Tuesday, September 23, 2008

Luminations: Coronary Luminology, Lipids, Laughs

Nakashima et al admit that "Despite the fact that millions of dollars have been spent over the last 50 years on atherosclerosis research, little is known about the development of early human atherosclerosis. There are several reasons why the research on early human atherosclerosis has not advanced. First, human atherosclerosis develops very slowly and at different rates from individual to individual, and it is difficult to distinguish between lesion initiation and progression. Second, a thickened intima is present in human arteries before atherosclerosis develops, but whether this intima forms the precursor for the later more advanced lesion is not fully understood. Third, the relationship between extracellular lipids and macrophages has not been clarified (UUUMMM... yeah hyper-reduction of human cholesterol may indeed lead to cancer -- see the SEAS trial... or J-Litt or IMPROVE-IT or hey...very SHARP mono-statinators...). It is generally believed that extracellular lipids are derived from foam cell death, but there are several examples that show that extracellular lipid occurs independently of macrophage cell death. Finally, there are no good animal models for the study of early atherogenesis. The morphological features of early atherosclerosis are different between humans and laboratory animal models, and it may be somewhat misleading to extrapolate the results obtained from animal models, to humans." (though rabbits are very cute and so are indeed are we, we aren't evolved exactly like herbivores) Thus...more Animal Pharm facts!


What we are certain of though is that HDL2 -- the large puffy HDLs -- are strongly associated with plaque regression, centenarian-lives/longevity, and cancer reduction (Michalaki et al Mol Cell Biochem. 2005 Jan;268(1-2):19-24).

How can we achieve higher HDL2, these wonderfully big ghetto-fab puff-daddies?




Cholesterol Intake on HDL2 and Reduction of Small Dense LDL

Olson et al researchers examined the effects of (!!)Cholesterol and (!!)Saturated fats on HDL2 (good) and HDL3 (bad) particle sizes.

  • Schonfeld G, Patsch W, Rudel LL, Nelson C, Epstein M, Olson RE.
    Effects of dietary cholesterol and fatty acids on plasma lipoproteins.
    J Clin Invest. 1982 May;69(5):1072-80.
    PMID: 7068846
    • ABSTRACT..... The effects of dietary cholesterol and fatty acids on low density and high density lipoproteins (LDL and HDL) were studied in 20 young men. After 2-3 wk of evaluations on ad lib. diets (Latin for eating without controls), basal diets, which consisted of 15% protein, 45% carbohydrates, 40% fat, and 300 mg/day of cholesterol, were given for 4-5 wk (Basal). The ratio of dietary polyunsaturated to saturated fatty acids (P/S) for different groups of subjects were 0.25, 0.4, 0.8, or 2.5. 750 and 1,500 mg/d of cholesterol were added to the basal diets as 3 and 6 eggs, respectively.

      RESULTS Total cholesterol and LDL cholesterol (READ: MORE SMALL DENSE LDL -- 'BAD') were lower in all subjects on the basal diets than on the ad lib. diets... Thus, both the cholesterol contents and P/S ratios of diets were important in determining LDL levels...

      On the diet with low P/S ratio (this means lowest PUFA proportion, highest S-A-T-U-R-A-T-E-D FATS), HDL2 rose (good), whereas this effect was absent on diets with high P/S ratios.

      CONCLUSION The response of LDL to dietary manipulations is consonant with epidemiologic data relating diets high in cholesterol and saturated fat to atherogenesis (NO... NOT TRUE. Mono-statinators rot...substitute the words 'carbohydrates' and 'carbohydrates' respectively...cholesterol does not kill... Carbs/whole-grains do).

      The response of HDL2, however, is opposite to that of its putative role as a negative risk factor. Further work is needed to clarify this interesting paradox (THE EDITORS LIKELY MADE THE AUTHORS PUT THIS IN... TRANSLATION, WE'RE COMPLETELY BEFUDDLED BY THESE RESULTS).





