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The local news ran a very heartwarming story last night. A young girl, just under 10 years of age, passed away due to an incurable form of brain cancer, DIPG, which stands for Diffuse Intrinsic or Infiltrating Pontine Gliomas.
The story caught my attention as I had referred the mother to a doctor in our area enrolling patients for a clinical trial on photodynamic therapy to remove inoperable brain tumors. We were too late. There was nothing that could be done.
The family decided to bring their story to the public so others could participate before it's too late.
The devices used in the research were manufactured by Quantum Devices, Inc., Barneveld, WI. We actually participated in the writing of the protocol for this clinical trial.
Cari's story... http://www.nbc15.com/video/?autoStart=true&topVideoCatNo=default&clipId=5300728&flvUri=&partnerclipid=
A local family lost their daughter to a rare and aggressive brain tumor. Now, they are sharing their story, and a doctor says he may one day be able to cure the disease!
In June we spoke to Shannon, Jim and Cari Hadac at their Mt. Horeb home. Cari, Jim and Shannon's daughter was diagnosed with DIPG, which stands for Diffuse Intrinsic or Infiltrating Pontine Gliomas, in August of 2009.
DIPG is a very aggressive form of brain cancer, and once diagnosed a person typically lives about 6-months.
Jim says after they spoke with us, things took a turn for the worst.
"A switch was flipped and everything started changing," Jim says. The Hadac's were told Cari had 48-hours to live. Instead of taking her to the hospital, the Hadac's put Cari in their bed and held a vigil for their dying daughter. There were several close calls over the next few days.
"She had lots of last breaths. I think we went through the grieving process like 15 to 20 times," Shannon says.
Just days before her 10th birthday Cari passed away. "You go from carrying her out of the hospital when she's born," Jim says, "Six days before her tenth birthday to carrying her out to a funeral home."
Stuffed animals, photos, and the Happy Place which Cari helped build in front of her school in Mt. Horeb help Jim and Shannon get by.
But, what really drives them is the thought that one day soon there will be a cure. "That's what we have to live on and hoping that other families don't have to go through what we had to go through," Shannon say.
That day may be coming. Dr. Harry Whelan is a Neurology Professor at the Medical College of Wisconsin in Milwaukee.
For close to 25-years, Dr. Whelan has been looking for a way to treat children with DIPG. Traditional treatments haven't been effective. Dr. Whelan says it's because the tumor cells become so entangled with the regular brain cells that you end up killing all the cells with treatment.
"Any treatments strategies surgery, radiation and chemotherapy has the potential, particularly surgery and radiation if intense, of being equivalent to dynamiting by the power lines," Dr. Whelan says.
During his research, Dr. Whelan did have success with a process called photodynamic therapy.
During the treatment, a patient is given a special type of chemotherapy.
According to the doctor, the tumor cells absorb most of the chemo because they're "greedy." Doctors then insert an LED light that activates the chemo, kills the tumor and keeps the rest of the cells intact. "The light is like a switch that turns the therapy on," Dr. Whelan says.
Since Dr. Whelan's research was published, Dr. Andrew Kay of Australia has been able to improve upon it.
According to a study published in the Journal of Clinical Neuroscience, 50 percent of Dr. Kay's patients were relapse free. Dr. Kay worked with adults and used a laser instead of an LED light.
Now, Dr. Whelan is working on getting a laser of his own to see if he can duplicate those results in children.
"If we can reproduce that here in adults and in children that might be a new source of hope," Dr. Whelan says.
Until the research is done, the Hadac's have a word of advice for parent's that may have a child suffering from DIPG. "Just spend as much time as you can," Jim says.
The FDA has given Dr. Whelan and his team an investigational new drug number. They're the only ones in the country with an approval for this type of research. Now, they'll be able to do experimental therapy if they can get a patients permission. Dr. Whelan says the study should be completed in about three to five years.
Wednesday, November 17, 2010
Monday, October 25, 2010
More Research from 'Down Under'
We have again been blessed by some great research from the Southern Hemisphere, Melinda Fitzgerald of Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, Crawley, 6009, WA, Australia, has been kind enough to share her recent publication. I have just shared the abstract and the discussion, if you'd like to see more, let me know your opinion of the article!
