Why care about health? It’s about statistics.

The rate of cancer incidence has increased greatly in many countries and is expected to continue to increase, particularly in association with the aging of the population. Cancer is more often a diagnosis after age 65.  The rate of thyroid cancer in particular has increased greatly in women. The rate of developing some type of cancer during one’s lifetime is expected to reach 1 in 2 men and 1 in 3 women by the yea 2050, (MedScape) – or a more general 1 in 2 people, (medicalnewstoday) – those are not good odds.

It is common during youth to feel secure about health but our bodies tend to run out of stored nutrients as we age and metabolic pathways that we depend on to rebuild muscle and remove toxins or defective cells can become less effective. A healthy immune system also protects us from our own body’s normal rebuilding/regrowth of new cells. Defective ones are typically removed from growth areas in bone marrow before they enter circulation. Cancer cells are also removed on a regular basis when our immune systems are healthy.

Magnesium deficiency is a topic I keep stressing because the immune cells require magnesium in order to perform the apoptosis, killing, of defective or precancerous cells. The body’s defense systems are well developed but need fuel on a daily basis in order to be able to function as nature designed. While immune cells need magnesium in order to purposefully kill defective cells by apoptosis ( an enzyme is inserted into the cell which causes it to die and then the immune cell engulfs the debris and removes it for detoxification and excretion from the body), a cell that is deficient in magnesium or calcium may also undergo apoptosis due to the deficiency. (magnesium and apoptosis)

Too little Nrf2 may reduce immune system and antioxidant health but too much can be a problem in cancer cells that grow too rapidly. (Nrf2 overproduction and cancer)

Another person writing about the recent research in the area of Nrf2 shares more information about foods that help promote Nrf2 and how nature may have built in a mechanism within some foods that help prevent an over production of the important protein (Nrf2). See: “Activate Nrf2, then optimize: Brussel Sprouts.” – Bill Lagokos (patreon) /Spoiler, if not a fan of Brussel Sprouts the healthy phytonutrient that is discussed is also found in cruciferous vegetables including cabbage, cauliflower, broccoli, kohlrabi, and kale.

I personally am more sensitive to the group, especially if served raw or in larger quantities, but find steamed kale everyday tolerable to my digestive system. The bloating effect may be due to our good guy bacteria enjoying the fiber rich vegetables so much they produce the excess gas – but it can be a sign of healthy bacteria in our digestive tract. Irritable Bowel Syndrome can be affected by any food that causes bloating effects possibly due to TRP channel’s being activated by increased pressure. People with a history of IBS and other chronic pain syndromes may be suffereing from an underlying issue with overactive TRP ion channels. IBS and TRP channels are discussed on this site in a previous post. TRP channels are discussed in more detail with links on another website: Chronic Itch, migraines, IBS and stress; – that is one part frm a longer series: Relaxation and Stress, which is continued in:  Preeclampsia & TRP Channels.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Pomegranate peel may be the best part – medicinally

I’ve been experimenting with making pomegranate peel extract and it may be the best part medicinally but is quite acidic and quite bitter. Mary Poppins sang that a spoonful of sugar helped the medicine go down and she is on to something. Medicinal herbs may be the bitter ones.  Sugar does help with the taste, but excess amounts of it can help worsen inflammation, so just a spoonful is important. Diluting with extra water and adding a concentrated fruit juice also helped with flavor.

I’m taking notes but am still in the testing phase so this is a summary – yes it seems possible to make an extract from the peel and inner membrane part of the pomegranate. The taste is something that a sick person would tolerate because feeling better is worth a lot including drinking something not very good as quickly as possible. However the healthy person is still likely to prefer the pomegranate juice or juicy crunch of the seeds. If there are seasonal issues one simple experiment worked well – the juicy seeds freeze quite nicely so making a large batch of peel and membrane extract could include simply freezing the seeds for later use in salads or as a sweet and tangy treat. The juice is also tart but the peel extract I made was more acidic than coffee I added baking soda to make it less acidic and easier for the digestive system to tolerate.

