ANNUAL OTOLOGY CONFERENCE – ISOCON 2013 BENGALURU

The annual otology conference is one of the best conferences organised by the ENT fraternity in India.  It is a much awaited event and one of the well attended conferences. This  time it was held at Bangalore, Karnataka,  from November 8th 2013 to November 10 2013.  Bangalore being a major hub in  the  south,  attracted well over 800 delegates.  The event was organized at the NIMHANS convention  centre, which was well located, spacious, with comfortable seating and good air conditioning.  The organizers had done a good job.  The entire conference was managed by an  event management company.  Bar coding of delegate badges ensured that nobody gate crashed into the dining area and also for the entertainement events in the  evening.  

The focus of this conference was Transcanal endoscopic approach to the ear.  This approach was showcased by two surgeons from Italy.  Dr.Livio Presutti,  from Modena Italy and his contemporary Dr. Marchioni Daniele, also working in the same hospital.  Dr. Presutti’s presentation “ Physiological basis and principles of the Transcanal endoscopic approach to the ear” was excellent. 

His other lecture “Endoscopic procedures in Otoneurosurgery” was also an eye opener to the way of using angled endoscopes to reach those areas which cannot be reached with an operating microscope.  Dr.  Marchioni Daniele’s talk “Exclusive endoscopic approach to cholesteatoma” was also excellent.  He highlighted the use of angled endoscopes to eradicate cholesteatoma in the sinus tympani and the epitympanic regions.  This was followed the next day by live endoscopic cadaveric dissection, where we had a chance to learn the minute surgical anatomy of the middle ear.  They then performed live endoscopic Myringoplasty, tympanoplasty, and surgery for cholesteatoma.  The images were excellent.  The only drawback to this approach is that only one hand can be used for surgical manipulation since the other hand is used to hold the endoscope.  Hence, the operating field has to be bloodless, since suction cannot be used simultaneously like when operating under the operating microscope.  The cholesteatoma surgery performed by Dr. Marchioni was really outstanding.  He followed the cholesteatoma right back to the mastoid antrum.  The use of cartilage for reconstruction too was done perfectly.  Dr. Presutti also demonstrated great skill in decompressing  the tympanic segment of the facial nerve in a case of temporal bone fracture following trauma.  I think that these surgeons have ushered in the era of Endoscopic Otology in  India. 

Dr. Bethold Langguth, a psychiatrist from the University of Regensburg, Germany is the chairman of the executive board of the tinnitus research initiative.  He is part of the interdisciplinary tinnitus clinic in Regensburg.  He spoke on the Diagnosis and therapeutic management of tinnitus.  It was interesting to note that tinnitus involved even non-auditory brain areas and the relevance of the memory mechanisms in persistent tinnitus with its associated distress.

Of course our Indian colleagues like Dr. Vijendra and Dr. Mahadeviah too demonstrated some very interesting live surgery.  

Like in the American Academy meetings, for the first time, there were instructional courses between 8 and 10 in the mornings.  Dr. P.G. Visvanathan shared his experiences on cartilage tympanoplasty in this forum, which was well attended and which benefited us immensely.

Of course the entertainment in  the evening matched the academic sessions.  The world renowned percussionist Sivamani, entertained us on the first day followed  by live musical show by S.P. Balasubramaniam.

Hats off to Dr. Vijendra and his team for putting up such  a good show.  It was a pleasant experience at Bangalore.  Looking forward to the Chennai conference.  I am  sure that Dr.Ravi and his team will do a fine job there too.

New breakthroughs in pathophysiology and treatment for Noise Induced Hearing Loss (NIHL)

It's easy to say that we should avoid loud noises, but in reality, this is not always possible. Front-line soldiers or first responders do not have time to worry about the long-term effects of loud noise when they are giving their all. If, however, a drug could be developed to minimize the negative effects of loud noises, it would benefit one and all.

Noise-induced hearing loss, with accompanying tinnitus and sound hypersensitivity is a common condition which leads to communication problems and social isolation.

In a research report published in the September 2013 issue of The FASEB Journal, scientists describe exactly what type of damage noise does to the inner ear, and provide insights into a compound that may prevent noise-related damage.

To make this discovery, Shi and colleagues used three groups of 6 - 8 week old mice, which consisted of a control group, a group exposed to broadband noise at 120 decibels for three hours a day for two days, and a third group given single-dose injections of pigment epithelium-derived factor (PEDF) prior to noise exposure. PEDF is a protein found in vertebrates that is currently being researched for the treatment of diseases like heart disease and cancer. The cells that secrete PEDF in control animals showed a characteristic branched morphology, with the cells arranging in a self-avoidance pattern which provided good coverage of the capillary wall. The morphology of the same cells in the animals exposed to wide-band noise, however, showed clear differences -- noise exposure caused changes in melanocytes located in the inner ear.

At the present time, the only treatment strategies for hearing loss are hearing aids and cochlear implants. Drug therapies for noise-induced hearing loss have only recently been proposed and, to date, there are virtually no treatments that can repair the damage to the inner ear and reduce the impact of hearing loss.

Researchers from the University of Auckland, New Zealand, have discovered that a potent new drug restores hearing after noise-induced hearing loss in rats. The landmark discovery found that injection of an agent called 'ADAC', activates adenosine receptors in cochlear tissues, resulting in recovery of hearing function.

