Annual DIA Meeting June 2017 – Mark Your Calendar

 

Target Health Inc. is very pleased to announce that it’s Content Hub proposal, entitled How eSource Solutions are Impacting Clinical Research Sites, Patients, Regulators and Drug and Device Companies has been accepted to the DIA 2017 Annual Meeting.

 

DIA is excited to be piloting this new event where attendees will have the opportunity to interact with community leaders and have one-on-one conversations to gain rapid insight in a subject of value; or attain a deeper perspective of a compelling session given earlier in the meeting.

 

The Content Hub presentation/conversation has been scheduled for:

Day: Tuesday

Date: 6/20/2017

Time: 4:00PM – 4:30PM

 

The Content Hub is designed for 30 minute short presentations and seating for an intimate audience of 30 people in a non-traditional session setting.  The Content Hub is informal with a mix of different styles of seating to encourage relaxed conversations between the audience and the leader.  A vital component of the Content Hub is the opportunity for the audience to participate in active Q&A.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website, and if you like the weekly newsletter, ON TARGET, you’ll love the Blog.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

QUIZ

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Heart Tissue Grown on Spinach Leaves

 

Problem: How to establish a vascular system that delivers blood deep into the developing tissue.

 

Solution: Scientists have turned to the vascular system of plants to solve a major bioengineering problem blocking the regeneration of human tissues and organs, by successfully culturing beating human heart cells on spinach leaves that were stripped of plant cells.

 

In this sequence, a spinach leaf is stripped of its plant cells, a process called decellularization, using a detergent. The process leaves behind the leaf’s vasculature. Researchers at Worcester Polytechnic Institute (WPI) were able to culture beating human heart cells on such decelluralized leaves. Credit: Worcester Polytechnic Institute; ScienceDaily.com

 

 

Researchers face a fundamental challenge as they seek to scale up human tissue regeneration from small lab samples to full-size tissues, bones, even whole organs to implant in 1) ___ to treat disease or traumatic injuries: how to establish a vascular system that delivers blood deep into the developing tissue. Current bioengineering techniques, including 3-D 2) ___, can’t fabricate the branching network of blood vessels down to the capillary scale that are required to deliver the oxygen, nutrients and essential molecules required for proper tissue growth. To solve this problem, a multidisciplinary research team at Worcester Polytechnic Institute (WPI), the University of Wisconsin-Madison, and Arkansas State University-Jonesboro have successfully turned to 3) ___. They report their initial findings in the paper “Crossing kingdoms: Using decelluralized plants as perfusable tissue engineering scaffolds“ published online in advance of the May 2017 issue of the journal Biomaterials. “Plants and animals exploit fundamentally different approaches to transporting fluids, chemicals and macromolecules, yet there are surprising similarities in their vascular network structures,“ the authors wrote. “The development of decellularized plants for scaffolding opens up the potential for a new branch of science that investigates the mimicry between plant and 4) ___

 

In a series of experiments, the team cultured beating human heart cells on spinach leaves that were stripped of plant cells. They flowed fluids and microbeads similar in size to human blood cells through the spinach vasculature, and they seeded the spinach veins with human cells that line blood vessels. These proof-of-concept studies open the door to using multiple spinach 5) ___ to grow layers of healthy heart muscle to treat heart attack patients. Other decellularized plants could provide the framework for a wide range of tissue engineering technologies. “We have a lot more work to do, but so far this is very promising,“ said Glenn Gaudette, PhD, professor of biomedical engineering at WPI and corresponding author of the paper. “Adapting abundant plants that farmers have been cultivating for thousands of years for use in 6) ___ engineering could solve a host of problems limiting the field.“ In addition to Gaudette, the WPI research team includes Tanja Dominko, PhD, DVM, associate professor of biology and biotechnology, who studies molecular mechanisms of human cell development; Pamela Weathers, PhD, professor of biology and biotechnology, a plant biologist; and Marsha Rolle, PhD, associate professor of biomedical engineering, who focuses on vasculature tissue engineering. The collaborative team also includes human stem 7) ___ and plant biology researchers at Wisconsin and Arkansas. “This project speaks to the importance of interdisciplinary research,“ Gaudette said. “When you have people with different expertise coming at a problem from different perspectives, novel solutions can emerge.“

 

