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Biosea Health Health Benefits

Sleep Better with Seaweed

Sleep is a complex process, but we have many customers who say they sleep better with Seaweed. What? Why? So we dug back through our customer referrals and data from our trials and it turns out there may improvement in sleep. Sleep is not just duration – importantly the patterns of sleep determine how you feel about sleep.

What Customers Say

My new neighbour is an 72 year old engineer with dodgy knees. After a month he says his knees “might” be better, but he has been sleeping better. Not waking at 3am. And that’s enough for him to keep going for another couple of months.

We saw a 50% improvement score in our dysmenorrhea trial but did not think too much about. It made sense if period pain was reduced. It was not something we had really focused on, but participants reported that after seaweed they did not loose work or social activities and it may be that they actually slept better.

Data from 150 women after 8 weeks of eating seaweed.

A number of our testimonials say they feel better on seaweed

Does More Exercise Improve Sleep

The data shows the women in the trial had more energy, and found it easier to exercise. And there are many studies that show more exercise helps sleep patterns -just don’t do the exercise immediately prior to sleep! We don’t know if they had small incremental changes in exercise.

Reduced inflammation

Seaweed is a powerful anti-inflammatory functional food. Does the improvement in inflammation help sleep?

Neuronal Effect

We know from seaweed studies that it builds better brain pathways for people with dementia and may have some action with diseases such as Parkinsons? Do the improvement neural pathways led to better sleep.

Sleep Better with Seaweed – The Role of Vitamins and Minerals

A number of vitamins and minerals help sleep – and check out our vitamins (here) and minerals (here) of things we know help sleep.

  • Iron. Iron is a major component in our blood that provides oxygen to our cells and tissues. Seaweed is a good source of naturally available Fe.
  • Magnesium. Magnesium is a mineral that works wonders when it comes to releasing tension and helping you and your muscles to relax. Pacific Seamoss has some.
  • Vitamin D Other kelps and brown seaweeds have Vitamin D but Pacific Seamoss does not.
  • Melatonin, but melatonin is not in seaweed.
  • Tryptophan – in reasonable amounts – helps sleep
  • B vitamins. Seaweed is chock full of B3.
  • Calcium. There is not much Ca in Seaweed.
  • Vitamin E. Our Pacific
  • Potassium. K helps smooth muscle relax. Over 95% of westerners are deficient in K.

Further Reading

The Mayo clinic: 6 Tips to help you Sleep Better

  1. Stick to a sleep schedule. Set aside no more than eight hours for sleep
  2. Pay attention to what you eat and drink. Don’t go to bed hungry or stuffed
  3. Create a restful environment. Create a room that’s ideal for sleeping.
  4. Limit daytime naps.
  5. Include physical activity in your daily routine.
  6. Manage worries.
Categories
Biosea Health Health Benefits Pain Reduction

Natural Medicine for Joint Pain

Want a natural medicine for joint pain? One that is more effective than conventional analgesics or anti-inflammatories. In fact, medical practitioners advise against long term use of regular analgesics for joint pain. There are numerous remedies but the following 10 have proven trials. How much do you need? Most of these require a reasonable quantity consumed each day.

Joint pain, usually called arthritis (which means swollen joint) – in the back, hands, pelvis knees or ankles may be due to multiple causes. Some say that weight from obesity is the major cause – but more recently understanding is arthritis is primarily and inflammatory response. With over 104 different types of rheumatoid arthritis and osteoarthritis. (Read more here) it is not surprising that studies show various levels of pain relief. Not just with artificial drugs but also natural medicines.

Seaweed

Seaweed extracts such as fucoidan are effective. The fucoidan comes from brown seaweed, but red seaweed is effective and there is good evidence in animals and in humans that whole seaweed is even more effective. Should you take the whole plant or just an extract? Prof Lindsay Brown says the whole plant has various other nutrients and vitamins that have other benefits so you should eat the whole plant and forget the extracts. Customers have experienced remarkable reduction of arthritis from Pacific Seamoss.

SAM-e (S-adenosylmethionine)

SAM-e acts as an analgesic (pain reliever) and has anti-inflammatory properties. It may stimulate cartilage growth and also affects neurotransmitters, such as serotonin, which reduce pain perception. Two studies have shown that it relieves OA symptoms as effectively as non-steroidal anti-inflammatory drugs (NSAIDs) with fewer side effects and more prolonged benefit.

