Target Document as a User-Friendly, 21 CFR Part 11 eTMF


The first version of Target Document was released in 2006 and a new version is being released this month. Target Document is quite versatile as not only can it be used as an eTMF, it can be used by any industry as a robust, stand-alone document management system. Target Document is also reasonably priced and can be hosted by Target Health or your company/organization.


Target Document® is a secure, USER FRIENDLY, web-based document distribution and management system which enables users, depending on their roles and responsibilities to post, share, move, copy, import, electronically sign, search, and archive electronic documents, all within a web browser and without installing any software. Access to documents can also be timed to be viewed and/or “expired,“ and there is a communication tool which allows for discussions about specific documents. Target Document® reduces the need to distribute documents via email and is ideal for companies wanting their own system to communicate with vendors, CROs, study sites, CRAs, etc. It is also ideal for CROs needing to deal with many sponsors.


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 or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.


Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor



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Source: Kelvinsong – Own work, CC0, Wikipedia Commons



Components of a typical animal cell:


1. Nucleolus

2. Nucleus

3. Ribosome (little dots)

4. Vesicle

5. Rough endoplasmic reticulum

6. Golgi apparatus (or “Golgi body“)

7. Cytoskeleton

8. Smooth endoplasmic reticulum

9. Mitochondrion

10. Vacuole

11. Cytosol (fluid that contains organelles, comprising the cytoplasm)

12. Lysosome

13. Centrosome

14. Cell membrane


Autophagy, taken from the 1) ___, meaning “self-devouring“ and “hollow“, is the natural, regulated, destructive mechanism of the cell that disassembles unnecessary or dysfunctional components. Autophagy allows the orderly degradation and recycling of cellular components. In macroautophagy, targeted cytoplasmic constituents are isolated from the rest of the cell within a double-membraned vesicle known as an autophagosome. The autophagosome eventually fuses with lysosomes and the contents are degraded and recycled. Two additional forms of autophagy are also commonly described: microautophagy and chaperone-mediated autophagy (CMA). In disease, autophagy has been seen as an adaptive response to stress, which promotes 2) ___, whereas in other cases it appears to promote cell death and morbidity. In the extreme case of starvation, the breakdown of cellular components promotes cellular survival by maintaining cellular energy levels.


The name “autophagy“ was coined by Belgian biochemist Christian de Duve in 1963. The identification of autophagy-related 3) ___ in yeast in the 1990s let researchers figure out the mechanisms of autophagy, and led to the award of the 2016 Nobel Prize in Physiology or Medicine to Japanese autophagy researcher Yoshinori Ohsumi. Autophagy was first observed by Keith R. Porter and his student Thomas Ashford at the Rockefeller Institute. In January 1962 they reported an increased number of lysosomes in rat liver cells after addition of glucagon, and that some displaced lysosomes towards the center of the cell contained other cell organelles such as mitochondria. They called this autolysis after Christian de Duve and Alex B. Novikoff. However Porter and Ashford wrongly interpreted their data as lysosome formation (ignoring the pre-existing organelles). Lysosomes could not be 4) ___ organelles, but part of cytoplasm such as mitochondria, and that hydrolytic enzymes were produced by microbodies. In 1963 researchers published a detailed ultrastructural description of “focal cytoplasmic degradation,“ which referenced a 1955 German study of injury-induced sequestration. The study recognized three continuous stages of maturation of the sequestered cytoplasm to lysosomes, and that the process was not limited to injury states that functioned under physiological conditions for “reutilization of cellular materials,“ and the “disposal of organelles“ during differentiation. Inspired by this discovery, de Duve christened the phenomena “autophagy“. Unlike Porter and Ashford, de Duve conceived the term as a part of lysosomal function while describing the role of glucagon as a major inducer of cell degradation in the liver. With his student Peter, he established that lysosomes are responsible for glucagon-induced autophagy. This was the first time the fact that lysosomes were established as the sites of intracellular autophagy.