The paper’s first author is Joshua Gerslak, a graduate student in Gaudette’s lab, who helped design and conduct the experiments, and who developed an effective process for removing plant cells from spinach leaves by flowing or “perfusing“ a detergent solution through the leaves’ 8) ___. “I had done decellularization work on human hearts before and when I looked at the spinach leaf its stem reminded me of an aorta. So I thought, let’s perfuse right through the stem,“ Gershlak said. “We weren’t sure it would work, but it turned out to be pretty easy and replicable. It’s working in many other plants.“ When the plant cells are washed away what remains is a framework made primarily of cellulose, a natural substance that is not harmful to people. “Cellulose is biocompatible (and) has been used in a wide variety of regenerative medicine applications, such as cartilage tissue engineering, bone tissue engineering, and wound healing,“ the authors wrote. In addition to spinach leaves, the team successfully removed cells from parsley, Artemesia annua (sweet wormwood), and peanut hairy roots. They expect the technique will work with many plant species that could be adapted for specialized tissue regeneration studies. “The spinach leaf might be better suited for a highly-vascularized tissue, like cardiac tissue, whereas the cylindrical hollow structure of the stem of Impatiens capensis (jewelweed) might better suit an arterial graft. Conversely, the vascular columns of wood might be useful in bone engineering due to their relative strength and geometries,“ the authors wrote.

 

Using plants as the basis for tissue engineering also has economic and environmental benefits. “By exploiting the benign chemistry of plant tissue scaffolds, we could address the many limitations and high costs of synthetic, complex composite materials. Plants can be easily grown using good agricultural practices and under controlled environments. By combining environmentally friendly plant tissue with perfusion-based decellularization, we have shown that there can be a sustainable solution for pre-vascularized tissue 9) ___ scaffolds.“ At WPI, the research continues along several lines, Gaudette said, with studies to optimize the decellularization process and further characterize how various human cell types grow while they are attached to, and are potentially nourished by, plant-based 10) ___. Also, engineering a secondary vascular network for the outflow of blood and fluids from human tissue will be explored. On April 7, 2017, Gershlak presented the technology and early results as an invited speaker at the National Academy of Inventors inaugural Student Innovation Showcase in Boston, where he will detail the work for more than 200 accomplished inventors and technology commercialization leaders.

 

Source: Worcester Polytechnic Institute; Joshua R. Gershlak, Sarah Hernandez, Gianluca Fontana, Luke R. Perreault, Katrina J. Hansen, Sara A. Larson, Bernard Y.K. Binder, David M. Dolivo, Tianhong Yang, Tanja Dominko, Marsha W. Rolle, Pamela J. Weathers, Fabricio Medina-Bolivar, Carole L. Cramer, William L. Murphy, Glenn R. Gaudette. Crossing kingdoms: Using decellularized plants as perfusable tissue engineering scaffolds. Biomaterials, 2017; 125: 13 DOI: 10.1016/j.biomaterials.2017.02.011; Worcester Polytechnic Institute. “Heart tissue grown on spinach leaves: Researchers turn to the vascular system of plants to solve a major bioengineering problem blocking the regeneration of human tissues and organs“; ScienceDaily.com. More information here with an excellent video.

 

Good video for your kids, explaining the above

 

ANSWERS: 1) people; 2) printing; 3) plants; 4) animal; 5) leaves; 6) tissue; 7) cell; 8) veins; 9) engineering; 10) scaffolds

 

Human Forebrain Circuits Under Construction

 

During mid-to-late gestation, neurons migrate from deep brain structures to their appointed places and organize themselves into the key working tissue of what will become the human cortex, the outer layer of the brain and seat of higher-order mental functions. This building process is complex and especially vulnerable to genetic and environmental insults that can set the stage for autism, schizophrenia, and other neurodevelopmental brain disorders.

 

National Institutes of Health (NIH)-funded neuroscientists have created a 3D window into the human brain’s budding executive hub assembling itself during a critical period in prenatal development. What’s more, they used it to discover and experimentally correct defective cell migration caused by an autism-related disorder. The study on experiments with forebrain spheroids was published online in the journal Nature (April 26, 2017). The study advances a fast-developing “disease-in-a-dish“ technology, in which cultured neurons derived from an individual’s readily-accessible skin cells connect with each other to form 3D brain organoids or “spheroids.“ Although tiny, these replicate rudimentary circuitry that can reveal that person’s brain’s unique secrets — even from when it was still under construction.