The extract did help more of my symptoms than the seeds do. I’ve had early signs of finger numbness, possibly Raynaud’s Disease/Syndrome, which doesn’t really have any treatments. The extract helped restore feeling to my fingers but it was temporary, just that day so the larger quantity of the treatment mentioned in the last post on this topic which used 1 – 10 grams/kilogram for 8 weeks for hepatocellular carcinoma might be best spread out through the day for someone with a more severe illness. Half a cup per day for someone less ill and a half a cup every three to four hours throughout the hours spent awake for someone who is more severely ill might be what helps symptoms. If every cell of the body needs the substances, every hour of the twenty-four, then one dose one time per day might leave the body under-treated for most of the 24 hours and only relieve symptoms for a few hours.

Raynaud’s Syndrome/Disease is referred to by both names. It was mentioned in the search engine results but the article is only available as an Abstract which doesn’t mention any specific conditions: (1). The condition is discussed in an full text available article on oxidative stress and Nrf2. It mentions green tea extracts and Gingko biloba as possibly helping reduce oxidative stress: Review Article: Oxidative Damage and Antioxidative Therapy in Systemic Sclerosis,   (2).

Gingko biloba is also mentioned along with Raynaud’s Disease in this article. A standard dosage is mentioned as being used once or twice per day: “The standard clinical dose of EGb 761 is 120 mg (~1.7 mg/kg) once or twice daily;” Egb is a standardized formulation that contains a certain amount of the active phytonutrients of the Gingko biloba herb which are called gingkolides. It is a traditional herb that was used in cooking and as a medicine in Chinese and Japanese history for conditions such as asthma or as a cough medicine. In the discussion of Future Directions for research the authors suggest more study of dosing as the amount used in preclinical trials was significantly more than used in many clinical trials, “(100 mg/kg compared to <2 mg/kg, respectively),” although some used a larger dose, (300 mg daily).  (3).

I do take a capsule of Gingko biloba daily but not the Egb formulation. The dose I have been using is 60 mg standardized to include “24% Gingko Flavoglycosides = 14.4 mg and 6% Terpene Lactones = 3.6 mg” – which suggests it is a fairly low dose compared to some of the research studies that used 100-300 mg of the Egb formulation. (3)The Egb formulation also includes flavanoids which include one that has been found to help increase Nrf2:

“Beyond oxidant scavenging, the flavonoid isorhamnetin was able to upregulate antioxidant enzymes through Nrf2 activation.(3).

Take home point – clinical trials are a lot of work and accurate dosing, both amount used, concentration of the active phytonutrients, and frequency the dose is used throughout the day, and how large the patient is, are all important factors for effectiveness of the herbal preparation at relieving symptoms of a disease or preventing chronic illness.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

  1. DaigoSumiAikoManjiYasuhiroShinkaiTakashiToyamaYoshitoKumagai., Activation of the Nrf2 pathway, but decreased γ-glutamylcysteine synthetase heavy subunit chain levels and caspase-3-dependent apoptosis during exposure of primary mouse hepatocytes to diphenylarsinic acid., Toxicology and Applied Pharmacology, Vol. 223Issue 3, 15 September 2007, Pages 218-224.    http://www.sciencedirect.com/science/article/pii/S0041008X07002633 (1)
  2. Bogna Grygiel-Górniak and Mariusz Puszczewicz,Review Article: Oxidative Damage and Antioxidative Therapy in Systemic Sclerosis, Mediators of Inflammation, vol 2014 (2014), Article ID 389582, 11 pages. https://www.hindawi.com/journals/mi/2014/389582/. (2)
  3. Kevin M. Nash and Zahoor A. Shah., Current Perspectives on the Beneficial Role of Ginkgo biloba in Neurological and Cerebrovascular Disorders., Integr Med Insights. 2015; 10: 1–9.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640423/ (3)

Christmas miracles: “And Still I Rise” – Maya Angelou

Christmas miracles

Often are found when looking

With open eyes and heart.