      Highest Sat Fats and Cholesterol Promote HDL2 Concordant with Regression




      In addition to showing the HIGHEST INCREASE in HDL2 and the DEEPEST DROP in HDL3, Olson et al also discovered that the highest sat-fat ratios (4:1) produced the LOWEST apo B, HIGHEST apoA-I/apoA-II and LIGHTEST FLUFFIEST LDL-CHOL (see table III, IV, V). WOW. All good things. Sounds regressive to me. Quite (accidentally) awesome for these scientists from Washington and St Louis Med Schools out in Misery. Dr. Olson also authored a quite profoundly articulate paper entitled "Is it wise to restrict fat in the diets of children?" a few years after the above sat-fat discoveries.

      Brave scientist.



      Differences Between Moderate vs. High Cholesterol Intake

      Did the authors find a clinical difference between Cholesterol intake of 750 mg/day vs. 1500 mg/day? Of course! 1500mg per day (6 eggs) of cholesterol yielded lower apo B (bad) (102 mg/dl vs. 92 mg/dl) and VLDL (very bad stuff)(68 mg/dl vs. 48 mg/dl). The best total HDLs for any of the subgroups studied was: highest sat fats and highest cholesterol 1500mg/day -- 52 mg/dl vs. 50 mg/dl (3 eggs/750mg/d). Without a doubt, the most optimal HDL2/HDL3 ratio was achieved with the highest sat fat ratio and the highest cholesterol intake 1500mg/d 6 eggs daily (see Table).


      So...

      How do we achieve higher HDL2?

      Like a little piggy, I'm laughing all the way to the market to buy cholesterol/eggs *grin*

      If we take lessons learned from these 20 young men...If our diet consists of 40% fats and our caloric intake is ~2000 cal/day -- fats could comprise approximately (0.40 x 2000) = 800 cal/day. Fats are 9 cal/g -- this amount is equivalent to about 88 grams fat total.

      (Protein 15% 75 grams; Carbs 45% 225 grams OMG -- too much carbs)

      A portion of the fat would be MUFA (monounsaturated) and small amounts PUFA (olive oil, fish oil, GLA, chocolate, nuts, nut butters, veggies, etc) and a certain ratio of saturated fats. Add also the cholesterol equivalent of 6 eggs = 1500 mg cholesterol daily. One Tablespoon of Fat contains approx 13-15 grams fat. SATURATED SFA include butter, butter oil, ghee, virgin coconut oil, MCTs, lard, egg yolks, grass-fed meat, seafood, fish, mollusks, etc.

      (using omega-3 eggs adds in lutein 8x more per egg and fabulous DHA!)
      One large AA omega-3 egg contains about 4.5 grams fat of which 1.5 grams saturated




      Individual Genetic Variations

      The Missouri authors did point out that increases in LDL varied significantly among the male subjects. Like responses to Lp(a) reduction, it appears genetics and diet-gene interaction may play a large part. In the above trial, carb intake was extremely high and as we aware carbs modulate apo B and sdLDL (and HDL2). The meat used in the trial were from a 'local meat processor' in Missouri. Perhaps back then in the 1980s, the EPA + DHA content was already depleted from common meat sources. Many factors (high carbs high carbs high carbs, no EPA DHA, Cholesterol insufficiency) exist that may explain how the baseline HDLs of these young healthy robust mid-western study participants was only in the mid-40s.

      Curiously, apo E polymorphisms and other genetic influences (like PPAR-d a g) may be major players for the optimum diet for regression and fat intake. Pang et al studied apo E patterns in Hong Kong and noticed that carriers of E2 had the best highest apo E levels compared with homozygous apo E3. Other observations were that "Apolipoprotein E (apo E) allele frequencies were: epsilon2 8.7%, epsilon3 80.4% and epsilon4 10.9% with the genotype having a significant effect on plasma apo E concentration (p less than 0.001). Lipoprotein(a) levels were higher in women than men (geometric mean 15.2 versus 10.2 mg/dL, p less than 0.05) and in women with FSH above versus below 40 IU/L (185 versus 136 mg/L, p less than 0.05)." It's not clear to me yet how to discern our apo E polymorphisms without genetic testing and what is the precise diet-gene interaction because optimally the studies would consider the effects of a no-grains/Paleo diet, and unfortunately few take this stance in the medical literature.