 

Previous studies produced relatively primitive cortex spheroids that didn’t show how different regions of the forming structure interacted. In this study, 3D cell cultures were coaxed to become spheroids representing two specific regions of the forebrain and fused them together. The neuronal migrations were then tracked from a deep brain spheroid to a cortex spheroid that mimicked those seen during normal development. For the first time, this new model revealed the developing human forebrain, maturing by building circuits that balance excitatory with inhibitory brain systems. Neurons from spheroids resembling tissue in the lower forebrain region are seen migrating to create cortex circuitry with neurons from spheroids resembling tissue in the upper region. The former communicate a slowing-down (inhibition) of neural activity, while the latter communicate a speeding-up (excitation) of neural activity.

 

In spheroids derived from skin cells of patients with Timothy syndrome, an autism-related disorder of known genetic cause, the authors discovered a defect in the migration of patients’ neurons that caused them to move more frequently but less efficiently — and experimentally reversed it in the dish with a drug. According to the NIH, this recapitulation of a pivotal stage in the cortex’s formation demonstrates the technique’s promise for discovery — and even for testing potential interventions, and it moves us closer to realizing the goal of precision medicine for brain disorders. The exquisite timing and placement of these different neuron cell types is critical for establishing a balance between excitation and inhibition within brain circuits. This balance is thought to be disrupted in brain disorders. Replaying these developmental processes with a patient’s own cells, allows us to determine what distinguishes these different disorders at a molecular and cellular level. The authors added that the research provides a proof-of-concept for understanding the interaction of specific cell types and for building — as well as probing — circuits within personalized human microphysiological systems.

 

History of Cell Biology 101

Structure of a typical animal cell; Graphic credit: Royroydeb – Own work, CC BY-SA 4.0; Wikipedia Commons

 

Structure of a typical plant cell; Graphic credit: LadyofHats – Self-made using Adobe Illustrator. (The original edited was also made by me, LadyofHats), Public Domain, Wikipedia Commons

 

Graphic credit: National Center for Biotechnology Information; Vectorized by Mortadelo2005. – Public Domain, Wikipedia Commons

 

 

Editor’s note: The evolution of the cell is one of Science’s most awesome areas of study, leading to the origins of life itself. It is beyond our comprehension, why anyone able to contribute to the funding of research, inquiring into the mystery of life, and its pathologies, which cell biology does, why anyone would not be eager to do so. Perhaps Americans should vote to require that all politicians have an education high enough to enable them to understand the worlds of science, math, technology, engineering, and all the arts (which remind us of our humanity).

 

Stromatolites are left behind by cyanobacteria, also called blue-green algae. They are the oldest known fossils of life on Earth. This one-billion-year-old fossil is from Glacier National Park in the United States. Photo credit: P. Carrara, NPS – National Park Service – http://www.nature.nps.gov/geology/cfprojects/photodb/Photo_Detail.cfm?PhotoID=204; Public Domain, Wikimedia Commons

 

 

There are several theories about the origin of small molecules that led to life on the early Earth. They may have been carried to Earth on meteorites (see Murchison meteorite), created at deep-sea vents, or synthesized by lightning in a reducing atmosphere (see Miller-Urey experiment). There is little experimental data defining what the first self-replicating forms were. RNA is thought to be the earliest self-replicating molecule, as it is capable of both storing genetic information and catalyzing chemical reactions (see RNA world hypothesis), but some other entity with the potential to self-replicate could have preceded RNA, such as clay or peptide nucleic acid.

 

Cells emerged at least 3.5 billion years ago. The current belief is that these cells were heterotrophs. The early cell membranes were probably more simple and permeable than modern ones, with only a single fatty acid chain per lipid. Lipids are known to spontaneously form bilayered vesicles in water, and could have preceded RNA, but the first cell membranes could also have been produced by catalytic RNA, or even have required structural proteins before they could form. The eukaryotic cell seems to have evolved from a symbiotic community of prokaryotic cells. DNA-bearing organelles like the mitochondria and the chloroplasts are descended from ancient symbiotic oxygen-breathing proteobacteria and cyanobacteria, respectively, which were endosymbiosed by an ancestral archaean prokaryote. There is still considerable debate about whether organelles like the hydrogenosome predated the origin of mitochondria, or vice versa: see the hydrogen hypothesis for the origin of eukaryotic cells.

 

The cell (from Latin cella, meaning “small room“ is the basic structural, functional, and biological unit of all known living organisms. A cell is the smallest unit of life that can replicate independently, and cells are often called the “building blocks of life“. The study of cells is called cell biology. Cells consist of cytoplasm enclosed within a membrane, which contains many biomolecules such as proteins and nucleic acids. Organisms can be classified as unicellular (consisting of a single cell; including bacteria) or multicellular (including plants and animals). While the number of cells in plants and animals varies from species to species, humans contain more than 10 trillion cells. Most plant and animal cells are visible only under a microscope, with dimensions between 1 and 100 micrometers.