A lysosome is a membrane-bound organelle found in most animal cells. They are spherical vesicles which contain hydrolytic enzymes that can break down virtually all kinds of biomolecules. The lysosomes also act as the 5) ___ disposal system of the cell by digesting unwanted materials in the cytoplasm, both from outside of the cell and obsolete components inside the cell. There are three pathways of autophagy and these are mediated by the autophagy-related genes and their associated enzymes. Macroautophagy is the main pathway, used primarily to eradicate damaged cell organelles or unused 6) ___. This involves the formation of a double membrane known as an autophagosome, around the organelle marked for destruction. The autophagosome then travels through the cytoplasm of the cell to a lysosome, and the two organelles fuse. Within the lysosome, the contents of the autophagosome are degraded via acidic lysosomal hydrolases. Microautophagy, on the other hand, involves the direct engulfment of cytoplasmic material into the 7) ___. This occurs by invagination, meaning the inward folding of the lysosomal membrane, or cellular protrusion. Chaperone-mediated autophagy, or CMA, is a very complex and specific pathway, which involves the recognition by the hsc70-containing complex. This means that a protein must contain the recognition site for this hsc70 complex which will allow it to bind to this chaperone, forming the CMA- substrate/chaperone complex. This complex then moves to the lysosomal membrane-bound protein that will recognize and bind with the CMA receptor, allowing it to enter the cell.


One of the mechanisms of programmed cell death (PCD) is associated with the appearance of autophagosomes and depends on autophagy proteins. This form of cell death most likely corresponds to a process that has been morphologically defined as autophagic PCD. One question that constantly arises, however, is whether autophagic activity in dying cells is the cause of death or is actually an attempt to prevent it. Morphological and histochemical studies so far did not prove a causative relationship between the autophagic process and cell death. In fact, there have recently been strong arguments that autophagic activity in dying cells might actually be a survival 8) ___. Studies of the metamorphosis of insects have shown cells undergoing a form of PCD that appears distinct from other forms; these have been proposed as examples of autophagic cell death. Recent pharmacological and biochemical studies have proposed that survival and lethal autophagy can be distinguished by the type and degree of regulatory signaling during stress particularly after viral infection. Autophagy is essential for basal homeostasis; it is also extremely important in maintaining muscle homeostasis during physical exercise. Autophagy at the molecular level is only partially understood. A study of mice shows that autophagy is important for the ever changing demands of their nutritional and energy needs. Because autophagy decreases with age and 9) ___ is a major risk factor for osteoarthritis, the role of autophagy in the development of this disease is suggested. Proteins involved in autophagy are reduced with age in both human and mouse articular cartilage. Mechanical injury to cartilage explants in culture also reduced autophagy proteins. Autophagy is constantly activated in normal cartilage but it is compromised with age and precedes cartilage cell death and structural damage. These results suggest autophagy is a normal protective process (chondroprotection) i

n the 10) ___Sources:; Wikipedia


ANSWERS: 1) Greek; 2) survival; 3) genes; 4) cell; 5) waste; 6) proteins; 7) lysosome; 8) mechanism; 9) age; 10) joint


Yoshinori Ohsumi, 2016 Nobel Prize Winner (1945 to Present)


Photo by the Nobel Assembly at the Karolinska Institutet


Yoshinori Ohsumi, a Japanese cell biologist, has won the 2016 Nobel Prize for physiology or medicine for his discoveries on a process whereby cells essentially eat themselves. The process is called autophagy. The word autophagy originates from the Greek words auto-, meaning “self“, and phagein, meaning “to eat“. Think of autophagy as a cell’s internal spa or recycling plant. Cells use autophagy for self-renewal. When our cells are starved or otherwise stressed, they don’t immediately shut down. Instead, they employ autophagy to cannibalize their own components thus allowing the cell to stay alive during tough times. “By recycling part of the cellular content, autophagy allows our body to cope with starvation and with all types of stress,“ said biologist Maria Masucci of the Nobel Assembly. “By capturing invading viruses and bacteria, autophagy is essential for the body’s defense against infection.“