      Eggs on the other hand appear great! Perhaps the fox know best...
      • Effect of egg yolk feeding on the concentration and composition of serum lipoproteins in man. Beynen AC, Katan MB. Atherosclerosis. 1985 Feb;54(2):157-66.
      • The effect of egg yolk consumption on the composition of LDL and on the concentration of HDL subclasses was studied in healthy subjects.
      • Six volunteers consumed a diet low in cholesterol for 10 days and then daily added 6 egg yolks to their diet for another 10 days; the experiment was repeated 1 year later with the same subjects. Egg yolk consumption caused the cholesterol intake to increase by 1600 mg/day, and the fat intake by 7 energy % at the expense of carbohydrates; this increase was due almost exclusively to monounsaturated fatty acids.
      • RESULTS: Upon egg yolk feeding the mean level of serum total cholesterol rose by 13%; the bulk of this rise was due to LDL cholesterol, which increased by 21% (READ: REDUCTION IN sdLDL).
      • VLDL and IDL cholesterol decreased by 19 and 11% (good), and serum total triglycerides by 17% (great).
      • Marked relative increases of 35 (very good) and 36% (very very good) were seen in the cholesterol level of the HDL subfractions with densities of 1.055-1.075 g/ml (HDL1) and 1.075-1.100 g/ml (HDL2), respectively.
      • The HDL2/LDL cholesterol ratio increased by 16% (VERY VERY GOOD).
      • No change in cholesterol in HDL3 (d greater than 1.100 g/ml) was observed (GOOD!).
      • The increase in cholesterol in HDL isolated by density gradient ultracentrifugation significantly exceeded the increase in cholesterol in heparin-Mn2+ soluble HDL. This suggests the formation of apo E-containing HDL, i.e. HDLc, which has HDL density but is not soluble in heparin-Mn2+. (?translation please?...Is Krauss in the house?)
      • The composition of the LDL particles was significantly altered; the core became enriched in esterified cholesterol at the expense of triglycerides, and the ratio of core components to surface components increased by 7%. (read again: elimination of sdLDL and rise in round, puffy fluffy LDL particles *cheers!*)
        PMID: 3986015


      Cute...*laugh* I love eggs video

      Saturday, September 6, 2008

      Are We Fighting for the Wrong Oil in Iraq?

      Y'll know I LOVE LOVE fish oil... there are a multitude of reasons. More studies on fish oil exist than anything else I've ever looked at in PubMed -- including studies in every organ, every disease state, every type of cancer in vivo and in vitro, every animal, every nation, every journal. PubMed contains over 24,000+ articles on fish oil/epa dha/omega-3 currently in their database. And it seems to be growing exponentially!