 

The cell was discovered by Robert Hooke in 1665, who named the biological unit for its resemblance to cells inhabited by Christian monks in a monastery. Cell theory, first developed in 1839 by Matthias Jakob Schleiden and Theodor Schwann, states that all organisms are composed of one or more cells, that cells are the fundamental unit of structure and function in all living organisms, that all cells come from preexisting cells, and that all cells contain the hereditary information necessary for regulating cell functions and for transmitting information to the next generation of cells. Cells are of two types, eukaryotic, which contain a nucleus, and prokaryotic, which do not. Prokaryotes are single-celled organisms, while eukaryotes can be either single-celled or multicellular. Prokaryotic cells were the first form of life on Earth, characterized by having vital biological processes including cell signaling and being self-sustaining. They are simpler and smaller than eukaryotic cells, and lack membrane-bound organelles such as the nucleus. Prokaryotes include two of the domains of life, bacteria and archaea.

 

Three co-founders of cell theory:

 

Matthias Jakob Schleiden (1804-1881) was a German botanist and co-founder of cell theory, along with Theodor Schwann and Rudolf Virchow. Born in Hamburg, Schleiden was educated at University of Jena, then practiced law in Heidelberg, but soon developed his love for botany into a full-time pursuit. Schleiden preferred to study plant structure under the microscope. While a professor of botany at the University of Jena, he wrote Contributions to our knowledge of phytogenesis (1838), in which he stated that all parts of the plant organism are composed of cells. Thus, Schleiden and Schwann became the first to formulate what was then an informal belief as a principle of biology equal in importance to the atomic theory of chemistry. He also recognized the importance of the cell nucleus, discovered in 1831 by the Scottish botanist Robert Brown, and sensed its connection with cell division. Schleiden was one of the first German biologists to accept Charles Darwin’s theory of evolution. He became professor of botany at the University of Dorpat in 1863. He concluded that all plant parts are made of cells and that an embryonic plant organism arises from the one cell. He died in Frankfurt am Main on 23 June 1881. It was during the four years spent under the influence of Muller in Berlin, that Schwann’s most valuable work was done. Muller was at this time preparing his great book on physiology, and Schwann assisted him in the experimental work required. Schwann observed animal cells under the microscope, noting their different properties. Schwann found particular interest in the nervous and muscular tissues. He discovered the cells that envelope the nerve fibers, now called Schwann cells in his honor. Schwann discovered the striated muscle in the upper esophagus and initiated research into muscle contraction, since expanded upon greatly by Emil du Bois-Reymond and others. Muller directed Schwann’s attention to the process of digestion, and in 1837 Schwann isolated an enzyme essential to digestion, which he called pepsin. Schwann became chair of anatomy at the Belgian Catholic University of Leuven in 1839. Here he produced little new scientific work, the exception being a paper establishing the importance of bile in digestion. He nonetheless proved to be a dedicated and conscientious professor. In 1848, his compatriot Antoine Frederic Spring convinced him to transfer to the University of Liege, also in Belgium. At Liege, he continued to follow the latest advances in anatomy and physiology without himself contributing. He became something of an inventor, working on numerous projects including a human respirator for environments where the surroundings are not breathable. In his later years, Schwann found growing interest in theological issues. Three years after retiring, Schwann died in Cologne on 11 January 1882. There is a bronze statue of Theodor Schwann at the entrance of the Institute of Zoology, University of Liege, Belgium.

 

Cell theory

 

In 1837, Matthias Jakob Schleiden viewed and stated that new plant cells formed from the nuclei of old plant cells. While dining that year with Schwann, the conversation turned on the nuclei of plant and animal cells. Schwann remembered seeing similar structures in the cells of the notochord (as had been shown by Muller) and instantly realized the importance of connecting the two phenomena. The resemblance was confirmed without delay by both observers, and the results soon appeared in Schwann’s famous Microscopical Researches into the Accordance in the Structure and Growth of Animals and Plants, in which he declared that “All living things are composed of cells and cell products“. This became cell theory or cell doctrine. In the 19th century, physiological knowledge began to accumulate at a rapid rate, in particular with the 1838 appearance of the Cell theory of Matthias Schleiden and Theodor Schwann. It dramatically stated that organisms are made up of units called cells. At this time, cell theory was considered a radical idea. In the course of his verification of cell theory, Schwann proved the cellular origin and development of the most highly differentiated tissues including nails, feathers, and tooth enamel. Schwann established a basic principle of embryology by observing that the ovum is a single cell that eventually develops into a complete organism.