Scientists first described autophagy in the 1960s, after discovering the cellular version of a garbage can, known as the lysosome. Parts of your cells are like parts of a car: they wear down with time. A lysosome is a spherical bubble that moves through a cell and collects these broken parts. Like a digestive system, the lysosome fills with acids and enzymes to disassemble these parts into their basic units – proteins, sugars and lipids – so they can be reused. Belgian scientist Christian de Duve won the 1974 Nobel Prize in physiology or medicine for the discovery of the lysosome. Soon after spotting the lysosome, Duve and other researchers noticed another spherical trash can, except this one was larger and could consume huge portions of a cell. He called the process autophagy, but it was initially viewed as a one-off version of the lysosome, so only a handful of labs examined it over the next three decades.



Our cells have different compartments. Lysosomes are akin to a cell’s garbage can. They contain enzymes for digestion of cellular contents. Yoshinori Ohsumi won the 2016 Nobel Prize in medicine for research on a similar compartment called the autophagosome. It engulfs larger portions of the cell, before fusing with the lysosome, where the contents are degraded into smaller constituents. This process provides the cell with nutrients and building blocks for renewal. Photo by Photo by the Nobel Assembly at the Karolinska Institutet



In the early 1990s, Ohsumi’s lab created an experiment that involved starving baker’s yeast of nutrients. They noticed this stress caused the yeast cells to create these relatively huge, spherical trash cans – now known as autophagosomes. The structures were so big that the scientists could observe them with a regular light microscope, rather than a more time-consuming electron microscope.This event was a major breakthrough, because it meant Ohsumi’s team could watch the creation and movements of autophagosomes in real-time. This ability became the key to understanding how autophagosomes and autophagy work. Ohsumi and his colleagues then used chemicals to mutate individual genes in baker’s yeast to figure out what controlled autophagy. The team landed upon 15 crucial genes, published in 1992, which in essence launched a new branch of cell biology. “When I started my work, every year, probably 20 papers appeared on autophagy,“ said Ohsumi, who was in his lab when he learned about the news of his Nobel Prize. “Now it’s more than 5,000. It’s a huge change.“ His team also identified the first autophagy-related genes in mammals, which led others to examine the process in human disease. Too little autophagy is a common problem during old age. Diseases like Alzheimer’s and type 2 diabetes appear as our cells fail to clear out their gunk. On the flip side, too much autophagy can propel cancer or allow tumor cells to consume drugs.



The autophagy concept emerged during the 1960’s, when researchers first observed that the cell could destroy its own contents by enclosing it in membranes, forming sack-like vesicles that were transported to a recycling compartment, called the lysosome, for degradation. Difficulties in studying the phenomenon meant that little was known until, in a series of brilliant experiments in the early 1990’s, Yoshinori Ohsumi used baker’s yeast to identify genes essential for autophagy. He then went on to elucidate the underlying mechanisms for autophagy in yeast and showed that similar sophisticated machinery is used in our cells. Ohsumi’s discoveries led to a new paradigm in our understanding of how the cell recycles its content. His discoveries opened the path to understanding the fundamental importance of autophagy in many physiological processes, such as in the adaptation to starvation or response to infection. Mutations in autophagy genes can cause disease, and the autophagic process is involved in several conditions including cancer and neurological disease.