Near Infra-red Light Reduces Oxidative Stress and Preserves Function in CNS
Tissue Vulnerable to Secondary Degeneration Following Partial Transection of the Optic Nerve, Journal of Neurotrauma, (doi: 10,1089/neu.2010.1426) Melinda Fitzgerald: Assistant Professor, PhD, Carole A. Bartlett: MSc, Sophie C. Payne: BSc (Hons), Nathan S. Hart: Associate Professor, PhD, Jenny Rodger: Assistant Professor, PhD, Alan R. Harvey: Winthrop Professor, PhD, Sarah A. Dunlop: Professor, PhD
Abstract
Traumatic injury to the central nervous system is accompanied by the spreading damage of secondary degeneration, resulting in further loss of neurons and function. Partial transection of the optic nerve (ON) has been used as a model of secondary degeneration, where axons of retinal ganglion cells in ventral ON are spared from initial dorsal injury but are vulnerable to secondary degeneration. We have recently demonstrated that, early after partial ON injury, oxidative stress spreads through ventral ON vulnerable to secondary degeneration via astrocytes, and persists in the nerve in aggregates of cellular debris. In this study, we show that diffuse transcranial irradiation of the injury site with far red to near infrared (NIR) light (WARP 10 LED array, centre wavelength 670nm, irradiance 252 Wm-2, 30 minute exposure), as opposed to perception of light at this wavelength, reduced oxidative stress in areas of ON vulnerable to secondary degeneration, following partial injury. The WARP 10 NIR light treatment also prevented increases in NG2 immunopositive oligodendrocyte precursor cells (OPCs) that occurred in ventral ON as a result of partial ON transection. Importantly, normal visual function was restored by NIR light treatment with the WARP 10 LED array, as assessed using optokinetic nystagmus and the Ymaze pattern discrimination task. To our knowledge, this is the first demonstration that 670nm NIR light can reduce oxidative stress and improve function in the CNS following traumatic injury in vivo.
Discussion
In this partial injury study, we have demonstrated that treatment with NIR light (WARP 10 LED array, 670nm) reduced oxidative stress in areas of ON vulnerable to secondary degeneration. NIR light treatment also prevented the secondary increases in NG2 immunopositive OPCs that occurred as a result of partial ON transection. Importantly, visual function was restored to normal by NIR light treatment using the WARP 10 LED array, as assessed using optokinetic nystagmus and the Y-maze pattern discrimination task. To our knowledge, this is the first demonstration that 670nm NIR light can reduce oxidative stress and improve function in the CNS after traumatic injury in vivo.
Improvements in visual function following partial ON transection were achieved with daily 30 minute exposures to the WARP 10 array, for the six days immediately following injury. It is possible that the improvements in performance in the Y-maze pattern discrimination task were partially due to non-specific improvements in working memory with NIR light treatment (Michalikova et al., 2008). Similarly, improvements in optokinetic nystagmus may be influenced by neuroprotective mechanisms not directly related to protection of the injured ON, perhaps involving transfer of visual responses to motor commands (Delgado-Garcia, 2000; Haustead et al., 2008). However, electroretinogram responses in completely normal rats were not altered with exposure to 670nm NIR light LED arrays (Eells et al., 2003), indicating that our observed improvements in visual function following traumatic injury are likely to be a result of direct effects on the partially injured ON. Furthermore, our demonstration that 670nm NIR light penetrates to the injured ON as well as through the retina to the back of the eye supports the premise of a direct effect of NIR light on ON. Beneficial outcomes may also be due to direct effects of 670nm NIR light on RGC somata in the retina, although we did not observe improvements in RGC axonal profiles.
Traumatic injury to the CNS results in glutamate excitotoxicity and altered Ca2+ flux, which leads to oxidative stress and reduced function of neurons and glia (Park et al., 2004; Tezel, 2006). We have recently demonstrated that oxidative stress spreads rapidly through ON vulnerable to secondary degeneration, through the linked astrocytic network (Fitzgerald et al., 2010). In this study, we demonstrate that NIR light treatment using the WARP 10 array reduced this early oxidative stress in hypertrophic astrocytes of ventral ON vulnerable to secondary degeneration in vivo, as well as reducing the later accumulation of MnSOD immunoreactive aggregates within cellular debris (Fitzgerald et al., 2009a), 10 days after injury. Our observed effects of NIR light treatment in reducing secondary oxidative stress after traumatic injury are likely to be due to increases in cytochrome c oxidase activity, reduced reactive oxygen species and improvements in mitochondrial function that have been described in a number of in vitro and in vivo studies (Wong-Riley et al., 2005; Liang et al., 2006; Rojas et al., 2008).