 

In 1857, pathologist Rudolf Virchow posed the maxim Omnis cellula e cellula – that every cell arises from another cell. By the 1860s, cell doctrine became the conventional view of the elementary anatomical composition of plants and animals. Schwann’s theory and observations became the foundation of modern histology.

 

Timeline: History of Cell Biology

 

– 1632-1723: Antonie van Leeuwenhoek teaches himself to make lenses, constructs basic optical microscopes and draws protozoa, such as Vorticella from rain water, and bacteria from his own mouth.

– 1665: Robert Hooke discovers cells in cork, then in living plant tissue using an early compound microscope. He coins the term cell (from Latin cella, meaning “small room“) in his book Micrographia (1665).

– 1839: Theodor Schwann and Matthias Jakob Schleiden elucidate the principle that plants and animals are made of cells, concluding that cells are a common unit of structure and development, and thus founding the cell theory.

– 1855: Rudolf Virchow states that new cells come from pre-existing cells by cell division (omnis cellula ex cellula).

– 1859: Louis Pasteur (1822-1895) contradicts the belief that life forms can occur spontaneously (generatio spontanea) (although Francesco Redi had performed an experiment in 1668 that suggested the same conclusion).

– 1931: Ernst Ruska builds the first transmission electron microscope (TEM) at the University of Berlin. By 1935, he has built an EM with twice the resolution of a light microscope, revealing previously unresolvable organelles.

– 1953: Watson and Crick made their first announcement on the double helix structure of DNA on February 28.

– 1981: Lynn Margulis published Symbiosis in Cell Evolution detailing the endosymbiotic theory

 

DIABETES

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Fewer Exams and Better Eye Health?

 

According to an article published in the New England Journal of Medicine (April 19, 2017), adjusting the frequency of eye screenings for people with type 1 diabetes based on their risk of severe eye problems would result in fewer eye exams at lower cost and quicker diagnosis and treatment of advanced retinopathy, which can otherwise lead to vision loss. The findings are the latest from an ongoing study funded for more than 30 years by the National Institutes of Health.

 

To develop the new screening suggestions, the authors analyzed about 24,000 retinal exams obtained over three decades from about 1,400 participants in the Diabetes Control and Complications Trial and its follow-up, the Epidemiology of Diabetes Interventions and Complications study (DCCT/EDIC). The DCCT/EDIC investigators found that people with type 1 diabetes should get eye exams to detect diabetic retinopathy based on their risk, rather than on the automatic, annual schedule that is currently recommended. Diabetic retinopathy is the leading cause of blindness among working-age adults.

 

Several major medical groups currently recommend routine yearly eye exams, starting after three to five years of diabetes duration, for people with type 1 diabetes, a condition where the body does not make insulin. Diabetic retinopathy occurs when diabetes damages the light-sensitive tissue in the back of the eye. The DCCT/EDIC study suggests a new, more efficient screening strategy based on the presence and severity of retinopathy. For people with type 1 diabetes and a current average blood glucose level of 6 percent, the researchers recommend the following eye exam schedule:

 

— With no retinopathy, every four years.

— With mild retinopathy, every three years.

— With moderate retinopathy, every six months.

— With severe retinopathy, every three months.

 

The study also recommended people with higher current average blood glucose levels (for example, 8-10%, versus 6%) have eye exams more often, as they are at higher risk to develop eye disease. Overall, the study found the new, individualized schedule would result in earlier detection of advanced retinopathy that requires treatment to save vision compared with annual exams, while at the same time reducing the frequency of eye exams. Over 20 years, the new schedule would result in eight exams on average, a greater than 50% reduction in eye examinations compared with annual exams. The reduction in exam frequency could lower screening costs by about $1 billion over 20 years.

 

According to the authors, this new evidence-based screening schedule is based on taking photographs of the back of the eye, rather than physical examination with an ophthalmoscope. Retinal photography is a commonly used and widely available method to detect eye disease and is thought to be more accurate than only the physical exam in detecting diabetic eye disease. The authors added that further studies are needed to learn if the newly proposed screening strategy applies to type 2 diabetes.