Vlajkovic and his team's study investigates the potential of adenosine amine congener (ADAC) -- a selective A1 adenosine receptor agonist -- in the treatment of noise-induced hearing loss. Wistar rats were exposed to narrow-band noise for 2 -- 24 hours in an acoustic chamber to induce cochlear damage and permanent hearing loss. ADAC or placebo control was then administered by injection(s) in the abdomen, either as a single injection at six hours or multiple daily injections. The researchers measured the hearing in the rats before and after the treatments using a technique known as auditory brainstem response (ABR). They also used histological techniques to determine the number of missing cochlear sensory hair cells after noise exposure and the noise-induced production of free radicals.

Their results show that cochlear injury and hearing loss in rats exposed to narrow-band noise can be substantially restored by ADAC administration after noise exposure. Early treatment starting six hours after noise exposure was the most effective and provided greater recovery than late treatment starting 24 hours after noise exposure. The most sustainable treatment strategy was the one involving multiple injections of ADAC for five days after noise exposure. This therapy significantly attenuated noise-induced hearing loss and improved sensory hair cell survival.

Resveratrol, a substance found in red grapes and red wine, may have the potential to protect against hearing and cognitive decline, according to a published laboratory study from Henry Ford Hospital in Detroit.

The study shows that healthy rats are less likely to suffer the long-term effects of noise-induced hearing loss when given resveratrol before being exposed to loud noise for a long period of time. Resveratrol is a very powerful chemical that seems to protect against the body's inflammatory process as it relates to aging, cognition and hearing loss. The latest study focuses on the inflammatory process as it relates to aging, cognition and hearing loss.

It was designed to identify the potential protective mechanism of resveratrol following noise exposure by measuring its effect on cyclooxygenase-2 (or COX-2, key to the inflammatory process) protein expression and formation of reactive oxygen species, which plays an important role in cell signaling and homeostasis.

The study reveals that acoustic over-stimulation causes a time-dependent, up-regulation of COX-2 protein expression, and, resveratrol, significantly reduces reactive oxygen species formation, inhibits COX-2 expression and reduces noise-induced hearing loss following noise exposure in rats. Ultimately, these findings suggest that resveratrol may exert a protective effect from noise-induced hearing loss by the inhibition of COX-2 expression and reactive oxygen species formation, although other mechanism may also be involved.

An epilepsy drug shows promise in an animal model at preventing tinnitus from developing after exposure to loud noise, according to a new study by researchers at the University of Pittsburgh School of Medicine.

The team focused on an area of the brain that is home to an important auditory center called the dorsal cochlear nucleus (DCN). From previous research in a mouse model, they knew that tinnitus is associated with hyperactivity of DCN cells -- they fire impulses even when there is no actual sound to perceive. For the new experiments, they took a close look at the biophysical properties of tiny channels, called KCNQ channels, through which potassium ions travel in and out of the cell.

They found that mice with tinnitus have hyperactive DCN cells because of a reduction in KCNQ potassium channel activity. These KCNQ channels act as effective "brakes" that reduce excitability or activity of neuronal cells.

Tzounopoulos and his team tested whether an FDA-approved epilepsy drug called retigabine, which specifically enhances KCNQ channel activity, could prevent the development of tinnitus. Thirty minutes into the noise exposure and twice daily for the next five days, half of the exposed group was given injections of retigabine. The researchers found that mice that were treated with retigabine immediately after noise exposure did not develop tinnitus.

Such a medication could be a very helpful preventive strategy for soldiers and other people who work in situations where exposure to very loud noise is likely,

Source:

1. Federation of American Societies for Experimental Biology. "Now hear this: Scientists discover compound to prevent noise-related hearing loss." ScienceDaily, 29 Aug. 2013. Web. 29 Sep. 2013. 
2. Srdjan M. Vlajkovic, Kyu-Hyun Lee, Ann Chi Yan Wong, Cindy X. Guo, Rita Gupta, Gary D. Housley, Peter R. Thorne.Adenosine amine congener mitigates noise-induced cochlear injury. Purinergic Signalling, 2010; DOI:10.1007/s11302-010-9188-5
3. M. D. Seidman, W. Tang, V. U. Bai, N. Ahmad, H. Jiang, J. Media, N. Patel, C. J. Rubin, R. T. Standring. Resveratrol Decreases Noise-Induced Cyclooxygenase-2 Expression in the Rat Cochlea. Otolaryngology -- Head and Neck Surgery, 2013; DOI: 10.1177/0194599813475777
4. J. W. Middleton, T. Kiritani, C. Pedersen, J. G. Turner, G. M. G. Shepherd, T. Tzounopoulos. Mice with behavioral evidence of tinnitus exhibit dorsal cochlear nucleus hyperactivity because of decreased GABAergic inhibition. Proceedings of the National Academy of Sciences, 2011; 108 (18): 7601 DOI:10.1073/pnas.1100223108

The Exciting Science Behind Taste

We know that the human tongue can detect five tastes -- sweet, salt, sour, bitter and umami (a taste for identifying protein rich foods).

Taste cells are found in papillae, the little bumps on our tongues. These cells contain the receptors that interact with chemicals in foods to allow us to sense sweet, salty, sour, bitter, and umami. Taste cells are located in clusters called taste buds, which in turn are found in papillae, the raised bumps visible on the tongue's surface.

Two types of taste cells contain chemical receptors that initiate perception of sweet, bitter, umami, salty, and sour taste qualities. A third type appears to serve as a supporting cell.

A remarkable characteristic of these sensory cells is that they regularly regenerate. All three taste cell types undergo frequent turnover, with an average lifespan of 10-16 days. As such, new taste cells must constantly be regenerated to replace cells that have died.