      Here are indications where fish oil has been shown to be beneficial:
      --improves all neuropsych conditions: seizures, ADD, bipolar, depression, anxiety, anorexia, schizophrenia, PMDD, post-partum, migraines, autism, etc
      --cardioprotective against all cardiovascular conditions: arrythmias, atrial fibrillation, prevention primary and secondary events and mortality, regression on CIMT, reduction in Lp(a), increases HDL2b (good), reduces HDL3c (bad), improves TGs/small LDL/IDL/VLDL
      --reverses NASH/NAFLD in humans
      --neuroprotective against dementia and Alzheimer's and strokes
      --improves fitness, strength, and endurance in athletic performance -- hence it's recommended by all fitness, health, women's, men's magazines and of course Oprah at the supermarket
      --used by Olympic trainees and trainers
      --improves diabetes, glucoses, insulin resistance and hyperinsulinemia in sufficient doses
      --improves and reverses all diabetic-related complications: nephropathy, microalbumuria, proteinuria, retinopathy, and neuropathy
      --improves all female hormone-related conditions: PMS, perimenopause, hot flushes, menopausa, fibrocystic breast conditions
      --improves autoimmune and inflammatory chronic pain syndromes: fibromyalgia, osteomalacia, peripheral neuropathy
      --improves hypertension (dose-related benefit)
      --improves IQ in children (and adults... umm like me)
      --immunoprotective against all autoimmune disorders: Hashimoto's and Grave's Thyroiditis, Type 1 Diabetes, LADA, Lupus, Sjögren's syndrome, Fatty Liver, Rheumatoid Arithritis, IgG Nephropathy, Akylosing Spondylitis, Multiple Sclerosis, Infertility, Low sperm count, Endometriosis, Uterine Fibroids, etc.
      --improves all autoimmune and inflammatory skin conditions: Acne, Vitiligo, Acanthosis Nigricans, Psoriasis, Eczema, Atopic Dermatitis
      --serves as our first line of defense as a natural antibiotic: H. pylori ulcer disease, pathogenic bacteria (fungi are eukaryotic like our own mammalian cells therefore EPA DHA do not appear as effective, however pathogenic fungal infections are prevented by more potent saturated fats -- butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, oleic acid, and linoleic acid (short, medium and long carbon-chained fatty acids)
      --improves immunomodulation and reverses and prevents cancers: prostate, breast, colon, gliomas, e v e r y t h i n g
      --improves bones: osteopenia, osteoporosis
      --effectively reduces unwanted cell proliferation: wrinkles, warts, white hairs (j/k -- !!I wish), looking-like-a-walrus



      What are the side effects of fish oil?

      My kids will tell you it tastes gross (when I don't distract them enough), and sometimes they run away...

      Rarely, it can cause stomach upset -- go get a better, higher quality brand. Or try freezing it. The cardiologists that I work with advise storing it in the freezer; this somehow stabilizes the oils for dissolution further in the gut.

      Rarely, can it cause bleeding or bruising or when you are testing BGs (blood glucoses) the fingerstick bleeding may take a little longer to stop. Again, try a better quality brand or try reducing the dose (it is more likely the combined effects of aspirin, Plavix, vitamin E, ginko and/or other synergistically thinning effects).


      The side effects that I enjoy are:
      --great skin
      --great mood -- pro-active, optimistic, playful (makes me more divorce-proof, no joke)
      --great muscles
      --great endurance and workout recoveries
      --great weight loss/maintenance and satiety (blocks flushing from Slo-Niacin too -- great observation by WCCA guy!)


      Can you possibly add more?

      Friday, September 5, 2008

      Where are the B**lls?

      Many academians and highly respected experts have advocated the value of saturated fats but little is said in mainstream media. The lack of evidence of damage from fats were questioned even 10 yrs ago by daring health professionals at Tufts. Each year the evidence mounts. And so do the cases of autism, low-birth weight babies, preemies, degenerative nerve diseases, neuropsych disturbances, migraines, ADHD, afib, CAD, cancer, autoimmune diseases, arthritis, chronic pain, deaths and excessive morbidity.


      Great Balls of Fire

      Here are the people I *love* who fearlessly profess their knowledge and experience in hopes of trying to turn the tide of 'low-fat' idiocy and ret*rdness... And the truth never fails.

      --Dr.Davis, cardio-thoracic surgeon/author/researcher of TYP book fame and HEARTSCANBLOG pioneer for self-empowered healthcare and cardiology
      --Peter of Hyperlipid and biochem brilliance
      --UC Davis researchers German and Dillard (see below) persuasively challenge the status quo
      --Tufts researchers Lichtenstein et al published 10 years ago an extensive discussion on the downsides of 'fat-modified' food (see below)
      --Harvard researcher Dr.Mozzafarian who suggests keeping fat intake 30-40% of the diet and upping saturated fats (see below)



      Effects of dietary fats versus carbohydrates on coronary heart disease: a review of the evidence. Mozaffarian D. (Harvard) Curr Atheroscler Rep. 2005 Nov;7(6):435-45.