Reductions in oxidative stress in astrocytes may also protect oligodendrocytes in ventral ON vulnerable to secondary degeneration, with resultant beneficial effects on the integrity of myelin and visual function (Park et al., 2004; Williams et al., 2007;Fitzgerald et al., 2009a; Nave, 2010). However, due to the short term nature of the current study, myelin was not yet sufficiently disrupted to enable detection of improvements in myelination following treatment with NIR light. Nevertheless, the increases in NG2 immunopositive OPCs that occur in ON vulnerable to secondary degeneration were prevented with NIR light treatment using the WARP 10 LED array. Disruption to myelin causes increases in NG2 immunopositive cells (Franklin and Ffrench-Constant, 2008). We hypothesize therefore, that NIR light treatment may reduce oxidative stress in astrocytes leading to protection of oligodendrocytes and myelin, thereby preventing increased numbers of NG2 immunopositive OPCs in nerve vulnerable to secondary degeneration. Improvements in visual function would result from the preservation of myelin sheaths surrounding axons in areas of the ON vulnerable to secondary degeneration. NIR light treatment did not prevent reductions in β-III tubulin immunopositive axonal profiles or increases in resident or activated microglia / macrophages in ventral ON vulnerable to secondary degeneration.
However, visual function can be maintained with a small percentage of intact retinal ganglion cells (Sabel, 1999) and it may be that preservation of the myelin sheath is more important for preservation of function than large numbers of axons. Nevertheless it is likely that combinatorial treatment strategies that protect axons as well as reduce oxidative stress in glia, for example NIR light combined with the CNS specific neuroprotective calcium channel blocker lomerizine, will be required for even more effective prevention of secondary degeneration (Fitzgerald et al., 2009a; Fitzgerald et al., 2009b).
The relatively long duration for each treatment using the WARP 10 array necessitated repeated anaesthesia of experimental animals, which can be problematic. Therefore, assessing longer term outcomes using this successful treatment regime was beyond the scope of the current study. Treatment using a commercially available LED array delivering greater irradiance (VET 75 array), which provided a larger treatment area and potentially more thorough exposure to NIR light in a shorter time period, resulted in minimal improvements that were not sustained. It is possible that use of LED arrays with higher energy densities may enable reductions in treatment times.
Light in the red to NIR region of the spectrum has positive effects on a range of neural cells both in vitro and in vivo, when delivered by low energy laser or LED (Rochkind et al., 1990; Eells et al., 2004; Wong-Riley et al., 2005; Liang et al., 2008; Rochkind, 2009; Rochkind et al., 2009). LED delivery of NIR light avoids some of the potential pitfalls of low energy laser delivery, with flat arrays providing wider treatment areas and minimal heat production (Eells et al., 2004). It has been calculated that light emitted by LED arrays can penetrate tissue to a depth of 23cm (Beauvoit et al., 1994; Whelan et al., 2001) and we have demonstrated penetration of 670nm light over the distance of a few cm through skull, brain and associated tissue around the ON. Use of the arrays has been deemed a non-significant risk for use in humans by the FDA (Desmet et al., 2006). Our study indicates that 670nm NIR light offers a potential treatment for prevention of secondary degeneration following partial traumatic injury to the CNS, which may be particularly useful in combination with other neuroprotective agents. Use of NIR light LED arrays therefore represents a feasible alternative for treatment of secondary degeneration following traumatic injury to the CNS.
Near Infra-red Light Reduces Oxidative Stress and Preserves Function in CNS
Tissue Vulnerable to Secondary Degeneration Following Partial Transection of the Optic Nerve, Journal of Neurotrauma, (doi: 10,1089/neu.2010.1426) Melinda Fitzgerald: Assistant Professor, PhD, Carole A. Bartlett: MSc, Sophie C. Payne: BSc (Hons), Nathan S. Hart: Associate Professor, PhD, Jenny Rodger: Assistant Professor, PhD, Alan R. Harvey: Winthrop Professor, PhD, Sarah A. Dunlop: Professor, PhD
Abstract
Traumatic injury to the central nervous system is accompanied by the spreading damage of secondary degeneration, resulting in further loss of neurons and function. Partial transection of the optic nerve (ON) has been used as a model of secondary degeneration, where axons of retinal ganglion cells in ventral ON are spared from initial dorsal injury but are vulnerable to secondary degeneration. We have recently demonstrated that, early after partial ON injury, oxidative stress spreads through ventral ON vulnerable to secondary degeneration via astrocytes, and persists in the nerve in aggregates of cellular debris. In this study, we show that diffuse transcranial irradiation of the injury site with far red to near infrared (NIR) light (WARP 10 LED array, centre wavelength 670nm, irradiance 252 Wm-2, 30 minute exposure), as opposed to perception of light at this wavelength, reduced oxidative stress in areas of ON vulnerable to secondary degeneration, following partial injury. The WARP 10 NIR light treatment also prevented increases in NG2 immunopositive oligodendrocyte precursor cells (OPCs) that occurred in ventral ON as a result of partial ON transection. Importantly, normal visual function was restored by NIR light treatment with the WARP 10 LED array, as assessed using optokinetic nystagmus and the Ymaze pattern discrimination task. To our knowledge, this is the first demonstration that 670nm NIR light can reduce oxidative stress and improve function in the CNS following traumatic injury in vivo.