When sweet, bitter and umami molecules reach the tongue, they activate taste receptors in specialized cells called Type II taste cells. 'how do these taste cells tell the brain that they have detected something?' This question has been a longstanding missing link in our understanding of taste perception. The scientists already knew that activation of taste receptors on Type II cells initiates a complex chain of events inside the taste cells. What they found, as reported in the current issue of Nature, is that the final step involves the opening of a pore formed by CALHM1 (calcium-homeostasis-modulator-1) in the taste cell membrane. The open channel allows molecules of the neurotransmitter ATP to leave the taste cell and relay a signal to adjacent nerve cells connected to the brain.

Monell molecular neurobiologist Ichiro Matsumato, PhD, contributed to the work by showing that the gene for CALHM1 is expressed in Type II taste cells, but not in other types of taste tissue. Their findings demonstrate that the CALHM1 pore is localized specifically in cells that detect sweet, bitter and umami taste.

The necessity of CALHM1 for the ability to taste sweet, bitter, and umami was demonstrated in behavioral tests performed by Tordoff. Reasoning that mice lacking the CALMH1 channel would not be able to release ATP to send information about sweet, bitter and umami taste detection to the brain, Tordoff tested the taste preferences of Calhm1 'knockout' mice. Engineered by co-author Philippe Marambaud, PhD, of the Feinstein Institute for Medical Research, the knockout mice lack the gene that codes for CALHM1.

"Like humans, mice with an intact CALHM1 gene avidly drink sucrose and other sweeteners, and avoid bitter compounds such as quinine. However, mice lacking CALHM1 are very unusual," said Tordoff. "These mice treat sweeteners and bitter compounds as if they were water. They behave as if they can't taste them at all."

Responses to salty and sour tastes were not affected by the missing gene because perception of these taste qualities is mediated via a different set of taste cells.

Of the five taste sensations -- sweet, bitter, sour, salty and umami -- sour is arguably the strongest yet the least understood. Sour is the sensation evoked by substances that are acidic, such as lemons and pickles. The more acidic the substance, the more sour the taste.

Acids release protons. How protons activate the taste system had not been understood. The USC team expected to find protons from acids binding to the outside of the cell and opening a pore in the membrane that would allow sodium to enter the cell. Sodium's entry would send an electrical response to the brain, announcing the sensation that we perceive as sour.

Instead, the researchers found that the protons were entering the cell and causing the electrical response directly.

"In order to understand how sour works, we need to understand how the cells that are responsive to sour detect the protons," said senior author Emily Liman, associate professor of neurobiology in the USC College of Letters, Arts and Sciences.

"In the past, it's been difficult to address this question because the taste buds on the tongue are heterogeneous. Among the 50 or so cells in each taste bud there are cells responding to each of the five tastes. But if we want to know how sour works, we need to measure activity specifically in the sour sensitive taste cells and determine what is special about them that allows them to respond to protons."

Liman and her team bred genetically modified mice and marked their sour cells with a yellow florescent protein. Then they recorded the electrical responses from just those cells to protons.

The ability to sense protons with a mechanism that does not rely on sodium has important implications for how different tastes interact, Liman speculates.

"This mechanism is very appropriate for the taste system because we can eat something that has a lot of protons and not much sodium or other ions, and the taste system will still be able to detect sour," she said. "It makes sense that nature would have built a taste cell like this, so as not to confuse salty with sour."



References:

1. Akiyuki Taruno, Valérie Vingtdeux, Makoto Ohmoto, Zhongming Ma, Gennady Dvoryanchikov, Ang Li, Leslie Adrien, Haitian Zhao, Sze Leung, Maria Abernethy, Jeremy Koppel, Peter Davies, Mortimer M. Civan, Nirupa Chaudhari, Ichiro Matsumoto, Göran Hellekant, Michael G. Tordoff, Philippe Marambaud, J. Kevin Foskett. CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. Nature, 2013; DOI:10.1038/nature11906
2. Monell Chemical Senses Center. "Scientists help identify a missing link in taste perception."ScienceDaily, 6 Mar. 2013. Web. 8 Mar. 2013.
3. Rui B. Chang, Hang Waters, Emily R. Liman. A proton current drives action potentials in genetically identified sour taste cells. Proceedings of the National Academy of Sciences, 2010; DOI:10.1073/pnas.1013664107
4. University of Southern California (2010, November 25). How people perceive sour flavors: Proton current drives action potentials in taste cells. ScienceDaily. Retrieved March 8, 2013, from http://www.sciencedaily.com­/releases/2010/11/101124114709.htm

Temporary Hearing Deprivation Can Lead to 'Lazy Ear'

Scientists have gained new insight into why a relatively short-term hearing deprivation during childhood may lead to persistent hearing deficits, long after hearing is restored to normal. The research, published by Cell Press in the March 11 issue of the journal Neuron, reveals that, much like the visual cortex, development of the auditory cortex is quite vulnerable if it does not receive appropriate stimulation at just the right time.

It is well established that degraded sensory experience during critical periods of childhood development can have detrimental effects on the brain and behavior. In the classic example, a condition called amblyopia (also known as lazy eye) can arise when balanced visual signals are not transmitted from each eye to the brain during a critical period for visual cortex development.

An analogous problem may exist in the realm of hearing, in that children commonly experience a buildup of viscous fluid in the middle ear cavity, called otitis media with effusion, which can degrade the quality of acoustic signals reaching the brain and has been associated with long-lasting loss of auditory perceptual acuity," explains senior study author, Dr. Daniel Polley from the Massachusetts Eye and Ear Infirmary.