 

Two books, Christmas miracles of hope across cultures and time. Each contain wisdom from around the world and are a delight to keep or share. Samples shared for educational purposes within the guidelines of fair use, copyrighted work by Maya Angelou and Dr. Wayne W. Dyer, shared without permission by the editor/publisher or author, a Christmas miracle nevertheless, hope rises eternal when love burns brightly within us:

From The 100 Best Poems of All Time, Edited by Leslie Pockell, 2001, Warner Books, Inc., (1)

A poem that lasts a lifetime and crosses generations, page 175, is by the renowned poet and Pulitizer Prize winning author, and also singer, dancer, and actor, activist, teacher, Dr. Maya Angelou (1928-2014 ) encourages people of all races, genders, abilities to persist and believe in themselves. She recites part of the poem and discusses it in a video, youtube.com And Still I Rise.

As a child she had to face the danger of simply crossing the railroad tracks into the side of town that was not the safe and familiar neighbors who all knew one another but was a danger and risk of rape. Facing Evil, youtube.

She had difficulties  as a child after her parents divorced and she and her brother were sent to live with their grandmother and then later were returned to their mother. As a seven year old she was molested and after telling her family the man was killed and young Maya did not talk for several years feeling that her voice was dangerous. The children were sent back to their grandmother when nothing seemed to be helping restore Maya’s voice. Her grandmother reassured her that she would speak when she was ready and relieved the pressure on the young child, eventually she was speaking to her brother but remained mute for several years with other people. A concerned teacher, Mrs. Flowers, and she helped by introducing young Maya to books and poetry and encouraged her to read them all, read all the books in the library – now that is a challenge, and young Maya accepted with hesitation but with courage that grew into greatness.

As a teen there were no black streetcar conductors in California where her family was living at the time, no female black streetcar conductors and she set out to become the first one – and succeeded as a teenager, her six feet in height may have helped. She became a teen mother at age 16 but finished her high school degree anyway. Dancing, singing and writing followed, and eventually she went on to become more politically active and worked with Martin Luther King, Jr.. She continued her activism even after the sorrow of his assassination. She became a teacher and started charter schools for underprivileged community children later in her life. (The Story about Maya Angelou that you never heard in her own words. youtube)

She eventually was awarded the Presidential Medal of Freedom and was awarded with over fifty honorary degrees over the course of her lifetime. (Wikipedia)

She encourages us to recognize that nothing human can be alien to us, both the negative and the positive that exists in anyone of us might be something we are capable of, so stretch up to the greatness and who knows what might be possible. I Am Human, Maya Angelou, youtube

 

Still I Rise

Maya Angelou (1928- )

 

You may write me down in history

With your bitter, twisted lies,

You may trod me in the very dirt

But still, like dust, I’ll rise.

 

Does my sassiness upset you?

Why are you beset with gloom?

‘Cause I walk like I’ve got oil wells

Pumping in my living room.

 

Just like moons and like suns,

With the certainty of tides,

Just like hopes springing high,

Still I’ll rise.

 

Did you want to see me broken?

Bowed head and lowered eyes?

Shoulders falling down like teardrops,

Weakened by my soulful cries.

 

Does my haughtiness offend you?

Don’t you take it awful hard

‘Cause I laugh like I’ve got gold mines

Diggin’ in my own back yard.

 

You may shoot me with your words,

You may cut me with your eyes,

You may kill me with your hatefulness,

But still like air; I’ll rise.

 

Does my sexiness upset you?

Does it come as a surprise

That I dance like I’ve got diamonds

At the meeting of my thighs? Out of the huts of history’s shame

 

I rise

Up from a past that’s rooted in pain

I rise

I’m a black ocean, leaping and wide,

Welling an swelling I bear in the tide.

 

Leaving behind nights of terror and fear

I rise

 

Into a daybreak that’s wonderously clear

I rise

Bringing the gifts that my ancestors gave,

I am the dream and hope of the slave.

I rise

I rise

I rise.

 

Women of color, whether black or indigenous to various parts of the world have been more at risk of violence and sexual assault. It is history’s shame and sadly it is still a current problem around the world. Respect all women as we would all like to be respected and would like our mothers, sisters, and grandmothers to be protected and appreciated. Without women we would have no children to grow into loving men and women to care for future generations.

