presently keratoconus is treated through eyeglasses, hard contact lenses, and a newer treatment, INTACS plastic rings inserted into the mid layer of the cornea to flatten it, changing the shape and location of the cone.
In 15-20% of the cases, cornea transplant surgery is necessary. The Cornea Research Foundation of America is one of 9 sites in the U.S. currently participating in a new clinical research investigation to study the benefits of corneal collagen cross-linking (CXL) in subjects with progressive keratoconus and corneal ectasia after prior refractive surgery. These studies are the first in the U.S. of CXL designed to assess the safety and effectiveness of CXL for slowing the progression of both of these conditions.
"Because the FDA usually requires data from two separate studies before approving a new drug or device, we are conducting two cross-linking studies: one is for the treatment of keratoconus and the other is for treatment of post-refractive ectasia, a rare complication of refractive surgery," says Marianne Price, executive director of the Cornea Research Foundation of America.
The FDA permitted study is sponsored by Swiss-based Peschke Meditrade GmbH. Corneal collagen cross-linking is a procedure that involves administering riboflavin and UVA in carefully selected parameters that strengthen the front layers of the cornea and avoid damage to the back of the eye. The riboflavin and UVA light source that is used for CXL are both investigational in the United States and are not yet approved by the FDA.
The Foundation started the collagen cross-linking study in January 2008. The FDA has given permission for enrollment of 160 patients into each study. People interested in more information about the study or participating in the study can contact the Cornea Research Foundation of America. Subjects may be eligible for the study if they have the following in one or both eyes, or are:
Expert Source: Dr. Marianne Price, executive director of the Cornea Research Foundation of America. Dr. Price is a sought after speaker and published author, a member of the American Academy of Ophthalmology, the Association for Research in Vision and Ophthalmology, the American Society of Cataract & Refractive Surgery, and Ophthalmic Women Leaders. Dr. Price holds a bachelor's degree in engineering science from the University of Notre Dame and both an MBA in finance and a doctorate in medical and molecular genetics from Indiana University.
Retinal detachment, a condition that afflicts about 10,000 Americans each year, puts an individual at risk for vision loss or blindness.
In a new study in the current issue of the New England Journal of Medicine, a leading ophthalmologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center writes, however, that a high probability of reattachment and visual improvement is possible by using one of three currently available surgical techniques.
"Although no randomized trials have been conducted that show definitively that one procedure is best for every situation, improvements in these surgical techniques have led to effective treatments for most patients," says Dr. Donald J. D'Amico, ophthalmologist-in-chief at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, professor and chairman of ophthalmology at Weill Cornell Medical College, and an international leader in vitreoretinal surgery.
Although relatively rare, retinal detachment can occur when holes, tears or breaks appear in the light-sensitive retina as a result of trauma or pulling away of the gelatinous mass, known as the vitreous, that fills the back of the eye. Retinal tears occur most often in adults over age 60, but may occur much earlier, particularly in those with high myopia. The sudden onset of light flashes and "floaters" could be the warning signs of an impending retinal detachment, although these symptoms do not always mean that a retinal tear has occurred. Surgery is the only treatment for a retinal detachment.
In the article "Primary Retinal Detachment," Dr. D'Amico offers his recommendations for treating a 57-year-old man who experiences sudden flashes and floaters in one eye, progressive loss of vision and a retinal detachment.
The three surgical options currently in use to treat such a case are:
1. Scleral Buckling. A common way to treat a retinal detachment, scleral buckling surgery has been performed with success for several decades. In this procedure, a piece of silicone is sutured onto the outside wall of the eyeball and left in place permanently to create an indentation, or buckle, that restores contact with the detached retina. The individual tears are then closed by a localized scar that is induced with a freezing probe or laser. According to Dr. D'Amico, scleral buckling is a relatively involved procedure and requires the use of a hospital operating room. It is usually performed on an outpatient basis with local anesthesia with intravenous sedation, and the overall success rate for reattachment is about 90 percent.
2. Pneumatic Retinopexy. A newer and less invasive procedure than scleral buckling, pneumatic retinopexy is usually done in the retina specialist's office under local anesthesia. The procedure involves injecting a gas bubble into the vitreous cavity of the eye, then positioning the patient's head so that the bubble floats to the break in the detached retina. The bubble spans and closes the retinal break, and this allows the natural forces in the eye to reattach the retina. The break is permanently sealed by the application of a freezing probe or laser to create a scar around the break. The gas bubble then resolves over several days, and in successful cases, the retina is left reattached without a trip to the operating room, and with no permanent buckling material applied to the eye. According to Dr. D'Amico, pneumatic retinopexy is not suitable for every patient and has a somewhat lower success rate with initial treatment than does scleral buckling or vitrectomy. Nevertheless, he says, because of its minimally invasive attributes, and the fact that an attempted pneumatic does not reduce the ultimate chance for success if additional surgery is required for recurrent detachment, patient and surgeons increasingly select pneumatic retinopexy for suitable primary retinal detachments after a careful discussion of the limitations.