Dr. Polley and his colleague Dr. Maria Popescu from Vanderbilt University implemented a method to reversibly block hearing in one ear in infant, juvenile, and adult rats then looked at how auditory brain areas were impacted by the temporary hearing loss.

They observed that the temporary hearing loss in one ear distorted auditory patterning in the brain, weakened the deprived ear's representation and strengthened the open ear's representation. The scope of reorganization was most striking in the cortex (and not "lower" parts of the auditory pathway) and was more pronounced when hearing deprivation began in infancy than in later life. Therefore, it appears that maladaptive plasticity in the developing auditory cortex might underlie "amblyaudio," in a similar fashion to the contributions of visual cortex plasticity to amblyopia.

"The good news about amblyaudio is that it is unlikely to be a permanent problem for most people," concludes Dr. Polley. "Even if the acoustic signal isn't improved within the critical period, the mature auditory cortex still expresses a remarkable degree of plasticity. We know that properly designed visual training can improve visual acuity in adult amblyopia patients. We are gearing up now to study whether auditory perceptual training may also be a promising approach to accelerate recovery in individuals with unresolved auditory processing deficits stemming from childhood hearing loss."

Journal reference:
Maria V. Popescu, Daniel B. Polley. Monaural Deprivation Disrupts Development of Binaural Selectivity in Auditory Midbrain and Cortex. Neuron, 2010; 65 (5): 718-731 DOI:10.1016/j.neuron.2010.02.019

Health risks for women suffering from Migraine with aura

Women who have migraines with aura, which are often visual disturbances such as flashing lights, may be more likely to have problems with their heart and blood vessels, and those on newer contraceptives may be at higher risk for blood clots,

The first study showed that migraine with aura is a strong contributor to the development of major cardiovascular events such as heart attack and stroke. After high blood pressure, migraine with aura was the second strongest single contributor to risk of heart attacks and strokes, It came ahead of diabetes, current smoking, obesity, and family history of early heart disease. while people with migraine with aura have an increased risk, it does not mean that everyone with migraine with aura will have a heart attack or stroke. People with migraine with aura can reduce their risk in the same ways others can, such as not smoking, keeping blood pressure low and weight down and exercising.

The second study looked at women with migraine who take hormonal contraceptives and the occurrence of blood clots. The study involved women with migraine with and without aura who were taking both newer contraceptives such as the contraceptive patch and ring and older contraceptives. Women with migraine with aura were more likely to have experienced blood clot complications such as deep vein thrombosis with all types of contraceptives than women with migraine without aura. The occurrence of blood clot complications was also higher in women with migraine who took contraceptives than women taking the contraceptives who did not have migraine.

Women who have migraine with aura should be sure to include this information in their medical history and talk to their doctors about the possible higher risks of newer contraceptives

Migraine with aura is associated with a twofold increased risk of stroke, The risk was highest among young women with migraine with aura who smoke and use estrogen containing contraceptives. An international team of researchers analysed the results of nine studies on the association between any migraine (with and without aura) and cardiovascular disease. They show that migraine with aura is associated with a twofold increased risk of ischemic stroke. This risk is further increased by being female, age less than 45 years, smoking, and estrogen containing contraceptive use. In light of these findings, the authors recommend that young women who have migraine with aura should be strongly advised to stop smoking, and methods of birth control other than estrogen containing contraceptives should be considered. They suggest that patients who have migraine with aura should be followed closely and treated aggressively for modifiable cardiovascular risk factors.

Citations:

American Academy of Neurology (AAN). "Migraine with aura may lead to heart attack, blood clots for women." ScienceDaily, 15 Jan. 2013. Web. 3 Mar. 2013.

Location and role of ion channels of the cochlea

Anthony Ricci, PhD, associate professor of otolaryngology, and colleagues at the University of Wisconsin and the Pellegrin Hospital in France found that the ion channels responsible for hearing aren't located where scientists previously thought. The discovery turns old theories upside down, and it could have major implications for the prevention and treatment of hearing loss

Location is important, because our entire theory of how sound activates these channels depends on it. Now we have to re-evaluate the model that we've been showing in textbooks for the last 30 years."

Deep inside the ear, specialized cells called "hair cells" sense vibrations in the air. The cells contain tiny clumps of hairlike projections, known as stereocilia, which are arranged in rows by height. Sound vibrations cause the stereocilia to bend slightly, and scientists think the movement opens small pores, called ion channels. As positively charged ions rush into the hair cell, mechanical vibrations are converted into an electrochemical signal that the brain interprets as sound.

But after years of searching, scientists still haven't identified the ion channels responsible for this process. To pinpoint the channels' location, Ricci and colleagues squirted rat stereocilia with a tiny water jet. As pressure from the water bent the stereocilia, calcium flooded into the hair cells. The researchers used ultrafast, high-resolution imaging to record exactly where calcium first entered the cells. Each point of entry marked an ion channel.

The results were surprising: Instead of being on the tallest rows of stereocilia, like scientists previously thought, Ricci's team found ion channels only on the middle and shortest rows.

Ion channels on hair cells not only convert mechanical vibrations into signals for the brain, but they also help protect the ear against sounds that are too loud. Through a process called adaptation, the ear adjusts the sensitivity of its ion channels to match the noise level in the environment. Most people are already familiar with this phenomenon, Ricci said, though they might not realize it. "If you watch TV in bed and you have the sound turned down low, you can hear fine when you're going to sleep," he said. "But then when you get up in the morning and turn on the news, you have to turn the volume up."