Indian frankincense – Boswellia serrate

The active components (Boswellic acids) have anti-inflammatory and analgesic (pain-relieving) properties. It also may help prevent cartilage loss and inhibit the autoimmune process. In a 2008 study, the extract, also known as Loxin 5, significantly improved OA pain and function within seven days. An Indian study also revealed it slowed cartilage damage after three months of use.

Osteo arthritis versus rheumotoid arthritis – courtesy of Grace and Able.

Capsaicin – Capsicum frutescens

Capsaicin temporarily reduces substance P, a pain transmitter. Its pain-relieving properties have been shown in many studies, including a 2010 study published in Phytotherapy Research, which revealed a 50 percent reduction in joint pain after three weeks of use. It is available as a topical cream, gel or patch

Tumeric/Curcumin –Curcuma longa

Curcumin is the chemical in turmeric that can reduce joint pain and swelling by blocking inflammatory cytokines and enzymes. A 2010 clinical trial using a turmeric supplement showed long-term improvement in pain and function in patients with knee OA. A small 2012 study using a curcumin product, BCM-95, showed more reduced joint pain and swelling in patients with active RA when compared to diclofenac sodium.

Avocado-soybean Unsaponifiables (ASU)

ASU blocks pro-inflammatory chemicals, prevents deterioration of synovial cells, which line joints, and may help regenerate normal connective tissue. A large three-year study published in 2013 showed that ASU significantly reduced progression of hip OA compared with placebo. A 2008 meta-analysis found that ASU improved symptoms of hip and knee OA, and reduced or eliminated NSAID use.

Cat’s Claw – Uncaria tomentosa

Cat’s claw is an anti-inflammatory that inhibits tumor necrosis factor (TNF), a target of powerful RA drugs. It also contains compounds that may benefit the immune system. A small 2002 trial showed it reduced joint pain and swelling by more than 50 percent compared with placebo. Look for a brand that is free of tetra-cyclic oxindole alkaloids.

Fish Oil (Omega-3 fatty acids EPA and DHA)

Omega-3s block inflammatory cytokines and prostaglandins, and are converted by the body into powerful anti-inflammatory chemicals called resolvins. EPA and DHA have been extensively studied for RA and dozens of other inflammatory conditions. A 2010 meta-analysis found that fish oil significantly decreased joint tenderness and stiffness in RA patients and reduced or eliminated NSAID use. Recent studies have shown it is little better than placebo.

Gamma Linolenic Acid (GLA)

GLA is an omega-6 fatty acid that the body converts into anti-inflammatory chemicals. In one trial, 56 patients with active RA showed significant improvement in joint pain, stiffness and grip strength after six months and progressive improvement in control of disease activity at one year. A smaller study found that a combination of GLA and fish oil significantly reduced the need for conventional pain relievers.

Ginger – Zingiber officinale

Ginger has been shown to have anti-inflammatory properties similar to ibuprofen and COX-2 inhibitors. In a 2012 study, a specialized ginger extract reduced inflammatory reactions in RA as effectively as steroids did. Earlier studies showed that taking a certain extract four times daily reduced osteoarthritis pain in the knee after three months of treatment, and another taken twice daily worked about as well as ibuprofen taken three times daily for hip and knee OA pain

Cannabidiol (CBD)

CBD is recent addition, and data is not yet clear. Cannabinoids are thought to influence the body’s own endocannabinoid system, which regulate biological functions such as metabolism, pain sensation and nervous system functions. Animal studies show CBD reduces pain and inflammation, and it may ease anxiety and improve sleep, but human research is needed. One study found synthetic-derived CBD was effective for knee OA pain. The FDA has approved CBD-derived drugs for rare childhood epileptic conditions.

Other Natural Products

There are many other natural medicines for relief of pain, and these include pine back extract, rosehips, and green lipped mussel extracts.

References

[1] Makkar, F & Chakraborty, K 2017, Antidiabetic and anti-inflammatory potential of sulphated polygalactans from red seaweeds Kappaphycus alvarezii and Gracilaria opuntia, International Journal of Food Properties, vol. 20, no. 6, pp. 1326-37.