      Recommendations arising from the traditional diet-coronary heart disease (CHD) paradigm, which focuses on effects of total and saturated fat on serum total and low-density lipoprotein cholesterol, may have failed to reduce CHD risk and inadvertently exacerbated dyslipidemia, insulin resistance, and weight gain, particularly among individuals who are older, female, sedentary, or obese. A suitable dietary paradigm must consider types and qualities of fats and carbohydrates consumed, their effects on a range of intermediary risk factors, and characteristics that may modify individual susceptibility. Based on current evidence, replacement of total, unsaturated, and even possibly S A T U R A T E D fats with refined, high-glycemic index carbohydrates is unlikely to reduce CHD risk and may increase risk in persons predisposed to insulin resistance (H E L L O . . . EVERYONE?). In contrast, a diet that is 1) rich in whole grains and other minimally processed carbohydrates; 2) includes moderate amounts of fats (approximately 30%-40% of total energy), particularly unsaturated fats and omega-3 polyunsaturated fats from seafood and plant sources; 3) is lower in refined grains and carbohydrates; and 4) eliminates packaged foods, baked goods, and fast foods containing trans fatty acids, will likely reduce the risk of CHD.
      PMID: 16256001




      Dietary fats, carbohydrate, and progression of coronary atherosclerosis in postmenopausal women. Mozaffarian D, Rimm EB, Herrington DM. (Harvard) Am J Clin Nutr. 2004 Nov;80(5):1175-84

      BACKGROUND: The influence of diet on atherosclerotic progression is not well established, particularly in postmenopausal women, in whom risk factors for progression may differ from those for men.
      OBJECTIVE: The objective was to investigate associations between dietary macronutrients and progression of coronary atherosclerosis among postmenopausal women. DESIGN: Quantitative coronary angiography was performed at baseline and after a mean follow-up of 3.1 y in 2243 coronary segments in 235 postmenopausal women with established coronary heart disease. Usual dietary intake was assessed at baseline.
      RESULTS: The mean (+/-SD) total fat intake was 25 +/- 6% of energy. In multivariate analyses, a HIGHER S A T U R A T E D F A T intake was associated with a smaller decline in mean minimal coronary diameter (P = 0.001) and less progression of coronary stenosis (P = 0.002) during follow-up.... Monounsaturated and total fat intakes were not associated with progression.
      CONCLUSIONS: In postmenopausal women with relatively low total fat intake, a greater SATURATED fat intake is associated with less progression of coronary atherosclerosis, whereas carbohydrate intake is associated with a greater progression.
      PMID: 15531663





      Saturated fats: what dietary intake?. German JB, Dillard CJ. (University of California, Davis) Am J Clin Nutr. 2004 Sep;80(3):550-9. Review. PMID: 15321792
      • "Public health recommendations for the US population in 1977 were to reduce fat intake to as low as 30% of calories to lower the incidence of coronary artery disease. These recommendations resulted in a compositional shift in food materials throughout the agricultural industry, and the fractional content of fats was replaced principally with carbohydrates. Subsequently, high-carbohydrate diets were recognized as contributing to the lipoprotein pattern that characterizes atherogenic dyslipidemia and hypertriacylglycerolemia."
      • "This review summarizes research findings and observations on the disparate functions of saturated fatty acids and seeks to bring a more quantitative balance to the debate on dietary saturated fat... Because agricultural practices to reduce saturated fat will require a prolonged and concerted effort, and because the world is moving toward more individualized dietary recommendations, should the steps to decrease saturated fatty acids to as low as agriculturally possible not wait until evidence clearly indicates which amounts and types of saturated fatty acids are optimal?"


      Dietary fat consumption and health. Lichtenstein AH, Kennedy E, Barrier P, Danford D, Ernst ND, Grundy SM, Leveille GA, Van Horn L, Williams CL, Booth SL. (Tufts University, Boston, MA) Nutr Rev. 1998 May;56(5 Pt 2):S3-19; discussion S19-28.