 

The results are the latest transformative findings from DCCT/EDIC. Beginning in 1983, the DCCT study enrolled 1,441 people between ages 13 and 39 with recent-onset type 1 diabetes. Half were assigned at random to intensive blood glucose treatment designed to keep blood glucose as close to the non-diabetic range as safely possible, and half to the conventional treatment at the time. The DCCT ended in 1993 when the intensive treatment group was found to have substantially less eye, nerve and kidney disease. All participants were then taught the intensive therapy and followed during the ongoing EDIC study. During the EDIC follow-up, the original intensive treatment group has continued to show a long-term benefit, with reduced development of kidney disease, severe eye problems, heart disease and stroke. They are also likely to live longer.

 

The online version of this news release contains a video: Animation: Diabetic Retinopathy as well as an image: A patient reads and eye chart. Credit: CDC

 

FDA Approves First Treatment for a Form of Batten Disease

 

Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency, is one of a group of disorders known as neuronal ceroid lipofuscinoses (NCLs), collectively referred to as Batten disease. CLN2 disease is a rare inherited disorder that primarily affects the nervous system. In the late infantile form of the disease, signs and symptoms typically begin between ages 2 and 4. The initial symptoms usually include language delay, recurrent seizures (epilepsy) and difficulty coordinating movements (ataxia). Affected children also develop muscle twitches (myoclonus) and vision loss. CLN2 disease affects essential motor skills, such as sitting and walking. Individuals with this condition often require the use of a wheelchair by late childhood and typically do not survive past their teens. Batten disease is relatively rare, occurring in an estimated two to four of every 100,000 live births in the United States.

 

The FDA has approved Brineura (cerliponase alfa) as a treatment for a specific form of Batten disease. Brineura is the first FDA-approved treatment to slow loss of walking ability (ambulation) in symptomatic pediatric patients 3 years of age and older. Brineura is an enzyme replacement therapy. Its active ingredient (cerliponase alfa) is a recombinant form of human TPP1, the enzyme deficient in patients with CLN2 disease. Brineura is administered into the cerebrospinal fluid (CSF) by infusion via a specific surgically implanted reservoir and catheter in the head (intraventricular access device). Brineura must be administered under sterile conditions to reduce the risk of infections, and treatment should be managed by a health care professional knowledgeable in intraventricular administration. The recommended dose of Brineura in pediatric patients 3 years of age and older is 300 mg administered once every other week by intraventricular infusion, followed by an infusion of electrolytes. The complete Brineura infusion, including the required infusion of intraventricular electrolytes, lasts approximately 4.5 hours. Pre-treatment of patients with antihistamines with or without antipyretics (drugs for prevention or treatment of fever) or corticosteroids is recommended 30 to 60 minutes prior to the start of the infusion.

 

The efficacy of Brineura was established in a non-randomized, single-arm dose escalation clinical study in 22 symptomatic pediatric patients with CLN2 disease and compared to 42 untreated patients with CLN2 disease from a natural history cohort (an independent historical control group) who were at least 3 years old and had motor or language symptoms. Taking into account age, baseline walking ability and genotype, Brineura-treated patients demonstrated fewer declines in walking ability compared to untreated patients in the natural history cohort. The safety of Brineura was evaluated in 24 patients with CLN2 disease aged 3 to 8 years who received at least one dose of Brineura in clinical studies. The safety and effectiveness of Brineura have not been established in patients less than 3 years of age.

 

The most common adverse reactions in patients treated with Brineura include fever, ECG abnormalities including slow heart rate (bradycardia), hypersensitivity, decrease or increase in CSF protein, vomiting, seizures, hematoma (abnormal collection of blood outside of a blood vessel), headache, irritability, increased CSF white blood cell count (pleocytosis), device-related infection, feeling jittery and low blood pressure. Brineura should not be administered to patients if there are signs of acute intraventricular access device-related complications (e.g., leakage, device failure or signs of device-related infection such as swelling, erythema of the scalp, extravasation of fluid, or bulging of the scalp around or above the intraventricular access device). In case of intraventricular access device complications, health care providers should discontinue infusion of Brineura and refer to the device manufacturer’s labeling for further instructions. Additionally, health care providers should routinely test patient CSF samples to detect device infections. Brineura should also not be used in patients with ventriculoperitoneal shunts (medical devices that relieve pressure on the brain caused by fluid accumulation).