Degradation – a central function in all living cells. In the mid 1950’s scientists observed a new specialized cellular compartment, called an organelle, containing enzymes that digest proteins, carbohydrates and lipids. This specialized compartment is referred to as a “lysosome“ and functions as a workstation for degradation of cellular constituents. The Belgian scientist Christian de Duve was awarded the Nobel Prize in Physiology or Medicine in 1974 for the discovery of the lysosome. New observations during the 1960’s showed that large amounts of cellular content, and even whole organelles, could sometimes be found inside lysosomes. The cell therefore appeared to have a strategy for delivering large cargo to the lysosome. Further biochemical and microscopic analysis revealed a new type of vesicle transporting cellular cargo to the lysosome for degradation. Christian de Duve, the scientist behind the discovery of the lysosome, coined the term autophagy, “self-eating“, to describe this process. The new vesicles were named autophagosomes.


During the 1970’s and 1980’s research focused on elucidating another system used to degrade proteins, namely the “proteasome“. Within this research field Aaron Ciechanover, Avram Hershko and Irwin Rose were awarded the 2004 Nobel Prize in Chemistry for “the discovery of ubiquitin-mediated protein degradation“. The proteasome efficiently degrades proteins one-by-one, but this mechanism did not explain how the cell got rid of larger protein complexes and worn-out organelles. Could the process of autophagy be the answer and, if so, what were the mechanisms? Yoshinori Ohsumi had been active in various research areas, but upon starting his own lab in 1988, he focused his efforts on protein degradation in the vacuole, an organelle that corresponds to the lysosome in human cells. Yeast cells are relatively easy to study and consequently they are often used as a model for human cells. They are particularly useful for the identification of genes that are important in complex cellular pathways. But Ohsumi faced a major challenge; yeast cells are small and their inner structures are not easily distinguished under the microscope and thus he was uncertain whether autophagy even existed in this organism. Ohsumi reasoned that if he could disrupt the degradation process in the vacuole while the process of autophagy was active, then autophagosomes should accumulate within the vacuole and become visible under the microscope. He therefore cultured mutated yeast lacking vacuolar degradation enzymes and simultaneously stimulated autophagy by starving the cells. The results were striking! Within hours, the vacuoles were filled with small vesicles that had not been degraded. The vesicles were autophagosomes and Ohsumi’s experiment proved that authophagy exists in yeast cells. But even more importantly, he now had a method to identify and characterize key genes involved this process. This was a major break-through and Ohsumi published the results in 1992.



In yeast (left panel) a large compartment called the vacuole corresponds to the lysosome in mammalian cells. Ohsumi generated yeast lacking vacuolar degradation enzymes. When these yeast cells were starved, autophagosomes rapidly accumulated in the vacuole (middle panel). His experiment demonstrated that autophagy exists in yeast. As a next step, Ohsumi studied thousands of yeast mutants (right panel) and identified 15 genes that are essential for autophagy.



Ohsumi now took advantage of his engineered yeast strains in which autophagosomes accumulated during starvation. This accumulation should not occur if genes important for autophagy were inactivated. Ohsumi exposed the yeast cells to a chemical that randomly introduced mutations in many genes, and then he induced autophagy. His strategy worked! Within a year of his discovery of autophagy in yeast, Ohsumi had identified the first genes essential for autophagy. In his subsequent series of elegant studies, the proteins encoded by these genes were functionally characterized. The results showed that autophagy is controlled by a cascade of proteins and protein complexes, each regulating a distinct stage of autophagosome initiation and formation.



Ohsumi studied the function of the proteins encoded by key autophagy genes. He delineated how stress signals initiate autophagy and the mechanism by which proteins and protein complexes promote distinct stages of autophagosome formation.



Autophagy is an essential mechanism in our cells. After the identification of the machinery for autophagy in yeast, a key question remained. Was there a corresponding mechanism to control this process in other organisms? Soon it became clear that virtually identical mechanisms operate in our own cells. The research tools required to investigate the importance of autophagy in humans were now available. Thanks to Ohsumi and others following in his footsteps, we now know that autophagy controls important physiological functions where cellular components need to be degraded and recycled. Autophagy can rapidly provide fuel for energy and building blocks for renewal of cellular components, and is therefore essential for the cellular response to starvation and other types of stress. After infection, autophagy can eliminate invading intracellular bacteria and viruses. Autophagy contributes to embryo development and cell differentiation. Cells also use autophagy to eliminate damaged proteins and organelles, a quality control mechanism that is critical for counteracting the negative consequences of aging. Disrupted autophagy has been linked to Parkinson’s disease, type 2 diabetes and other disorders that appear in the elderly. Mutations in autophagy genes can cause genetic disease. Disturbances in the autophagic machinery have also been linked to cancer. Intense research is now ongoing to develop drugs that can target autophagy in various diseases.