Children are our future and their care affects our shared future. Children learn best from human interaction, set down the electronic controls and read a book, point at the pictures, or just play pretend. A foam block can be a car or a house or an airplane or a mountain or a doorway to creativity. It can mark a starting line for a race around the room, it can be a ball that doesn’t bounce. Why would a child want a ball that doesn’t bounce? Because they just like to drop and throw and fetch and put it in a bucket or under a blanket and play peek a boo with a friendly face.

Electronic screen time is a limit for human time and often a limit for movement time. Children zero to three years old are absorbing everything they can and developing long term trust in other people as well as exploring the physical capability of climbing and jumping and dumping and throwing, and picking up and putting away can also be taught and modeled as a fun activity when a friendly face is guiding the play time.  (Too much screen time prevents young tots from meeting healthy movement guidelines.) “Clean up, Clean up, It’s time to clean up.” sung to any tune you want, just play the game along with the toddler and you may be surprised to find you have an older child who spontaneously sings it to there younger friends.

Trauma as a child or lack of social connection can lead to withdrawal or even autism like symptoms. Autism can have to do with lack of stimulation as a child. Children in under attended Romanian orphanages had autism like symptoms and if adopted early enough in life sometimes the symptoms improved. Lack of adequate sunshine and low vitamin D levels may have been involved based on more recent research, not discussed in this article about Romanian orphans however. The social isolation would also be increasing general oxidative stress levels and would also not be providing the touch and human connections that can help reduce oxidative stress.: (5)

See this post for more information about social connection, touch and oxidative stress: G3.4: Social contact would help protect against oxidative stress. (6) See G: Autoimmune and Vitamin D for more about prenatal  levels of vitamin D and autism risk. (7) Childhood levels of vitamin D may also be important to help prevent autism like symptoms from worsening, and there are a variety of reasons that vitamin D might not be as available even with adequate sunshine. Dark complected individuals living in Northern climates may be more at risk of low vitamin D levels and likely would benefit from a dietary source.

Very pale skinned individuals and others who burn easily in sunshine might need to avoid excess sun or excess vitamin D but would still need adequate amounts (like me, brown hair but freckle and burn with excess sun and have a vitamin D genetic difference that makes my receptors more active). The dietary or supplement might also need to be a more bioactive form than available in standard supplements for some genetic differences. And avoiding excess sunshine can be helpful if burning easily in the sun is a problem as excess can be a source of oxidative stress also.

Vitamin D3 is a bioactive form that would also bypass inhibition by the herbicide Roundup/glyphosate if CYP enzyme inhibition is limiting the ability of skin production of vitamin D with adequate sunshine – our world is not one gender, one race or even one food supply anymore. Some types of pathogens and chronic illnesses can also affect the ability to use or breakdown excess supplies of vitamin D so excess supplements are not necessarily a standard answer for everyone, (sarcoidosis is one).

Autism is something that affects more than any race, gender or ability. Comorbidity with other mental health and physical chronic illnesses are common. And it is seen in our pets as well: Autism Symptoms in Pets Rise as Pet Vaccination Rates Rise: (4). To quote a line from one of Dr. Maya Angelou’s poems which she describes as the survivor laugher apparatus, to Miss Rosie who rides a bus in New York and inspired by an older poem “Masks“, “I laugh…until I start to I cry…” See ~15:00 through the end of Facing Evil with Maya Angelou, Youtube.

Autism makes me cry more than laugh for the children and the pets. Prior to around 1930 the condition was basically unheard of in the psychiatric and pediatric psychiatric fields. Histories and patient case studies are available dating back centuries and a thorough review of the scientific literature that is available is discussed in the book Denial: How Refusing to Face the Facts about Our Autism Epidemic Hurts Children, Families, and Our Future, by Mark Blaxill and Dan Olmsted. (8) The condition may be more of risk when several important nutrients are not available during early pregnancy and continuing into childhood; vaccinations may be involved but it is not a single factor problem. Ultrasounds and electromagnetic radiation from modern electronic devices may also be involved in the increase of autism and other chronic illnesses. Genetic differences that are involved in detoxification of oxidative stress or with the important nutrients involved in detoxification and immune system strength are also likely involved. I cry more than I laugh because Denial does not heal anyone. Dr Maya Angelou shares some inspiring words about being kind and generous, laughing and teaching and is asked about any words of guidance for the New Year and encourages us to “tell the truth, to yourself first, and to the children; live in the present, don’t deny the past, and live in the present;…” in an interview with George Stroumboulopoulos, on George Stroumboulopoulos Tonight, 2014: https://www.youtube.com/watch?v=8zAsr8bq7vk,

She is a great teacher for any year, and her words carry wisdom for any New Year’s resolutions.