 

Health care providers should also monitor vital signs (blood pressure, heart rate, etc.) before the infusion starts, periodically during infusion and post-infusion in a health care setting. Health care providers should perform electrocardiogram (ECG) monitoring during infusion in patients with a history of slow heart rate (bradycardia), conduction disorder (impaired progression of electrical impulses through the heart) or structural heart disease (defect or abnormality of the heart), as some patients with CLN2 disease can develop conduction disorders or heart disease. Hypersensitivity reactions have also been reported in Brineura-treated patients. Due to the potential for anaphylaxis, appropriate medical support should be readily available when Brineura is administered. If anaphylaxis occurs, infusion should be immediately discontinued and appropriate treatment should be initiated.

 

The FDA will require the Brineura manufacturer to further evaluate the safety of Brineura in CLN2 patients below the age of 2 years, including device related adverse events and complications with routine use. In addition, a long-term safety study will assess Brineura treated CLN2 patients for a minimum of 10 years.

 

The FDA granted this application Priority Review and Breakthrough Therapy designations. Brineura also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The sponsor is also receiving a Rare Pediatric Disease Priority Review Voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive Priority Review of a subsequent marketing application for a different product. This is the tenth rare pediatric disease priority review voucher issued by the FDA since the program began.

 

The FDA granted approval of Brineura to BioMarin Pharmaceutical Inc.

 

Homage to Spinach: 1 Spinach Pie

Besides being delicious, this is a wonderfully versatile dish because it’s good warm or cold; indoors or outside; dinner, brunch, snack. ©Joyce Hays, Target Health Inc.

 

This recipe turned out so well, we have it about twice every month. ©Joyce Hays, Target Health Inc.

 

 

Ingredients

 

2.5 lbs. spinach, chopped (you can substitute frozen; thaw it well)

1/4 cup olive oil

4 large onions, diced

2 bunches scallions (use white and (tender only) green part

6 fresh garlic cloves, sliced

1/2 cup parsley, chopped

1/2 cup fresh dill, chopped

1/2 cup fresh cilantro, chopped

1/4 tsp. ground nutmeg (buy the whole nutmeg and freshly grate it)

Pinch black pepper or to taste

Pinch chili flakes

1/2 lb. feta cheese, crumbled

4 eggs, lightly beaten

1/2 lb. ricotta or cottage cheese

 

Directions

 

1. Preheat oven to 350 degrees

2. Wash and drain the chopped spinach at least 3 times, to be sure you get all of the sand and grit out. Nothing ruins a spinach recipe more, than biting down on sand. The last time this happened, I had to throw the whole baked dish, out, after serving it. If using frozen spinach, thaw completely and squeeze out excess water. Spinach should be dry.

 

This is the third washing, and now draining. It ruins all of your efforts, if the final result ends up with chewing on sand or grit. ©Joyce Hays, Target Health Inc.

 

 

3. Chop everything that needs chopping or slicing.

 

Chopping everything on the same cutting board. ©Joyce Hays, Target Health Inc .

 

 

4. Heat the olive oil in a large pan. Saute the onions, garlic and scallions until tender.

5. Add the spinach, parsley, and dill and cook for 5 to 10 minutes until the spinach is wilted and heated through. Add the nutmeg and season with salt and pepper.

6. If using frozen spinach, you will want to cook until excess moisture evaporates. Spinach mixture should be on the dry side.

 

Sautee the onion, garlic, scallion. ©Joyce Hays, Target Health Inc.

 

To the onion/garlic mix add all the chopped spinach, all the herbs, all the seasoning and cook stirring occasionally, for 5 to 10 minutes. ©Joyce Hays, Target Health Inc.

 

 

7. Remove from heat and set the spinach aside to cool.

 

8. In a large mixing bowl, combine the feta cheese, eggs, and ricotta cheese. Add the cooled spinach mixture and mix until combined.

To the eggs, I added the feta and ricotta. ©Joyce Hays, Target Health Inc.

 

After the cooked spinach mixture has cooled way down, add it to the egg/ricotta bowl and combine well. ©Joyce Hays, Target Health Inc.

 

 

9. Oil a deep bake dish, with 1 teaspoon of olive oil, and pour the spinach mixture in. Use a spatula to scrape all the spinach out of the mixing bowl.

 

Entire spinach mixture is poured from the bowl into an oiled baking dish. Try to use a baking dish that also goes from oven to table. ©Joyce Hays, Target Health Inc.

 

 

10. Bake the spinach pie section for 40 minutes, then remove from oven to cool for about 10 minutes.

 

Spinach mixture has been baked and just out of the oven. Now it will cool down for about 10 minutes. ©Joyce Hays, Target Health Inc.