Yoshinori Ohsumi was born 1945 in Fukuoka, Japan. He received a Ph.D. from University of Tokyo in 1974. After spending three years at Rockefeller University, New York, USA, he returned to the University of Tokyo where he established his research group in 1988. He is since 2009 a professor at the Tokyo Institute of Technology. Ohsumi becomes the 23rd Nobel Prize winner from Japan, and the country’s sixth medicine laureate. Of the 107 Nobel awards for physiology and medicine, Ohsumi becomes only the 39th to win as the sole recipient.


Key Publications

Takeshige, K., Baba, M., Tsuboi, S., Noda, T. and Ohsumi, Y. (1992). Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. Journal of Cell Biology 119, 301-311

Tsukada, M. and Ohsumi, Y. (1993). Isolation and characterization of autophagy-defective mutants of Saccharomyces cervisiae. FEBS Letters 333, 169-174

Mizushima, N., Noda, T., Yoshimori, T., Tanaka, Y., Ishii, T., George, M.D., Klionsky, D.J., Ohsumi, M. and Ohsumi, Y. (1998). A protein conjugation system essential for autophagy. Nature 395, 395-398

Ichimura, Y., Kirisako T., Takao, T., Satomi, Y., Shimonishi, Y., Ishihara, N., Mizushima, N., Tanida, I., Kominami, E., Ohsumi, M., Noda, T. and Ohsumi, Y. (2000). A ubiquitin-like system mediates protein lipidation. Nature, 408, 488-492

The Nobel Assembly, consisting of 50 professors at Karolinska Institutet, awards the Nobel Prize in Physiology or Medicine. Its Nobel Committee evaluates the nominations. Since 1901 the Nobel Prize has been awarded to scientists who have made the most important discoveries for the benefit of mankind.

Sources: Karolinska Institutet;; The New York Times


New Mechanism to Treat Parkinson’s Disease


Analogous to how a computer virus corrupts data, the presence of abnormal a-synuclein in neurons can damage healthy a-synuclein protein, which promotes the formation of additional aggregates. These aggregates then pass from one neuron to another just as computer viruses move to other computers on the same network.


According to an article published online in Science (30 September 2106), it was found in a study in mice that it was possible to reduce the progression of the toxic aggregates of a protein known as a-synuclein that are found in the brains of Parkinson’s disease patients. The results suggest that another protein called lymphocyte-activation gene 3 (LAG3) plays a role in transmitting a-synuclein aggregates from one brain cell to another and could provide a possible target to slow the progression of Parkinson’s disease.


For the study, the authors used a synthetic form of abnormal -synuclein, called pre-formed fibrils, to induce Parkinson’s disease-like symptoms in mice. When doing this, the authors ultimately focused on the protein LAG3 based on its role as a transmembrane protein and the fact that it binds to fibrils much more tightly than healthy a-synuclein protein. These transmembrane proteins are large molecules with components located both on the interior and the exterior of cells; some transmembrane proteins function as gatekeepers that allow specific molecules to enter or exit cells.