To segue briefly back to the Nrf2 topic I’ve been writing about – too much or too little of many things can be a problem. Too much play or too much work, too much isolation or too much stimulation, too much sunshine or too little too much vitamin D or too little, and too much antioxidant stimulating Nrf2 or too little can all be problems for the body. Some individuals may have different levels of too much or too little than average due to genetic differences or other cellular changes. There are some types of cancer cells that over produce Nrf2, (“primary malignant brain tumors (glioblastomas, WHO °IV gliomas, GBM)”) (9), so it also is not a cure-all or safe in any quantity if scientists did learn how to synthesize it directly instead of depending on our bodies to produce what we need.

We learn from each other and across cultures, across time, we have many similarities and Our Greatest Teachers include spiritual leaders and religious figures from many cultures. A brief summary of several is shared in a book by Dr. Wayne D Dyer in the section, “Our Greatest Teachers” – from “Real Magic; Creating Miracles in Everyday Life” by Dr. Wayne W. Dyer (Harper Collins Publishers, 1992, 1st Ed.) (2001 edition)

page 32,

Without exception all of our greatest teachers, and those who have made the greatest impact on humanity, have been spiritual beings. They did not limit themselves to the five senses in any way. All of the great teachers and doctrines, including Christianity, Buddhism, Judaism, Islam, Sufism, and Confucianism, have left us with  a similar message. Go within, discover your invisible higher self, know God is the love that is within you.”

“These spiritual masters were all miracle makers. They were here to teach us about the incredible power that resides within each of us. It seems ironic that as a people we have become obsessed with what divides us, with war and building of more and more powerful delivery systems of hatred and killing, yet the most influential and revered of thee world’s teachings all have a message of love. For example:

page 33,

Christianity: God is love, and he who abides in love abides in God, and God abides in him.

Buddhism: He that loveth not, knoweth not God. For God is love.

Judaism: Love is the beginning and end of the Torah.

Confucianism: Love belongs to the high nobility of Heaven, and is the quiet home where man should dwell.

Sufism:   Sane and insane, all are searching lovelorn

                    For Him, in mosque, temple, church alike.

                    For only God is the One God of Love,

                    And Love calls from all these, each one His home.

 

Home is within us, we only have to open our hearts and inner eye to see it.

Our greatest teachers come to us when we are ready to learn, we only have to open the door and let them into our minds and souls.

 

A doorway opened

Is a gateway to learning

What’s needed to know.

 

Merry Christmas and Happy New Year.

A gift from nature to help us build Nrf2 (10) and which may improve digestion  (11) and bone density are the licorice flavored Fennel Seeds that might be served in a tiny dish as an appetizer or after a meal at an Indian food restaurant. The tiny crunchy seeds can be eaten directly raw or may be toasted.  A few pinches, a teaspoon or two are a reasonable digestive health aid and even seem to freshen the breath somewhat as there is also a slight minty flavor to the more predominant licorice flavor. They are sold in larger quantities, (400 gram package), in India food markets but may be found in a one ounce jar in the spice section as they are also added to soups in Western recipes. One interaction caution is for women using estrogen based birth control pills. Fennel also contains estrogen like phytonutrients which may interfere with the use of the birth control pills as a pregnancy preventative. (11) Regarding quantity for health benefits – a study on bone density effects in post menopausal women did not find 300 mg per day effective (12) – that would be less than an 1/8 th of a teaspoon. I have seen a portion described as “a handful” in an unlinked source, which is about 1/4 – 1/2 cup, and which would be a lot compared to what I eat in a day but an 1/8gh teaspoon wouldn’t be much at all. I eat a pinch or two, 1/4 to 1/2 teaspoon at a time several times per day. So a tablespoon (three teaspoons) to an 1/8 th cup (two tablespoons or 6 teaspoons) might be consumed throughout the day when snacking from an open dish as seen in the image below. They do seem to help settle my stomach after a meal.