That's because at night, when everything is quiet, the ear turns up its amplifier to hear softer sounds. "But when you get up in the morning," Ricci said, "and the kids are running around and the dog is barking, the ear has to reset its sensitivity so you can hear in noisier conditions without hurting your ear."

Defects in the ear's adaptation process put people at risk for both age-related and noise-related hearing loss. Understanding adaptation is a fundamental step in preventing hearing loss, said Robert Jackler, MD, the Edward C. and Amy H. Sewall Professor in Otorhinolaryngology at Stanford.

"Many forms of hearing loss and deafness are due to disturbances in the molecular biology of the hair cell," said Jackler, who was not involved in the study. "When you understand the nuts and bolts of how the hair cell works, you can understand how it goes wrong and can set about learning how to fix it."

Other scientists have attempted similar experiments in the past, but they used less-sensitive imaging techniques. "Our microscope took images at 500 frames per second," said Ricci, who led the imaging experiments. "That's much faster than it's ever been done before."

Ricci and colleagues also used hair cells from rats, while previous experiments had been done in bullfrogs. Because mammals have fewer, more widely spaced rows of stereocilia, the team was able to determine the precise location of the ion channels.

Citations:

1. Stanford University Medical Center. "How Human Ear Translates Vibrations Into Sounds: Discovery Of Ion Channel Turns Ear On Its Head." ScienceDaily, 28 Apr. 2009. Web. 3 Mar. 2013.
2. Maryline Beurg, Robert Fettiplace, Jong-Hoon Nam & Anthony J Ricci. Localization of inner hair cell mechanotransducer channels using high-speed calcium imaging. Nature Neuroscience, 2009; DOI:10.1038/nn.2295

Is there a relationship between hearing and touch?

There are good reasons to suspect that hearing and touch might have a common genetic basis. Sound-sensing cells in the ear detect vibrations and transform them into electrical impulses. Likewise, nerves that lie just below the surface of the skin detect movement and changes in pressure, and generate impulses. The similarity suggests that the two systems might have a common evolutionary origin—they may depend on an overlapping set of molecules that transform motion into signals that can be transmitted along nerves to the brain.

People with a certain form of inherited hearing loss have increased sensitivity to low frequency vibration. The research findings, which were published in Nature Neuroscience,reveal previously unknown relationships between hearing loss and touch sensitivity. Those suffering from hereditary DFNA2 hearing impairment is caused by a mutation which disrupts the function of many hair cells in the inner ear. This mutation, the researchers suspected, might also affect the sense of touch. Tiny, delicate hairs in our inner ear vibrate to the pressure of the sound waves. The vibrations cause an influx of positively charged potassium ions into the hair cells. This electric current produces a nerve signal that is transmitted to the brain which results in hearing. The potassium ions flow through a channel in the cell membrane and again out of the hair cells. This potassium channel, a protein molecule called KCNQ4, is destroyed by the mutation in such hearing-impaired people. The sensory cells gradually die off due to overload. They found that KCNQ4 is present not only in the ear, but also in some sensory cells of the skin. Clearly there are parallels to hearing, As a first step, the researchers in the Jentsch lab created a mouse model for deafness by generating a mouse line that carries the same mutation in the potassium channel as a patient with this form of genetic hearing loss. The touch receptors in the skin where the KCNQ4 potassium channel is found did not die off due to the defective channel like they did in the ear, but instead showed an altered electric response to the mechanical stimuli in the mutated mouse. They reacted much more sensitively to vibration stimuli in the low frequency range. The sensation of touch varies greatly from person to person -- some people are much more sensitive to touch than others. DFNA2 patients are extremely sensitive to vibrations,

In recent years about 70 genes have been identified in humans, mutations in which trigger hearing loss or deafness. Surprisingly, no genes have been found that negatively influence the sense of touch,

In another study, to see whether the sense of touch also has a hereditary component, the researchers first studied 100 pairs of twins -- 66 pairs of monozygotic twins and 34 dizygotic pairs of twins. Monozygotic twins are genetically completely identical; dizygotic twins are genetically identical to 50 percent. The tests showed that the touch sensitivity of the subjects was determined to more than 50 percent by genes. Furthermore, hearing and touch tests showed that there is a correlation between the sense of hearing and touch.

The researchers decided it would take too much time to analyze which of the approximately 70 genes that adversely affect the sense of hearing may also negatively affect the sense of touch. Therefore, the researchers focused specifically on patients with Usher syndrome, a hereditary form of hearing impairment, in which the patients progressively become blind. Usher syndrome patients have varying degrees of hearing impairment, and the disease is genetically very well studied. There are nine known Usher genes carrying mutations which cause the disease. The studies revealed that not all patients with Usher-syndrome have poor tactile acuity and touch sensitivity. The researchers showed that only patients with Usher syndrome who have a mutation in the gene USH2A have poor touch sensitivity. This mutation is also responsible for the impaired hearing of 19 patients. The 29 Usher-syndrome patients in whom the mutation could not be detected had a normal sense of touch. The researchers thus demonstrated that there is a common genetic basis for the sense of hearing and touch.