To test the role of LAG3, authors compared normal mice with those that lacked the gene for LAG3 and were unable to make that specific protein. When normal mice were injected with a-synuclein fibrils, they quickly developed Parkinson’s disease-like symptoms, including changes in movement, grip strength, and the eventual death of dopamine neurons, the type of brain cell most affected by the disease. However, the mice lacking LAG3 that received fibril injections appeared to have normal grip strength and movement and had no significant loss of dopamine neurons. The authors also looked at neurons that had been removed from both types of mice and grown in vitro. When a-synuclein fibrils were added to normal neurons, they were quickly pulled into the cells and passed along to neighboring cells; however, this was seen only in very few neurons from the mice that lacked LAG3. The authors also knew from these experiments that LAG3 was important for the neurons’ ability to take up a-synuclein fibrils and that antibodies that block the activity of LAG3 are being tested in clinical trials as a form of cancer immunotherapy. Therefore, the authors were curious to see whether we could use similar antibodies to block the function of LAG3. Results showed that neurons treated with the LAG3 antibodies behaved similarly to the neurons that lacked LAG3.  There was a considerable decrease in their ability to take up fibrils and to pass them on to neighboring neurons. These results suggested that LAG3 function could be blocked by antibodies, providing a possible means to slow or stop the progression of Parkinson’s disease.


The authors are currently testing the LAG3 antibody in animal models of Parkinson’s disease to further explore possible therapeutic and protective effects against the progression of disease symptoms.


Parkinson’s Disease Alters Brain Activity Over Time


Parkinson’s disease is a neurodegenerative disorder that destroys neurons in the brain that are essential for controlling movement. While many medications exist that lessen the consequences of this neuronal loss, none can prevent the destruction of those cells. Clinical trials for Parkinson’s disease have long relied on observing whether a therapy improves patients’ symptoms, but such studies reveal little about how the treatment affects the underlying progressive neurodegeneration. As a result, while there are treatments that improve symptoms, they become less effective as the neurodegeneration advances. A new study, published in Neurology (15 July 2016), could remedy this issue by providing researchers with measurable targets, called biomarkers, to assess whether a drug slows or even stops the progression of the disease in the brain.


The authors used functional magnetic resonance imaging (fMRI) to measure activity in a set of pre-determined brain areas in healthy controls, individuals with Parkinson’s disease, and patients with two forms of “atypical Parkinsonism“  that have symptoms similar to those of Parkinson’s disease 1) multiple systems atrophy (MSA) and 2) progressive supranuclear palsy (PSP). The authors selected the specific brain regions, which are critical for movement and balance, based on the findings of past studies in people with these three conditions. The participants each underwent two scans spaced a year apart, during which they completed a test that gauged their grip strength. In terms of results, the healthy controls showed no changes in neural activity after a year, whereas the participants with Parkinson’s showed reductions in the response of two brain regions called the putamen and the primary motor cortex. Previous research had shown reduced activity in the primary motor cortex of Parkinson’s patients, but the new study is the first to suggest that this deficit worsens over time. Activity decreased in MSA patients in the primary motor cortex, the supplementary motor area, and the superior cerebellum, while the individuals with PSP showed a decline in the response of these three areas and the putamen. The authors now hope to use its newly discovered biomarkers, in addition to one it had previously identified, to test whether an experimental medication known to improve Parkinson’s symptoms also slows the progression of those brain changes. The authors stated that these markers allow us to evaluate disease-modifying therapeutics because we know that the control group doesn’t change over a year but patient groups do. Thus we can now see whether a therapeutic prevents that change from occurring, and if it does, then that suggests it might have a disease-modifying effect.


FDA Warns Against the Use of Homeopathic Teething Tablets and Gels


Homeopathic teething tablets and gels are distributed by CVS, Hyland’s, and possibly others, and are sold in retail stores and online.