[2] Kumar, S.A., Brown, L. Seaweeds as potential therapeutic interventions for the metabolic syndrome. Rev Endocr Metab Disord 14, 299–308 (2013). https://doi.org/10.1007/s11154-013-9254-8

[3] John O, Mouatt P, Prasadam I , Xiao Y, Panchal S, Brown L 2019 The edible native Australian fruit, Davidson’s plum (Davidsonia pruriens), reduces symptoms in rats with diet-induced metabolic syndrome, Journal of Functional Foods, (56) Pages 204-215, ISSN 1756-4646,
https://doi.org/10.1016/j.jff.2019.03.018.

[4] Kumar M & Sharma S (2020) Toxicological effects of marine seaweeds: a cautious insight for human consumption, Critical Reviews in Food Science and Nutrition, DOI: 10.1080/10408398.2020.1738334

[5] D’Orazio, N.; Gemello, E.; Gammone, M.A.; De Girolamo, M.; Ficoneri, C.; Riccioni, G. Fucoxantin: A Treasure from the Sea. Mar. Drugs 201210, 604-616.

[6] Tirtawijaya, G., Haque, M. N., Choi, J. S., Moon, I. S., Meinita, M. D. N., Choi, J.-S., & Hong, Y.-K. (2019). Spinogenesis and Synaptogenesis Effects of the Red Seaweed Kappaphycus alvarezii and Its Isolated Cholesterol on Hippocampal Neuron Cultures. Preventive Nutrition and Food Science, 24(4), 418. (PubMed)

[7] Wanyonyi, S., Du Preez, R., Brown, L., Paul, N. A., & Panchal, S. K. (2017). Kappaphycus alvarezii as a food supplement prevents diet-induced metabolic syndrome in rats. Nutrients, 9(11), 1261.(Pubmed)

[8] du Preez, R.; Paul, N.; Mouatt, P.; Majzoub, M.E.; Thomas, T.; Panchal, S.K.; Brown, L. Carrageenans from the Red Seaweed Sarconema filiforme Attenuate Symptoms of Diet-Induced Metabolic Syndrome in Rats. Mar. Drugs 202018, 97.

[9] Zakaria, A, Jais, MR & Ishak, R 2018, Analgesic properties of Nigella sativa and Eucheuma cottonii extracts  Journal of natural science, biology, and medicine, vol. 9, no. 1, p. 23.

[10] Myers SP, O’Connor J, Fitton JH, et al. A combined phase I and II open label study on the effects of a seaweed extract nutrient complex on osteoarthritis. Biologics. 2010;4:33-44. Published 2010 Mar 24. doi:10.2147/btt.s8354

[11] Sekar, S., Shafie, S., Prasadam, I. et al. Saturated fatty acids induce development of both metabolic syndrome and osteoarthritis in rats. Sci Rep 7, 46457 (2017). https://doi.org/10.1038/srep46457

[12] 10 Supplements for Arthritis Arthritis Foundation

Categories
Biosea Health Pain Reduction

Seaweed Reduces Back Pain

Seaweed reduces back pain was not something we were told about when we introduced Pacific Seamoss in 2019. But then we had many customers of Pacific Seamoss come back and tell us they had reduction of back pain. They had other benefits, but reduction in pain was widely reported and in particular natural arthritis relief.

Inflammation in joints occurs for many reasons, the two most common being overuse and arthritis. Both conditions interfere with normal function and stop us from leading a healthy active life. With Pacific Seamoss our customers are reporting pain and inflammation is reduced in arthritic or injured joints. They say they are active again, and greatly appreciate the better quality of life. Even our more athletic customers tell us their niggling training injuries have disappeared.

Reasons for less back pain

A seminal Nature publication by Professors Brown and Xiao in 2019 [11] said that the rats in a functional food study was related to the reduction in inflammation rather than obesity that the experiment studied. Along with the large reduction in inflammation in liver and gut, changes in microbiome, the animals fed functional food had additional cartilage. There are many reasons that Pacific Seamoss reduce back pain.