Citations:

1. Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch. "People with DFNA2 hearing loss show increased touch sensitivity, study shows." ScienceDaily, 12 Dec. 2011. Web. 3 Mar. 2013.
2. Matthias Heidenreich, Stefan G Lechner, Vitya Vardanyan, Christiane Wetzel, Cor W Cremers, Els M De Leenheer, Gracia Aránguez, Miguel Ángel Moreno-Pelayo, Thomas J Jentsch, Gary R Lewin. KCNQ4 K+ channels tune mechanoreceptors for normal touch sensation in mouse and man. Nature Neuroscience, 2011; DOI:10.1038/nn.2985
3. Helmholtz Association of German Research Centres. "Hearing and touch have common genetic basis: Gene mutation leads to impairment of two senses." ScienceDaily, 1 May 2012. Web. 3 Mar. 2013.
4. Henning Frenzel, Jörg Bohlender, Katrin Pinsker, Bärbel Wohlleben, Jens Tank, Stefan G. Lechner, Daniela Schiska, Teresa Jaijo, Franz Rüschendorf, Kathrin Saar, Jens Jordan, José M. Millán, Manfred Gross, Gary R. Lewin. A Genetic Basis for Mechanosensory Traits in Humans. PLoS Biology, 2012; 10 (5): e1001318 DOI:10.1371/journal.pbio.1001318

Protein that converts sound waves into electrical waves in the cochlea discovered

For scientists who study the genetics of hearing and deafness, finding the exact genetic machinery in the inner ear that responds to sound waves and converts them into electrical impulses, the language of the brain, has been something of a holy grail.

The physical basis for hearing and mechanotransduction involves receptor cells deep in the ear that collect vibrations and convert them into electrical signals that run along nerve fibers to areas in the brain where they are interpreted as sound.

What happens in hearing is that mechanical vibration waves traveling from a sound source hit the outer ear, propagate down the ear canal into the middle ear and strike the eardrum. The vibrating eardrum moves a set of delicate bones that communicate the vibrations to a fluid-filled spiral in the inner ear known as the cochlea. .

Inside the cochlea are specialized "hair" cells that have symmetric arrays of extensions known as stereocilia protruding out from their surface. The movement of the fluid inside the cochlea causes the stereocilia to move, and this movement causes ion channels to open. The opening of these channels is a signal monitored by sensory neurons surrounding the hair cells, and when those neurons sense some threshold level of stimulation, they fire, communicating electrical signals to the auditory cortex of the brain.

Scientists at The Scripps Research Institute (TSRI) in La Jolla, CA, have identified a critical component of this ear-to-brain conversion -- a protein called TMHS. This protein is a component of the so-called mechanotransduction channels in the ear, which convert the signals from mechanical sound waves into electrical impulses transmitted to the nervous system. Not only have the scientists finally found a key protein in this process, but the work also suggests a promising new approach toward gene therapy. In the laboratory, the scientists were able to place functional TMHS into the sensory cells for sound perception of newborn deaf mice, restoring their function. In some forms of human deafness, there may be a way to stick these genes back in and fix the cells after birth," TMHS appears to be the direct link between the spring-like mechanism in the inner ear that responds to sound and the machinery that shoots electrical signals to the brain. When the protein is missing in mice, these signals are not sent to their brains and they cannot perceive sound.

Specific genetic forms of this protein have previously been found in people with common inherited forms of deafness, and this discovery would seem to be the first explanation for how these genetic variations account for hearing loss.

TMHS turns out to play a role in a molecular complex called the tip link, which several years ago was discovered to cap the stereocilia protruding out of hair cells. These tip links connect the tops of neighboring stereocilia, bundling them together, and when they are missing the hair cells become splayed apart.

But the tip links do more than just maintain the structure of these bundles. They also house some of the machinery crucial for hearing -- the proteins that physically receive the force of a sound wave and transduce it into electrical impulses by regulating the activity of ion channels. The molecules that form the tip links were identified in the same laboratory previously, but the ion channels and the molecules that connect the tip link to the ion channels remained elusive. For years, scientists have eagerly sought the exact identity of the proteins responsible for this process.

In this study scientists showed that TMHS is one of the lynchpins of this process, where it is a subunit of the ion channel that directly binds to the tip link. When the TMHS protein is missing, otherwise completely normal hair cells lose their ability to send electrical signals.

Journal Reference:

1. Wei Xiong, Nicolas Grillet, Heather M. Elledge, Thomas F.J. Wagner, Bo Zhao, Kenneth R. Johnson, Piotr Kazmierczak, Ulrich Müller. TMHS Is an Integral Component of the Mechanotransduction Machinery of Cochlear Hair Cells. Cell, 2012; 151 (6): 1283 DOI:10.1016/j.cell.2012.10.041
2. Scripps Research Institute. "Scientists identify molecules in the ear that convert sound into brain signals." ScienceDaily, 6 Dec. 2012. Web. 20 Feb. 2013.

Two-photon microscopy offers look inside intact cochlea

For the first time, researchers have snapped pictures of mouse inner ear cells using an approach that doesn’t damage tissue or require elaborate dyes. The approach could offer a way to investigate hearing loss and may help guide the placement of cochlear devices or other implants.

The small delicate cochlea and associated parts are encased in the densest bone in the body.  With standard anatomical imaging techniques such as MRI, the inner ear just looks like a small grey blob. “We can’t biopsy it, we can’t image it, so it’s very difficult to figure out why people are deaf,” said ear surgeon and neuroscientist Konstantina Stankovic of the Massachusetts Eye and Ear Infirmary in Boston.  