The FDA is warning consumers that homeopathic teething tablets and gels may pose a risk to infants and children and FDA recommends that consumers stop using these products and dispose of any in their possession. Consumers should seek medical care immediately if their child experiences seizures, difficulty breathing, lethargy, excessive sleepiness, muscle weakness, skin flushing, constipation, difficulty urinating, or agitation after using homeopathic teething tablets or gels. According to the FDA, teething can be managed without prescription or over-the-counter remedies and recommends that parents and caregivers not give homeopathic teething tablets and gels to children and seek advice from their health care professional for safe alternatives.“


The FDA is analyzing adverse events reported to the agency regarding homeopathic teething tablets and gels, including seizures in infants and children who were given these products, since a 2010 safety alert about homeopathic teething tablets. The FDA is currently investigating this issue, including testing product samples. The agency will continue to communicate with the public as more information is available. Homeopathic teething tablets and gels have not been evaluated or approved by the FDA for safety or efficacy. The agency is also not aware of any proven health benefit of the products, which are labeled to relieve teething symptoms in children. The FDA is also encouraging health care professionals and consumers to report adverse events or quality problems experienced with the use of homeopathic teething tablets or gels to the FDA’s MedWatch Adverse Event Reporting program:


Complete and submit the report online at; or

Download and complete the form, then submit it via fax at 1-800-FDA-0178.


Holiday Apple Marzipan Cake




Same recipe baked in a deep pie dish. ©Joyce Hays, Target Health Inc.



Baked in the deep pie dish. Moist and luscious. I had to put the brakes on every taste bud, to keep from

having another piece. Jules had many more, but then, he has more lee-way. ©Joyce Hays, Target Health Inc.



Baked in the spring-form pan and equally delicious. ©Joyce Hays, Target Health Inc.





1 teaspoon + butter as needed, to grease the cake pan or dish

1/2 cup almond flour, more for dusting cake pan

3 eggs

1 can 11 ounces, marzipan. If you don’t have it locally, buy it online, here:

1/2 cup granulated sugar

Pinch salt

3/4 cup heavy cream

3/4 cup almond milk

10 to 15 apples, washed, dried, cored and sliced with a mandolin, very thinly, about 3 cups

Powdered sugar

Pinches of cinnamon over each layer of apples & marzipan



You need a mandolin for this recipe, a few ingredients and the rest is pretty easy. Be careful not to cut

fingers. The mandolin is razor sharp. Young kids probably shouldn’t use it. ©Joyce Hays, Target Health Inc.



I use this almond flour all the time, for practically everything. I get it at FreshDirect and Amazon.

©Joyce Hays, Target Health Inc.





1. Heat oven to 350 degrees. With plenty of butter, smear a cake pan or dish, about 9 x 5 x 2 inches, or a 10-inch round deep pie plate or a spring-form cake pan. If using a spring-form pan, line it first with parchment, then smear it with butter.

2. Next, dust cake pan with flour, rotating pan so flour sticks to all the butter. Next, invert dish to get rid of excess flour.

3. Prepare apples and slice them with mandolin. I took the skin off the first apple, but then I decided to leave the skin on. It’s healthier, so why bother, right?



I peeled the first apple, but then decided to leave the skins on the rest of the apples. ©Joyce Hays, Target Health Inc.



4. In a large bowl, whisk eggs until frothy. Do this by hand, not in the electric mixer. Add granulated sugar and salt and whisk until combined. Add cream and milk and whisk until smooth. Add 1/2 cup flour and stir just to combine, not more. Don’t stir the flour too much.



Mixing the batter, with a gift from a good friend (whisk). ©Joyce Hays, Target Health Inc.



5. Layer the apple slices in the cake pan or dish. Over each layer, sprinkle marzipan (take from the can; crumble it up with your fingers) and a tiny bit of cinnamon. Don’t make stacks of the slices. Distribute the slices all over the bottom of the dish, as one layer. Then do the next layer and so on, until there is a whole lot of apple slices, marzipan, cinnamon. The apple slices should come almost to the top. The thinner the apple slices, the better the dessert will be.



Starting, above, the first layer of thinly sliced apples. ©Joyce Hays, Target Health Inc.



Same recipe, different baking dish. Above is the first layer of apple slices, marzipan and cinnamon.