Fennel seeds, raw.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

  1. Leslie Pockell, editor, The 100 Best Poems of All Time, Warner Books, Inc., March 1, 2001, https://www.amazon.com/100-Best-Poems-All-Time/dp/0446676810 (1)
  2. Dr. Wayne W. Dyer, Real Magic; Creating Miracles in Everyday Life, Harper Collins Publishers, 1992, 1st Ed. / 2001 edition: https://www.harpercollins.com/9780060935825/real-magic (2001 Edition)
  3. Bonus for those who read the reference list, a compilation of children’s and teenager’s poetry: Reflections of Youth, The American Library of Poetry, 2002, Houlton, ME, www.libraryofpoetry.com (current 2017 through 1998 Division winner’s poetry can be read online, the 2002 book may be out of print. The current 2017 collection entitled Treasured is available for purchase: http://www.libraryofpoetry.com/treasured.html) (“American Pride” a poem by Lisa Sanchez, Div. III, Grade 8-9, 2002)(“The Plumed Praises” a poem by Karen Christopher, Div. II, Grade 6-7, 2002)
  4. Autism is something that affects more than any race, gender or ability. Comorbidity with other mental health and physical chronic illnesses are common. And it is seen in our pets as well: Autism Symptoms in Pets Rise as Pet Vaccination Rates Rise http://www.thevaccinereaction.org/2017/04/autism-symptoms-in-pets-rise-as-pet-vaccination-rates-rise/
  5. Autism can have to do with lack of stimulation as a child. Children in under attended Romanian orphanages had autism like symptoms and if adopted early enough in life sometimes the symptoms improved. Lack of adequate sunshine and low vitamin D levels may have been involved based on more recent research, not discussed in this article however. The social isolation would also be increasing general oxidative stress levels and not providing the touch and human connections that can help reduce oxidative stress.: https://www.washingtonpost.com/national/health-science/what-children-from-romanian-orphanages-can-tell-us-about-autism/2017/05/12/c8d772a2-3004-11e7-9dec-764dc781686f_story.html?utm_term=.2d12277deaa2
  6. See this post for more information about social connection, touch and oxidative stress:

    G3.4: Social contact would help protect against oxidative stress. effectiveselfcare.infohttps://effectiveselfcare.info/2017/09/30/social-contact-protect-against-oxidative-stress/

  7. G. Autoimmune and Vitamin D, effectivecare.info, https://effectivecare.info/g-autoimmune-%26-vit-d
  8. Mark Blaxill, Dan Olmsted, Denial: How Refusing to Face the Facts about Our Autism Epidemic Hurts Children, Families, and Our Future., Skyhorse Publishing, July 25, 2017, https://www.barnesandnoble.com/w/the-denial-mark-blaxill/1125631541#/
  9. Z Fan, A-K Wirth, D Chen, C J Wruck, M Rauh, M Buchfelder, and N Savaskan,

    Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis., Oncogenesis. 2017 Aug; 6(8): e371.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608917/ (9)

  10. Preventive role of chamomile flowers and fennel seeds extracts against liver injury and oxidative stress induced by an immunosuppressant drug in rats., Hepatoma Research, [S.l.], v. 1, n. 3, p. 125-35, oct. 2015. ISSN 2454-2520. http://hrjournal.net/article/view/1165 (10) *Hepatocellular carcinoma is discussed.
  11. Fennel: Uses, Side Effects, Interactions, and Warnings, WebMD.com, https://www.webmd.com/vitamins-supplements/ingredientmono-311-fennel.aspx?activeingredientid=311&activeingredientname=fennel (11)
  12. Masumeh Ghazanfarpour, Elham Amini, Talat Khadivzadeh, Masoudeh Babakhanian, Bahareh Nouri, Hassan Rakhshandeh, and Maliheh Afiat., 

    The Effect of Short-term Treatment with Fennel on Bone Density in Postmenopausal Women: A Randomized Controlled Trial., J Menopausal Med. 2017 Aug; 23(2): 124–130.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606910/ (12)