3. Vitrectomy. In contrast to scleral buckling, vitrectomy is a surgery within the eye in which the vitreous gel is removed. Because vitreous traction is the typical cause of the retinal tears in a detachment, this approach has the advantage of directly attacking the underlying cause of the detachment. Vitrectomy surgery -- a few decades old -- is a newer surgery than scleral buckling, and it is continually improving due to innovations in instrumentation and technique. Recent studies have shown success rates comparable to those of scleral buckling. Dr. D'Amico notes that there is a very strong shift toward vitrectomy, and away from buckling, for retinal detachment, particularly by younger surgeons and for patients that have detachment after cataract surgery. Vitrectomy for detachment may be associated with a higher risk of postoperative cataract, and this appears to be its main disadvantage compared to buckling, which has lower risk of cataract but higher risk of other complications. In cases where bleeding in the vitreous gel is present with the detachment, a vitrectomy approach is clearly preferred to remove the vitreous hemorrhage in order to gain better visualization to find and repair tears or holes in the retina. Vitrectomy, like scleral buckling, is typically done on an outpatient basis with local anesthesia with intravenous sedation.
For the patient described in the vignette who went to his ophthalmologist with classic symptoms of primary retinal detachment, including flashing lights, floaters and progressive loss of vision, Dr. D'Amico's first recommendation would be to perform a pneumatic retinopexy. "I would select this option for this patient because this specific detachment is well-suited to pneumatic retinopexy by virtue of the retinal breaks being located close together in the superior retina, which is the easiest location to treat with an intraocular gas bubble. Furthermore, the procedure can be done immediately in the doctor's office at lower cost and with fewer risks of complications, compared to buckling or vitrectomy, and it also compares quite favorably with the other procedures with having a 75 percent chance of restoring vision to 20/50 or better after this minimally invasive procedure," Dr. D'Amico says.
As with any surgery, there are risks associated with each of these techniques. For example, vitrectomy can cause cataract or elevated pressure inside the eye, especially in people with glaucoma; scleral buckling can cause a change in the shape of the eye that may require alteration of the eyeglass prescription; and pneumatic retinopexy often requires more than one surgery to reattach the retina.
"The benefits of surgery, however, far outweigh the risks," says Dr. D'Amico, who performs all of these procedures. "No matter which procedure the surgeon chooses, there is a very good chance today that a patient's retina can be reattached and his or her vision preserved."
Malaria, one of the oldest diseases known to man, has shown no signs of slowing down as it ages.
More than 1 million children die from malaria in sub-Saharan Africa each year, and in areas along the Thailand/Cambodian border multiple drug-resistant strains of the disease are becoming commonplace.
With the previously mainstay antimalarial drug chloroquine nearly ineffective due to drug resistance and traditional public health approaches such as mosquito netting offering uneven results, two new papers by University of Notre Dame biologist Michael Ferdig suggest that the means of combating this old foe may lie in the new tools of genomics and bioinformatics.
In the papers, Ferdig points out that development of the malaria parasite Plasmodium falciparum in the blood is driven by a number of different genes expressed at different times and at different levels. Exactly what influences such transcriptional changes remains elusive, particularly in regard to important phenotypes like drug resistance.
Ferdig and his collaborators combined classical genetics with cutting-edge genomic methods to illuminate previously unrecognized transcriptional complexity and variation in Plasmodium falciparum and possibly master regulators within large copy number variants that contribute to the drug-resistant phenomena in malaria parasites.
By uncovering the genetic "architecture" of numerous drug responses and identifying key regulators that control these responses, Ferdig hopes to map new approaches to conquering drug resistant malarial genes.
One paper from the Ferdig lab appeared in the journal PLoS Biology. The second, in collaboration with Tim Anderson at Southwest Biomedical Research Foundation, appeared in PLoS Genetics .
Research from the Medical Research Council (MRC) Toxicology Unit at the University of Leicester shows that nitric oxide (NO) can change the computational ability of the brain.
This finding has implications for the treatment of neurodegenerative diseases such as Alzheimer's Disease and our understanding of brain function more generally.
The research is led by Professor Ian Forsythe and is reported in the journal Neuron on 26th November.
Professor Forsythe, of the MRC Toxicology Unit, explains: "It is well known that nerve cells communicate via the synapse - the site at which chemical messengers (neurotransmitters such as acetylcholine or glutamate) are packaged and then released under tight control to influence their neighbours.
"Nitric oxide is a chemical messenger which cannot be stored and can rapidly diffuse across cell membranes to act at remote sites (in contrast to conventional neurotransmitters which cannot pass across cell membranes).
"It is broadly localized in the central nervous system, where it influences synaptic transmission and contributes to learning and memory mechanisms. However, because it is normally released in such minute quantities and is so labile, it is very difficult to study.
"We have exploited an in vitro preparation of a giant synapse -called the calyx of Held, developed here at the University of Leicester in the 1990s- and its target in the auditory pathway to explore nitric oxide signalling in the brain.
"We show that NO is made in response to incoming synaptic activity (activity generated by sound received by the ear) and that it acts to suppress a key potassium ion-channel (Kv3). Normally these ion-channels keep electrical potentials very short-lived, but nitric oxide shifts their activity, slowing the electrical potentials and reducing information passage along the pathway, acting as a form of gain control.
"Surprisingly, the whole population of neurons were affected, even those neurons which had no active synaptic inputs, so indicating that nitric oxide is a 'volume transmitter' passing information between cells without the need for a synapse. Such a function is ideal for tuning neuronal populations to global activity. On the other hand, too much nitric oxide is extremely toxic and will cause death of nerve cells; so within the kernel of this important signaling mechanism are the potential seeds for neurodegeneration, which if left unchecked contribute to the pathologies of stroke and dementias."
In the future Professor Forsythe's research group will be trying to understand how these signalling mechanisms are applicable elsewhere in the brain and will investigate how aberrant signalling contributes to neurodegenerative disease processes such as in Alzheimer's disease.