Stankovic and her colleagues took a peek at inner ear cells using an existing technique called two-photon microscopy. Stankovic and her colleagues took a peek at inner ear cells using an existing technique called two-photon microscopy. This approach shoots photons at the target tissue, exciting particular molecules that then emit light. The researchers worked with mice exposed to 160 decibels of sound for two hours. Then they removed the rodents’ inner ears, which includes the spiraled, snail-shaped cochlea and other organs. Instead of cutting into the cochlea, the researchers peered through the “round window” — a middle ear opening covered by a thin membrane that leads to the cochlea.

The approach yielded clear images of rows of the inner ear’s hair cells, tiny hairlike structures that detect sound vibrations, enabling hearing. Unlike in control mice, ears of noise-exposed mice had visible damage: Whole sections of ear cells were wiped out, Stankovic reported February 17 at the annual meeting of the American Association for the Advancement of Science.

She hopes the approach will not only shed light on the various kinds of damage that lead to hearing loss, but that it also will help guide the insertion of implants.  In the future, the imaging approach might help guide the placement of an experimental device that extracts energy from the inner ear, acting as a tiny battery. The new device, developed by Stankovic and colleagues, doesn’t generate enough power to run a cochlear implant. It could, however, act as a sensor, monitoring for infections or sensing drug levels.

Such devices might prove very useful for monitoring all sorts of physiological responses, says biomedical engineer Philippe Renaud of Swiss Federal Institute of Technology in Lausanne. They could prove especially useful, he says, in patients for whom devices need to be small, delicate and efficient, such as those undergoing deep brain stimulation.

Citations:

K. M. Stankovic. Treating deafness with better vision: cellular level optical imaging of the inner ear. Annual meeting of the American Association for the Advancement of Science, Boston. Presented February 17, 2013

Imaging technique offers look inside hearing loss
By Rachel Ehrenberg in Science news

http://www.sciencenews.org/view/generic/id/348394/description/Imaging_technique_offers_look_inside_hearing_loss

Gene therapy - barriers and breakthroughs

Gene therapy is the use of DNS as a pharmaceutical agent to treat disease. It derives its name from the idea that DNA can be used to supplement or alter genes within an individual's cells as a therapy to treat disease. The most common form of gene therapy involves using DNA that encodes a functional, therapeutic gene to replace a mutated gene. Other forms involve directly correcting a mutation, or using DNA that encodes a therapeutic protein drug (rather than a natural human gene) to provide treatment. In gene therapy, DNA that encodes a therapeutic protein is packaged within a "vector", which is used to get the DNA inside cells within the body. Once inside, the DNA becomes expressed by the cell machinery, resulting in the production of therapeutic protein, which in turn treats the patient's disease.

Gene therapy using an Adenovirus vector. A new gene is inserted into a cell using an adenovirus. If the treatment is successful, the new gene will make functional protein to treat a disease.

Gene therapy is still in its infancy, with obvious challenges around targeting damaged cells and creating corrective genes. An equally important challenge, addressed by this research, is finding ways to transport the corrective genes into the cell. This is a problem, because of the poor permeability of cell membranes.  There are several barriers to gene delivery, The genetic material must be protected during transit to a cell, it must pass into a cell, it must survive the cell's defense mechanisms, and it must enter into the cell's guarded nucleus.

If all of these barriers can be overcome, gene therapy would be a valuable technique with profound clinical implications. It has the potential to correct a number of human diseases that result from specific genes in a person's DNA makeup not functioning properly - or not at all. Gene therapy would provide a mechanism to replace these specific genes, swapping out the bad for the good. Safety is a primary concern when working with gene therapy. Some of the first attempts at gene therapy used viruses to insert DNA into cells. Viruses can be dangerously toxic, however, and this fact was tragically demonstrated a decade ago when an 18-year-old boy enrolled in a gene therapy study had a massive immune reaction to the viruses used. He died just a few days into the treatment from multiple organ failure, precipitating an immediate halt to the trial.

Several patients in gene therapy clinical trials have developed leukemia as a result of their treatment. The underlying cause of leukemia is thought to be that the viral vectors used to carry the therapeutic gene into cells (gamma-RVs) integrate into the genome of the cells disrupting the natural control of cancer-associated genes (a process known as insertional mutagenesis).

In gene therapy, the viruses are often equipped with additional genes, such as for immune mediators or for proteins inducing programmed cell death. However, these gene products can harm the body if they are released at the wrong moment or at excessive levels. It would be advantageous, if these switches could be turned on and off at a specific time. In order to construct such a switch, the researchers inserted synthetic segments of DNA into the viral genetic material in the direct vicinity of the transferred gene. In the infected cell, this construct is transcribed together with the transferred gene into a single messenger RNA (mRNA) molecule. The switch is operated using an agent which is added to cells infected with the virus. The substance is precisely fitted to bind to the RNA molecule and induces it to cut itself up. Thus, the potentially dangerous protein cannot be produced. The researchers copied this regulation mechanism from bacteria which use RNA switches to regulate production of numerous proteins.

Since then, many alternatives to viruses have emerged for use in gene therapy, including synthetic molecules like "dendrimers," a word that derives from the Greek word for "tree." Similar to trees, dendrimers are branching molecules that are slightly positively charged. This allows them to be loaded with DNA (which is slightly negative charged) for insertion into a cell. Dendrimers seem to offer many advantages over viruses. They may be much less toxic, and they may offer other advantages in terms of cost, ease of production, and the ability to transport very long genes. If they can be designed to efficiently -- and safely -- shuttle genes into human cells, then they may be a more practical solution to gene therapy than viruses. So far, laboratory experiments with different types of dendrimers have shown that they can insert genes into cells, but only with very low efficiency.