©Joyce Hays, Target Health Inc.



Using a deep pie dish for this recipe. ©Joyce Hays, Target Health Inc.



First layer of apple slices and marzipan is done. Next will come the cinnamon.

©Joyce Hays, Target Health Inc.



Layers have just about reached the top of the cake pan. ©Joyce Hays, Target Health Inc.



The last layer should only be made up of very thin apple slices. No marzipan on the top layer. ©Joyce Hays, Target Health Inc.



6. Pour the batter over the apple slices, to as close to the top of dish as you can, without the batter dripping over the side. There might be some leftover batter, depending on the size of your pan or dish.



Batter has been poured over the top layer of apple slices. You can be sure it trickles down, just the way it should. J ©Joyce Hays, Target Health Inc.



Going in oven, about to bake. ©Joyce Hays, Target Health Inc.



Later version of this cake, baked in a deep pie dish. ©Joyce Hays, Target Health Inc.



7. Bake for about 40 minutes, or until the top is nicely browned and a knife inserted into it comes out clean. Sift some powdered sugar over it and serve warm or at room temperature. Let it cool down for about an hour, then serve.

8. This dessert does not keep well; serve within a couple of hours of making it.

9. Serve with cool whip or real whipped cream or vanilla ice cream or delicious as is.



Mouth-wateringly good! ©Joyce Hays, Target Health Inc.



Friday night we started our meal with chilled Italian Ceretto which is like a cross between Sauvignon Blanc and a

Chardonnay. We had crudit?s with two dips: a low calorie yogurt/dill dip and hummus. A new warm

cabbage-with-turkey-bacon, recipe followed (will share later) and the apple marzipan cake.



We’ve discovered a new white from the Piedmont district in Northern Italy, that’s affordable and delicious. We were at one of our favorite Italian restaurants, looking to try something new and different. We were presented with two different whites and chose the one above. Ceretto “Blange“ Langhe Ameis 2014. With the first sip, we knew we had made the right choice.. Back home, we ordered more in time to celebrate the beginning of Jules’ birthday month. This gorgeous white, made from the indigenous grape Arneis, is like a Sauvignon Blanc or a non flinty tasting Chardonnay. This full bodied wine offers, subtle fruity flavors with an oaky layer, which is strange, because fermentation takes place in stainless steel barrels. There must be more to learn here. Will keep you posted.


Saturday we went to our first opera of the MetOpera Season, Tristan and Isolde, Wagner’s greatest masterpiece, in my opinion and autobiographical. Part of what makes this opera so special is first, of course, the gorgeous music, second, the libretto, which Wagner also wrote. It reveals Wagner’s philosophy of life, influenced not only by his own life experiences (his mother died giving birth to Wagner) but also by contemporary German philosophers.


When Tristan and Isolde first opened, it was regarded as lewd and much too sexual. In time this great opera greatly influenced future composers. In my limited musical experience, I have never heard a piece of music that has been able to sustain one melody, one theme, successfully for nearly five hours. In short, for many in the Saturday MetOpera audience, this was a transcendental experience.


This opera is almost 5 hours long, but time flew by, because of the glorious music. This was a multi-media, star studded production with the great Sir Simon Rattle conducting, Nina Stemme brilliantly singing Isolde, golden toned, Stuart Skelton singing Tristan and well-loved, Rene Pape as King Marke. These world-famous opera greats, gave the audience 100% what they had come to hear. The ovations were never ending. I stood cheering Brava and Bravo with tears streaming down my face, I love that last aria so much along with the flawless Act 2. Oh what an experience! As we departed this magical source of great pleasure and joy, people were declaring, “a once in a life time experience.“ I concur. It’s probably sold out for the rest of the Season, but try to see this outstanding production.


Prelude, Act 1, Tristan and Isolde


Nina Stemme singing Isolde’s final aria



From Our Table to Yours !


Bon Appetit!