Discussion
In this partial injury study, we have demonstrated that treatment with NIR light (WARP 10 LED array, 670nm) reduced oxidative stress in areas of ON vulnerable to secondary degeneration. NIR light treatment also prevented the secondary increases in NG2 immunopositive OPCs that occurred as a result of partial ON transection. Importantly, visual function was restored to normal by NIR light treatment using the WARP 10 LED array, as assessed using optokinetic nystagmus and the Y-maze pattern discrimination task. To our knowledge, this is the first demonstration that 670nm NIR light can reduce oxidative stress and improve function in the CNS after traumatic injury in vivo.
Improvements in visual function following partial ON transection were achieved with daily 30 minute exposures to the WARP 10 array, for the six days immediately following injury. It is possible that the improvements in performance in the Y-maze pattern discrimination task were partially due to non-specific improvements in working memory with NIR light treatment (Michalikova et al., 2008). Similarly, improvements in optokinetic nystagmus may be influenced by neuroprotective mechanisms not directly related to protection of the injured ON, perhaps involving transfer of visual responses to motor commands (Delgado-Garcia, 2000; Haustead et al., 2008). However, electroretinogram responses in completely normal rats were not altered with exposure to 670nm NIR light LED arrays (Eells et al., 2003), indicating that our observed improvements in visual function following traumatic injury are likely to be a result of direct effects on the partially injured ON. Furthermore, our demonstration that 670nm NIR light penetrates to the injured ON as well as through the retina to the back of the eye supports the premise of a direct effect of NIR light on ON. Beneficial outcomes may also be due to direct effects of 670nm NIR light on RGC somata in the retina, although we did not observe improvements in RGC axonal profiles.
Traumatic injury to the CNS results in glutamate excitotoxicity and altered Ca2+ flux, which leads to oxidative stress and reduced function of neurons and glia (Park et al., 2004; Tezel, 2006). We have recently demonstrated that oxidative stress spreads rapidly through ON vulnerable to secondary degeneration, through the linked astrocytic network (Fitzgerald et al., 2010). In this study, we demonstrate that NIR light treatment using the WARP 10 array reduced this early oxidative stress in hypertrophic astrocytes of ventral ON vulnerable to secondary degeneration in vivo, as well as reducing the later accumulation of MnSOD immunoreactive aggregates within cellular debris (Fitzgerald et al., 2009a), 10 days after injury. Our observed effects of NIR light treatment in reducing secondary oxidative stress after traumatic injury are likely to be due to increases in cytochrome c oxidase activity, reduced reactive oxygen species and improvements in mitochondrial function that have been described in a number of in vitro and in vivo studies (Wong-Riley et al., 2005; Liang et al., 2006; Rojas et al., 2008).
Reductions in oxidative stress in astrocytes may also protect oligodendrocytes in ventral ON vulnerable to secondary degeneration, with resultant beneficial effects on the integrity of myelin and visual function (Park et al., 2004; Williams et al., 2007;Fitzgerald et al., 2009a; Nave, 2010). However, due to the short term nature of the current study, myelin was not yet sufficiently disrupted to enable detection of improvements in myelination following treatment with NIR light. Nevertheless, the increases in NG2 immunopositive OPCs that occur in ON vulnerable to secondary degeneration were prevented with NIR light treatment using the WARP 10 LED array. Disruption to myelin causes increases in NG2 immunopositive cells (Franklin and Ffrench-Constant, 2008). We hypothesize therefore, that NIR light treatment may reduce oxidative stress in astrocytes leading to protection of oligodendrocytes and myelin, thereby preventing increased numbers of NG2 immunopositive OPCs in nerve vulnerable to secondary degeneration. Improvements in visual function would result from the preservation of myelin sheaths surrounding axons in areas of the ON vulnerable to secondary degeneration. NIR light treatment did not prevent reductions in β-III tubulin immunopositive axonal profiles or increases in resident or activated microglia / macrophages in ventral ON vulnerable to secondary degeneration.