  • Pacific Seamoss contains plant sterols and other macronutrients that interfere with the chronic inflammation process.
  • It is a pre-biotic – up-regulating your healthy gut bacteria that pump inflammation-reducing short-chain fatty acids into the bloodstream.
  • It has a high daily level of nutrients and trace elements such as potassium, Zinc, Selenium and Calcium
  • With high levels of Vitamins including A, B1, B2, and B6
  • Good levels of Sulphur

In addition in animal studies, it was more effective than aspirin as an analgesic. [9]

There are clinical trials with seaweed from the brown seaweeds and extracts of fucoidans, and show reduction in arthritis with extracts of kelp [10] but Pacific Seamoss is whole food, is available, has vitamins and minerals and consumers report outstanding results.

Seaweed reduces back pain testimonials

For some testimonials for back pain check out testimonials on this site here. Here are just 4 simple ones. It seems it takes 4 to 6 weeks before people notice, and it will be because the body gets used to pain. It takes a while to realise that pain is not there.

  • Chris – a 65 year old ex parquet flooring business owner could not stand up without hanging onto a support and with pain. After 3 months of seaweed he realised when he stood up, the creak and crack were still there, but the pain had gone.
  • Wayne, a printer realised when he stood up, knees bent, with a box of paper the pain had reduced. Took 4 weeks
  • Gray realised after a month that he woke up without knee pain. After 2 months he could do a fun run with his kids – something he had been unable to do for 10 years.
  • Lindsay had a back pain for over 15 years. Realised after 3 weeks that he had no more pain.

These customers were consuming about 4 grams of seaweed per day. Some have reduced down to 2.5 g and finding that pain relief continues. Stopping for a couple of weeks means the pain returns.

What Causes Back Pain

Causes of Back pain (from VeryWell Health) are varied, and more study will be needed to understand where seaweed may assist in the natural management of back pain.

Natural Medicines

The Arthritis Foundation says that there are 10 vitamins and supplements, backed by science, that help relieve arthritis pain. You can read more on natural medicine for joint pain here.

Knee and Back Pain Prevalence

It is just not back pain. Knee pain is the second most common chronic pain condition in the U.S. behind back pain. Over one-third of all Americans will have a knee pain issue at some point in their lives. Between 15% and 20 % of men will encounter knee pain, and almost 20% of women will have knee pain.

References

[1] Makkar, F & Chakraborty, K 2017, Antidiabetic and anti-inflammatory potential of sulphated polygalactans from red seaweeds Kappaphycus alvarezii and Gracilaria opuntia, International Journal of Food Properties, vol. 20, no. 6, pp. 1326-37.

[2] Kumar, S.A., Brown, L. Seaweeds as potential therapeutic interventions for the metabolic syndrome. Rev Endocr Metab Disord 14, 299–308 (2013). https://doi.org/10.1007/s11154-013-9254-8

[3] John O, Mouatt P, Prasadam I , Xiao Y, Panchal S, Brown L 2019 The edible native Australian fruit, Davidson’s plum (Davidsonia pruriens), reduces symptoms in rats with diet-induced metabolic syndrome, Journal of Functional Foods, (56) Pages 204-215, ISSN 1756-4646,
https://doi.org/10.1016/j.jff.2019.03.018.

[4] Kumar M & Sharma S (2020) Toxicological effects of marine seaweeds: a cautious insight for human consumption, Critical Reviews in Food Science and Nutrition, DOI: 10.1080/10408398.2020.1738334

[5] D’Orazio, N.; Gemello, E.; Gammone, M.A.; De Girolamo, M.; Ficoneri, C.; Riccioni, G. Fucoxantin: A Treasure from the Sea. Mar. Drugs 201210, 604-616.

[6] Tirtawijaya, G., Haque, M. N., Choi, J. S., Moon, I. S., Meinita, M. D. N., Choi, J.-S., & Hong, Y.-K. (2019). Spinogenesis and Synaptogenesis Effects of the Red Seaweed Kappaphycus alvarezii and Its Isolated Cholesterol on Hippocampal Neuron Cultures. Preventive Nutrition and Food Science, 24(4), 418. (PubMed)

[7] Wanyonyi, S., Du Preez, R., Brown, L., Paul, N. A., & Panchal, S. K. (2017). Kappaphycus alvarezii as a food supplement prevents diet-induced metabolic syndrome in rats. Nutrients, 9(11), 1261.(Pubmed)

[8] du Preez, R.; Paul, N.; Mouatt, P.; Majzoub, M.E.; Thomas, T.; Panchal, S.K.; Brown, L. Carrageenans from the Red Seaweed Sarconema filiforme Attenuate Symptoms of Diet-Induced Metabolic Syndrome in Rats. Mar. Drugs 202018, 97.