Using the principles of evolution and natural selection, that were initially conceived by Charles Darwin, they have now developped an efficient and safe gene delivery approach based on non-viral genetic elements, called transposons. Transposons are mobile DNA elements that can integrate into 'foreign' DNA via a 'cut-and-paste' mechanism. In a way they are natural gene delivery vehicles. The researchers constructed the transposons in such a way that they can carry the therapeutic gene into the target cell DNA. Doing so, they obviate the need to rely on viral vectors

This research describes a model peptide sequence, dubbed GeT (gene transporter), which wraps around genes, transports them through cell membranes and helps their escape from intracellular degradation traps. The process mimics the mechanisms viruses use to infect human cells. GeT was designed to undergo differential membrane-induced folding -- a process whereby the peptide changes its structure in response to only one type of membranes. This enables the peptide, and viruses, to carry genes into the cell. Interestingly, the property also makes it antibacterial and so capable of gene transfer even in bacteria-challenged environments. To prove the concept, the researchers used GeT to transfer a synthetic gene encoding for a green fluorescent protein -- a protein whose fluorescence in cells can be seen and monitored using fluorescence microscopy. The design can serve as a potential template for non-viral delivery systems and specialist treatments of genetic disorders.

To create the new gene therapy vector, Jans and colleagues used pieces of different genes to create a protein called a "modular DNA carrier," which can be produced by bacteria. This protein carries therapeutic DNA and delivers it to a cell's nucleus, where it reprograms a cell to function properly. In the laboratory, these carrier proteins were combined with therapeutic DNA and attached to cell membrane receptors and the nuclear import machinery of target cells. In turn, the packaged DNA moved into the cell through the cytoplasm and into the nucleus.

Genetically-engineered spider-silk proteins represent a versatile and useful new platform polymer for non viral gene delivery. The scientists describe modifying spider silk proteins so that they attach to diseased cells and not healthy cells. They also engineered the spider silk to contain a gene that codes for the protein that makes fireflies glow in order to provide a visual signal (seen using special equipment) that the gene has reached its intended target. In lab studies using mice containing human breast cancer cells, the spider-silk proteins attached to the cancer cells and injected the DNA material into the cells without harming the mice.

For the first time ever, chitosan nanoparticles have been used as a carrier for gene therapy in the ear. Chitosan is produced from shrimp shells. researchers attempted to use chitosan as a carrier to deliver drugs and genes to the inner ear in guinea pigs. Chitosan was able to deliver drugs through the membrane that covers the tiny gap between the middle ear and inner ear. Chitosan was also able to deliver genes to the hair cells. Whether or not the results from guinea pigs can be transferred to human ears remains uncertain. However, chitosan is non-toxic and is not harmful to cells. Chitosan is therefore better than other carriers and has characteristics that mean it could potentially be used with patients. Extremely small nanoparticles in the range of 50-200 nm (nanometres) are formed spon­taneously when the positively charged chitosan and negatively charged genes are mixed. Chitosan does a good job packaging up DNA and RNA's relatively large molecules. When the nanoparticles have passed through a membrane, chitosan packages up the gene molecules so they return to their normal size again. Chitosan also creates gaps between cells, which facilitate the absorption of medicine.

Researchers from Johns Hopkins and Northwestern universities have discovered how to control the shape of nanoparticles that move DNA through the body and have shown that the shapes of these carriers may make a big difference in how well they work in treating cancer and other diseases. A major advance in this work is that Mao and his colleagues reported that they were able to "tune" these particles in three shapes, resembling rods, worms and spheres, which mimic the shapes and sizes of viral particles. "We could observe these shapes in the lab, but we did not fully understand why they assumed these shapes and how to control the process well," Mao said. These questions were important because the DNA delivery system he envisions may require specific, uniform shapes. The worm-shaped particles resulted in 1,600 times more gene expression in the liver cells than the other shapes," Mao said. This means that producing nanoparticles in this particular shape could be the more efficient way to deliver gene therapy to these cells.  The particle shapes used in this research are formed by packaging the DNA with polymers and exposing them to various dilutions of an organic solvent. DNA's aversion to the solvent, with the help of the team's designed polymer, causes the nanoparticles to contract into a certain shape with a "shield" around the genetic material to protect it from being cleared by immune cells.


Source:

1. Wikipedia
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3. Federation of American Societies for Experimental Biology (2009, September 2). Finding The ZIP-code For Gene Therapy: Scientists Imitate Viruses To Deliver Therapeutic Genes. ScienceDaily. Retrieved January 13, 2013, from http://www.sciencedaily.com­/releases/2009/08/090831130749.htm 
4. Helmholtz Association of German Research Centres (2012, August 21). Viruses with integrated gene switch. ScienceDaily. Retrieved January 13, 2013, from http://www.sciencedaily.com­/releases/2012/08/120821114738.htm 
5. National Physical Laboratory (2011, August 12). Scientists copy the ways viruses deliver genes.ScienceDaily. Retrieved January 13, 2013, from http://www.sciencedaily.com­/releases/2011/08/110811094836.htm 
6. American Institute of Physics (2009, April 30). First Large-scale Computer Simulation Of Gene Therapy. ScienceDaily. Retrieved January 13, 2013, from http://www.sciencedaily.com­/releases/2009/04/090429152430.htm 
7. Northwestern University. "Shape matters in DNA nanoparticle therapy: Particles could become a safer, more effective delivery vehicle for gene therapy." ScienceDaily, 12 Oct. 2012. Web. 13 Jan. 2013.