Aniridia is a genetic disorder predominantly affecting the eye, caused by PAX6 haploinsufficiency due to mutations in one allele. Patients present vision loss and, in some cases, other systemic abnormalities. Increasing the expression of PAX6 early in life could block the progression of the disease. Now, Rabiee et al. Used a pharmacological approach in vitro and in a rodent model of Pax6.
The aim is to study is to evaluate doxycycline as a treatment for HHT with the proposed 'HHT Clinical Trial Protocol'. Rare disease presents a number of challenges in clinical trial design, including recruitment challenges, related power limitations and less knowledge about outcomes measurement. Considering these limitations, as well as the large variability in epistaxis measures across HHT patients, a crossover-trial design, with each subject receiving the study drug and placebo, and therefore serving as their own control, has been selected, including randomization and blinding, to limit bias in measuring this subjective outcome.
- Genetic mouse models of AVMs include those for hereditary hemorrhagic telangiectasia (HHT; Rendu-Osler-Weber syndrome) with mutations in endoglin or activin receptor-like kinase 1 (Alk1) 172.
- TOUCHPAD DRIVER SUPPORT Synaptics' TouchPad device drivers are customized and supported by notebook manufacturers to meet specific driver requirements for their individual products. To ensure the appropriate driver for your device, always use the driver your specific notebook OEM supports.
This study will investigate doxycycline, given its demonstrated anti-angiogenic and anti-inflammatory properties, as well as compelling effects in arteriovenous malformation (AVM) models. Doxycycline also has the advantages of a proven safety track record for long-term use, oral administration and low cost. Doxycycline suppresses vascular endothelial growth factor (VEGF)-induced cerebral matric metalloproteinase-9 (MMP-9) activity in vivo in the mouse model, and has anti-inflammatory effects as well, via inhibition of pro-inflammatory cytokines. In human brain vascular malformation tissue, there is evidence of increased expression of MMP-9 and VEGF and another tetracycline, minocycline, has attenuated brain hemorrhage in the mouse. Recently, a small retrospective case series reported sustained reduction in nasal hemorrhage in seven HHT patients treated with oral doxycycline. We hypothesize that oral doxycycline will reduce nasal hemorrhage in HHT subjects, through anti-angiogenic and/or anti-inflammatory mechanisms, both of which have been implicated in HHT.
This is a double-blind randomized placebo-controlled trial (N=30) of oral doxycycline (100mg twice daily, 6-month course) in HHT subjects with moderate-severe recurrent nasal hemorrhage. Drug dosing and safety monitoring will be tailored specifically to the agent studied. The primary outcome will be reduction of bleeding minutes per week. In addition, vascular malformation tissue (cutaneous) will be obtained pre and post-treatment, and stained for inflammatory, angiogenic and bone morphogenetic protein-9 (BMP9)-activin A receptor like type1(ALK1)-endoglin- Smad1/5/9 pathway markers. In addition, pre-excision, vascular malformations will be imaged with speckle variance optical coherence tomography (SVOCT), in vivo non-invasive micro-angiography to measure lesion structure, vessel volume and vessel density, as previously described. If the drugs studied are effective at reducing nasal hemorrhage, this will have important clinical implications for HHT patients, and the tissue and imaging may provide important insights into mechanisms.
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The good thing about studying rats is you don't have to travel very far. Fordham University evolutionary biologist Jason Munshi-South studies biodiversity and evolution right here in New York City. His study subjects—rats and mice—are abundant here.
Munshi-South thinks of the city as a grand evolutionary experiment. When he looks at a map of New York City, he sees the city's parks and green spaces as wildlife islands. Movement within islands is free, but between islands is restricted.
White-footed mice, for example, thrive in city parks but not on concrete and asphalt. Munshi-South can tell which park a mouse is from, and how it moves around the city, from its genetic code. Central Park mice, he's found, are relatively isolated. Mice from Van Cortlandt Park and the other parks in the Bronx, where there are more trees and shrubbery, move a bit more freely.
It's necessary to understand what cities are doing if we really want to understand ecology and evolution.
A few hundred years of the city's history—during which time parks were constructed and then isolated from each other—is inscribed in mouse DNA this way. Studying rodent evolution in a changing urban environment allows him to glimpse evolution in real time, within the span of a scientific career.