However, visual function can be maintained with a small percentage of intact retinal ganglion cells (Sabel, 1999) and it may be that preservation of the myelin sheath is more important for preservation of function than large numbers of axons. Nevertheless it is likely that combinatorial treatment strategies that protect axons as well as reduce oxidative stress in glia, for example NIR light combined with the CNS specific neuroprotective calcium channel blocker lomerizine, will be required for even more effective prevention of secondary degeneration (Fitzgerald et al., 2009a; Fitzgerald et al., 2009b).
The relatively long duration for each treatment using the WARP 10 array necessitated repeated anaesthesia of experimental animals, which can be problematic. Therefore, assessing longer term outcomes using this successful treatment regime was beyond the scope of the current study. Treatment using a commercially available LED array delivering greater irradiance (VET 75 array), which provided a larger treatment area and potentially more thorough exposure to NIR light in a shorter time period, resulted in minimal improvements that were not sustained. It is possible that use of LED arrays with higher energy densities may enable reductions in treatment times.
Light in the red to NIR region of the spectrum has positive effects on a range of neural cells both in vitro and in vivo, when delivered by low energy laser or LED (Rochkind et al., 1990; Eells et al., 2004; Wong-Riley et al., 2005; Liang et al., 2008; Rochkind, 2009; Rochkind et al., 2009). LED delivery of NIR light avoids some of the potential pitfalls of low energy laser delivery, with flat arrays providing wider treatment areas and minimal heat production (Eells et al., 2004). It has been calculated that light emitted by LED arrays can penetrate tissue to a depth of 23cm (Beauvoit et al., 1994; Whelan et al., 2001) and we have demonstrated penetration of 670nm light over the distance of a few cm through skull, brain and associated tissue around the ON. Use of the arrays has been deemed a non-significant risk for use in humans by the FDA (Desmet et al., 2006). Our study indicates that 670nm NIR light offers a potential treatment for prevention of secondary degeneration following partial traumatic injury to the CNS, which may be particularly useful in combination with other neuroprotective agents. Use of NIR light LED arrays therefore represents a feasible alternative for treatment of secondary degeneration following traumatic injury to the CNS.
Thursday, September 16, 2010
New Research from Division of Biomedical Sciences & Biochemistry, Research School of Biology, Australian National University; Sydney, Australia
With our history of providing the most innovative research of light emitting diode or HEALS technology we feel an obligation to share the latest published paper entitled: "Gene and noncoding RNA regulation underlying photoreceptor protection: microarray study of dietary antioxidant saffron and photobiomodulation in rat retina" Riccardo Natoli, Yuan Zhu, Krisztina Valter, Silvia Bisti, Janis Eells, Jonathan Stone
Conclusion: Given alone, saffron and (more prominently) PBM (Photobiomodulation) both regulated significant numbers of genes and ncRNAs. Given before retinal exposure to damaging light, thus while exerting their neuroprotective action, they regulated much larger numbers of entities, among which ncRNAs were prominent. Further, the downregulation of known genes and of ncRNAs was prominent in the protective actions of both neuroprotectants. These comparisons provide an overview of gene expression induced by two neuroprotectants and provide a basis for the more focused study of their mechanisms.
PBM seems to act through at least two pathways, by reducing inflammation and by reducing oxidative damage. Future investigation of the ncRNAs regulated by PBM and saffron could reveal further clues to their mechanism of protection
Conclusion: Given alone, saffron and (more prominently) PBM (Photobiomodulation) both regulated significant numbers of genes and ncRNAs. Given before retinal exposure to damaging light, thus while exerting their neuroprotective action, they regulated much larger numbers of entities, among which ncRNAs were prominent. Further, the downregulation of known genes and of ncRNAs was prominent in the protective actions of both neuroprotectants. These comparisons provide an overview of gene expression induced by two neuroprotectants and provide a basis for the more focused study of their mechanisms.
PBM seems to act through at least two pathways, by reducing inflammation and by reducing oxidative damage. Future investigation of the ncRNAs regulated by PBM and saffron could reveal further clues to their mechanism of protection
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