[9] Zakaria, A, Jais, MR & Ishak, R 2018, Analgesic properties of Nigella sativa and Eucheuma cottonii extracts  Journal of natural science, biology, and medicine, vol. 9, no. 1, p. 23.

[10] Myers SP, O’Connor J, Fitton JH, et al. A combined phase I and II open label study on the effects of a seaweed extract nutrient complex on osteoarthritis. Biologics. 2010;4:33-44. Published 2010 Mar 24. doi:10.2147/btt.s8354

[11] Sekar, S., Shafie, S., Prasadam, I. et al. Saturated fatty acids induce development of both metabolic syndrome and osteoarthritis in rats. Sci Rep 7, 46457 (2017). https://doi.org/10.1038/srep46457

Categories
Biosea Health

Seaweed for Pain Relief

It is hard to believe that seaweed for pain relief has been studied and shown to have some good activity. But natural drugs and treatments are real and have been studied.

What is Pain?

Sensation of pain is vital for survival because it acts as an indicator to tissue-damaging condition in the body. Sensation of pain is initiated in peripheral pain receptors known as nociceptors that are only excited when there is noxious stimulus.[1] Nociceptors are free nerve endings that supply nerves to every tissue of the body except the brain and receptors can be activated by intense thermal, mechanical, or chemical stimuli. Tissue irritation or injury liberates chemicals such as prostaglandins (PGs), kinins, and potassium ion that stimulate nociceptors.[2]

Drugs for Pain Relief

Analgesic drugs are medication that reduce pain. There are several mechanisms of action to provide relief.

  • Drugs such as aspirin and ibuprofen block the formation of PGs; thus, nociceptors are not stimulated.[3]
  • Local anesthetics such as novocaine block the conduction of nerve impulse along the axons of first-order pain neurons, giving short-term pain relief.
  • Morphine and other opiate drugs act by changing the quality of pain perception in the brain.
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed medications and have proved to be useful in the management of chronic pain disorders, but prolonged use leads to renal and gastrointestinal side effects.[4] The use of NSAIDs among patients with first-time myocardial infarction was associated with persistent increased coronary risks.[5] There are also the tendency of increased new acute myocardial infraction risk with current use of some NSAIDs, especially parenteral NSAIDs.

Natural Plants and Extracts for Pain Relief

Marine organisms including seaweeds contain biological compounds that have medicinal properties such as analgesic and anti-inflammatory.[7] This research was from Cuba, and Cuba is renowned for lack of western drugs and uses natural products regularly.

So Zakaria and others in an experiment took mice and then gave them acetic acid and measured their writhing. And they confirmed that Pacific Seamoss may possess protective active constituents effective in reducing the sensation of pain in mice.

Read more here in their paper. [6]

Seaweed for Pain Relief

Customers of Pacific Seamoss experience period pain relief, or pain in exercise. Maybe this is part of the explanation.

References

1. Dubin AE, Patapoutian A. Nociceptors: The sensors of the pain pathway. J Clin Invest. 2010;120:3760–72. [PMC free article] [PubMed

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. Hoboken: John Wiley & Sons; 2014. [Google Scholar]

3. Wecker L, Crespo LM, Brody TM, Dunaway G, Faingold C, Watts S. Brody’s Human Pharmacology: Molecular to Clinical. Philadelphia, PA: Mosby/Elsevier; 2010. [Google Scholar]

4. Ruoff G, Lema M. Strategies in pain management: New and potential indications for COX-2 specific inhibitors. J Pain Symptom Manage. 2003;25:S21–31. [PubMed] [Google Scholar]

5. Shau WY, Chen HC, Chen ST, Chou HW, Chang CH, Kuo CW, et al. Risk of new acute myocardial infarction hospitalization associated with use of oral and parenteral non-steroidal anti-inflammation drugs (NSAIDs): A case-crossover study of Taiwan’s National Health Insurance claims database and review of current evidence. BMC Cardiovasc Disord. 2012;12:4. [PMC free article] [PubMed] [Google Scholar]