In a conversation with Nautilus, Munshi-South tells us more about New York City's signature rodents.
Hht Mice & Touchpads Drivers
You call evolution of wildlife in New York City a grand evolutionary experiment. Why?
Hht Mice & Touchpads Driver Printer
We have created these environments for ourselves to meet our needs, but then we also have all these other species that we brought here or that were already in the region and have come to inhabit the city. We have created essentially novel pressures on those organisms and they have to find ways to adapt or be extirpated from the city. This is something that has happened very rapidly—our cities have developed very quickly over the last few hundred years, especially in North America.
I don't think the white-footed mice in Central Park really get out of that park very often.
This is almost evolution in real time. It gives us a powerful sort of backyard study system to look at the basic forces of evolution within the span of a scientific career. I think urbanization and cities are particularly interesting because there are so many cities and we're seeing the same processes play out almost in replication. You almost have a replicated experiment taking place across the globe.
Cities occupy only a small part of the landscape, but their pressure on surrounding areas is immense, and so cities have become one of the major forces or drivers of lots of processes, at least on a regional scale. It's necessary to understand what cities are doing if we really want to understand ecology and evolution as it operates now. Because so many people live in cities, it's also useful from an educational and societal viewpoint. It's the nature that people experience, and they want to know more about it.
A few hundred years of the city's history—during which time parks were constructed and then isolated from each other—is inscribed in mouse DNA this way. Studying rodent evolution in a changing urban environment allows him to glimpse evolution in real time, within the span of a scientific career.
In a conversation with Nautilus, Munshi-South tells us more about New York City's signature rodents.
Hht Mice & Touchpads Drivers
You call evolution of wildlife in New York City a grand evolutionary experiment. Why?
Hht Mice & Touchpads Driver Printer
We have created these environments for ourselves to meet our needs, but then we also have all these other species that we brought here or that were already in the region and have come to inhabit the city. We have created essentially novel pressures on those organisms and they have to find ways to adapt or be extirpated from the city. This is something that has happened very rapidly—our cities have developed very quickly over the last few hundred years, especially in North America.
I don't think the white-footed mice in Central Park really get out of that park very often.
This is almost evolution in real time. It gives us a powerful sort of backyard study system to look at the basic forces of evolution within the span of a scientific career. I think urbanization and cities are particularly interesting because there are so many cities and we're seeing the same processes play out almost in replication. You almost have a replicated experiment taking place across the globe.
Cities occupy only a small part of the landscape, but their pressure on surrounding areas is immense, and so cities have become one of the major forces or drivers of lots of processes, at least on a regional scale. It's necessary to understand what cities are doing if we really want to understand ecology and evolution as it operates now. Because so many people live in cities, it's also useful from an educational and societal viewpoint. It's the nature that people experience, and they want to know more about it.
By looking at the genetic variation in mice, can you tell how mice move through the city?
We use genetic data to estimate how much gene flow there is between parks, basically how many individuals are moving per generation and spreading their genes. We build models of how we think white-footed mice and other species would move through the city, and test those models against the genetic data to see which ones are best predictive of movement.
We found that white-footed mice movement tracks vegetation and canopy cover. This has a lot of implications if you want to influence animal movement; if you don't want animals spreading disease, or maybe you want to make populations to flourish in the city. You could potentially do that by changing the composition of green space in the city.
So are the Central Park mice, for instance, isolated from those in parks farther north?
Hht Mice & Touchpads Drivers Ed
Yes, I don't think the white-footed mice in Central Park really get out of that park very often. In some of the other areas of the city, they do move around more. They seem to be able to get in and out of the big parks in the Bronx better. And some of the parks in eastern Queens. Those are the greener, less developed parks of the city.
Is the history of New York City inscribed in the genes of mice?
Partially, yes. We can imagine before Europeans the mice were everywhere, moving around. As Europeans developed New York City and southern Manhattan, and then agricultural areas everywhere else, the mice were probably still moving around for the most part through agricultural areas. But once you got to heavy urbanization of Manhattan about 150 years ago, and of the other boroughs about 120 years ago, in a matter of a few decades these parks were developed and became quite isolated.
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