 

 

11. While the spinach is baking, make the topping.

 

Topping Ingredients

 

4 eggs, beaten

1.5 cups plain Greek yogurt (FAGE)

Pinch salt

Pinch black pepper

Pinch paprika

1 cup creamy goat cheese or freshly grated kashkaval cheese, which I get from FreshDirect

 

 

Topping Directions

 

1. Add all of the above ingredients to a bowl and whisk with a fork or whisk tool.

 

Whisking the topping mixture with a fork (couldn’t find my whisk), until it’s nice and smooth. ©Joyce Hays, Target Health Inc.

 

 

2. After the spinach pie has been baked and has cooled down, with a spatula, scrape all of the topping from the bowl, pouring it onto the spinach pie. Do this slowly.

3. Smooth the topping so it’s evenly distributed over the spinach.

4. Bake in the same 350 degree oven for approximately 20 minutes. Keep your eye on the oven to be sure the topping doesn’t burn.

5. Serve nice and warm

 

Smells so-o good! ©Joyce Hays, Target Health Inc.

 

Third helping. ©Joyce Hays, Target Health Inc.

 

This spinach pie goes fast. ©Joyce Hays, Target Health Inc.

Homage to Spinach 2: Spinach Salad with Tomatoes, Avocado, Goat Cheese, Strawberries, Flax

Tasty, easy, healthy; make this one of your favorite salads, this summer. ©Joyce Hays, Target Health Inc.

 

This summer, we’re going to be eating fresh salads, loaded with super healthy ingredients, as the main dish, along with chilled wines. Fresh fruit and sugar-free jello cake for dessert. ©Joyce Hays, Target Health Inc.

 

 

Ingredients

 

1 box baby spinach, washed twice or three times, then dried on paper towel

2 or 3 plum tomatoes

1 avocado, cut in pieces

1 container creamy goat cheese, cut in pieces

4 sweet strawberries, cut in half or 1.5 cup of fresh watermelon pieces

1 cup of toasted flax seeds, or use some of the flax crackers and crush them into crumbs

1/4 cup fresh basil, chopped fine

1/4 cup fresh dill, chopped fine

 

Flax seeds are in the top 10 to 15 list of healthy foods to include in a regular diet. Keep a large jar out on your kitchen counter and simply throw a handful into nearly everything you make. ©Joyce Hays, Target Health Inc.

 

Using more flax seeds on everything, now. ©Joyce Hays, Target Health Inc.

 

Dressing

 

Make a simple dressing with:

walnut oil (not olive oil)

zest of 1 lemon

fresh lemon juice

4 garlic cloves squeezed

Pinch chili flakes

 

We had spinach pie with the spinach salad and fresh mango for dessert. Did not seem redundant at all. ©Joyce Hays, Target Health Inc.

 

Imagine living on an island with this sweet fruit growing everywhere. I’m going to try to create some mango desserts this summer. ©Joyce Hays, Target Health Inc.

Homage to Spinach 3: Baked Tofutti Spinach Spread or Dip, with Yogurt, Parmesan & Flax

Healthy, simple and easy to make. It turned out to be so-o delicious, that I made this my dinner. Fresh French baguette, slightly toasted, with spinach spread (or dip with crackers and/or cruditee) and icy Pouilly-Fuisse; mango for dessert. ©Joyce Hays, Target Health Inc.

 

Ingredients

 

2 stalks of scallion, chopped up to half the white section

6 fresh garlic cloves, sliced

? cup fresh dill, well chopped (save a twig for garnish)

2 cups of freshly grated parmesan cheese

2 (10 ounce) boxes of frozen spinach

2/3 cup of Greek yogurt (FAGE)

1 container Tofutti (soy cream cheese)

1/3 cup of Kraft mayonnaise

1 cup crumbs of flax seed crackers, or plain toasted flax seeds

 

Directions

 

Take frozen spinach out and let it thaw.

Preheat the oven to 375 degrees

When spinach is thawed out, with paper towels in each hand, squeeze excess liquid out of the spinach.

Oil some ramekins, one for each person; or a larger group bowl

Get out your food processor and pulse all the ingredients together

With a spatula, scrape out everything from the food processor and into the oiled baking dish(s) and bake for 20-30 minutes.

Serve as a side dish or simple main dish with chips, baguette and/or bread and a nice chilled Pouilly-Fuisse.

 

Still enjoying Louis Jadot, Pouilly-Fuisse. This wine was perfect with all three spinach recipes ©Joyce Hays, Target Health Inc.

 

 

From Our Table to Yours !

 

Bon Appetit!