6 Zakaria A, Jais MR, Ishak R. Analgesic Properties of Nigella Sativa and Eucheuma Cottonii Extracts. J Nat Sci Biol Med. 2018;9(1):23-26. doi:10.4103/jnsbm.JNSBM_131_17

7. Vázquez AI, Sánchez CM, Delgado NG, Alfonso AM, Ortega YS, Sánchez HC. Anti-inflammatory and analgesic activities of red seaweed Dichotomaria obtusata. Braz J Pharm Sci. 2011;47:111–8. [Google Scholar]

Categories
Biosea Health Health Benefits Period Pain

Seaweed and Fibromyalgia

Q. A customer who was looking for period pain relief asked us: I have fibromyalgia – does seaweed help reduce fibromyalgia?

A. We don’t have any participants in a pilot trial for dysmenorrhea who told us specificially they have fibromyalgia. We do have anecdotal feedback from other customers though. Fibromyalgia (for fibro) is complicated as it “rewires” the brain from pain. With Pacific Seamoss seaweed we know most customers say they feel better in a week to 10 days. Over the past decade seaweed is implicated in improvement.

What is Fibromyalgia

Fibromyalgia is often accompanied by fatigue and altered sleep, memory and mood. Checkout WebMD or the Mayo Clinic. People may have widespread muscle pain and tenderness is the most common symptoms.
Medication, yoga, acupuncture, exercise, Cognitive Behavior Therapy (CBT), and stress reduction may help manage symptoms.

  • Treatment can help, but this condition can’t be cured
  • Requires a medical diagnosis
  • Lab tests or imaging rarely required
  • Chronic: can last for years or be lifelong

Fibromyalgia may be triggered by a stressful event, including physical stress or emotional (psychological) stress. Possible triggers for the condition include an injury or a viral infection.

Will seaweed cause any fibromyalgia interaction?

We have not had any feedback from customers that it has done any harm, and they generally report positive improvements. Some have reported reduced restless leg syndrome. Seaweed won’t do you any harm at all – unless you are allergic to seaweed. About 5% of customers say they have some GI (gastro intenstinal) bloating – but you would do if you starting eating a can of baked beans a day. Most of these already have severe GI issues – and some eat no fibre etc. So the addition of fibre can be a shock when you have none. The majority of others find taking a smaller amount of seaweed (maybe 2 to 3 capsules per day) and eating it with other food removes any issues. Given that one of the strategies is improved diet, seaweed will support that.

Prof Lindsay Brown has been assessing seaweed for intervention in obesity related diseases for the past decade. [3] Kumar worked with Prof Brown and recently wrote a comprehensive review [4].

However, for the past 20 years various researchers [5] have been looking at brown seaweeds and in particular the fucoxanthin compounds for activity in diseases. A search on Google Scholar will show a number of recommendations and some research on seaweed and fibromyalgia. The difficulty is that none have progressed past the lab. The benefits may be as simple as reduction in iodine deficiency as iodine is considered a contributor to fibromyalgia. Pacific Seamoss contributes about 15% RDI (%DV). Other brown seaweeds have higher levels iodine.

Alternative Remedies

There are a range of other strategies, and one that seems counter intuitive is weighted blankets. Why – weighted blankets are commonly used to help with a variety of conditions from ADHD and autism to Restless Leg Syndrome. Even more importantly, these blankets may be able to help manage pain related to fibromyalgia. This blog is a good starter for further reading blog post

References

[1] Fibromyalgia Mayo Clinic https://www.mayoclinic.org/diseases-conditions/fibromyalgia/symptoms-causes/syc-20354780

[2] Fibromyalgia – WebMD https://www.webmd.com/fibromyalgia/default.htm

[3] Kumar, S.A., Brown, L. Seaweeds as potential therapeutic interventions for the metabolic syndrome. Rev Endocr Metab Disord 14, 299–308 (2013). https://doi.org/10.1007/s11154-013-9254-8

[4] Kumar M & Sharma S (2020) Toxicological effects of marine seaweeds: a cautious insight for human consumption, Critical Reviews in Food Science and Nutrition, DOI: 10.1080/10408398.2020.1738334

[5] D’Orazio, N.; Gemello, E.; Gammone, M.A.; De Girolamo, M.; Ficoneri, C.; Riccioni, G. Fucoxantin: A Treasure from the Sea. Mar. Drugs 201210, 604-616.