      • "Dietary Guidelines have emerged over the past 30 years recommending that Americans limit their consumption of total fat and saturated fat as one way to reduce the risk of a range of chronic diseases. However, a low-fat diet is not a no-fat diet."
      • "Dietary fat clearly serves a number of essential functions. For example, maternal energy deficiency, possible exacerbated by very low-fat intakes (less than 15% of energy), is one key determinant in the etiology of low birth weight (AND AUTISM??). The debate continues over recommendations for limiting total fat and saturated fatty acid intake in children.... More attention needs to be devoted to the effect of dietary fat reduction on the nutrient density of children's diets."
      • "The relationship between high-carbohydrate/low-fat diets and CHD is more ambiguous because high-carbohydrate diets induce dyslipidemia in certain individuals. Obesity among adults and children is now of epidemic proportions in the United States... However, the prevalence of obesity has increased during the same time period that dietary fat intake (both in absolute terms and as a percentage of total dietary energy) has decreased... Obesity is also an independent risk factor for the development of diabetes. The current availability of fat-modified foods offers the potential for dietary fat reduction and treatment of the comorbidities associated with diabetes. However, to date, few studies have documented the effectiveness of fat-modified foods as part of a weight loss regimen or in reduction in CHD risks among individuals with diabetes mellitus."
      • "The association between total dietary fat and cancer is still under debate (AND CHEAP INDUSTRIALLY REFINED VEGGIE OILS CONSISTENTLY CAUSE CANCER AND METASTASES IN LAB ANIMALS INCL HUMANS). While there is some evidence demonstrating associations between dietary fat intake and cancers of the breast, prostate, and colon, there are serious methodologic issues, including the difficulty in differentiating the effects of dietary fat independent of total energy intake...."

      Tuesday, September 2, 2008

      Waning Estrogen and HDL3b





      In Krauss and Williams et al research on lipoproteins in Bay Area Mormon kindreds, they talked about my favorite things (other than the sound of music)... on their relationship with HDL2b, the regression lipoprotein subfraction which performs in the vasculature like liquid D-R-A-N-O:
      --young age
      --low BMI/fat body composition
      --more alcohol (for women only -- j/k --the stats didn't reach significance)
      --estrogen (for getting our both mojo-jo-jo and HDL2b on) -- both natural and substituted

      Estrogen has great affects on improving HDL2b from birth to menopause for women (and men too?). And after menopause, women have a pattern of elevated HDL3c/3b like men (not pretty -- the blip above for 3b is even greater than the 3b blip for men Fig 1 below). Not shown in the data or graphs, the authors note that for the subjects taking estrogen replacement did display greater levels of the larger-sized HDL3a and HDL2a. No mention of HDL2b which was odd since estradiol has been shown to increase HDL2b quite significantly in menopausal women. The authors also didn't report the specific type of estrogen estradiol (better) v. Premarin (bad).

      I found this article so neat on many levels -- the authors really focused on subfractions of a previously under-appreciated lipoprotein ignored by statinators, the HDLs 'happy' good cholesterol. They are not from a major medical academic institution (LBL does not have that distinction around here). And lastly they used technology that we love at TYP to 'track' health/health status.


      -BG

      Monday, September 1, 2008

      Our Paleo Princess-Party!

      Our first wheat-free birthday party occurred a few weeks ago. Needless to say it required a little more preparation than previous parties!

      Fortunately I was really inspired by Anna and her wonderful coconut flour chocolate cookies and the rest of the menu became easy. Anna's original recipe is here where she also includes some great low-carb cooking ideas. When I went to Whole Foods to gather the ingredients, I discovered quite at the last minute that they did not carry the primary ingredient... the coconut flour! So instead we improvised and had almond chocolate chip cookies instead. Apparently they were a hit (or... the princess swimmers were just really really HUNGRY). (warning: The cookie dough had a weird grassy unpleasant smell from the garbanzo bean flour (I presume) but it all disappeared while baking.)

      The cookies smelled and looked and tasted even better than REAL CHOCOLATE CHIP COOKIES. (even without the primary ingredient!!)


      Improvised Almond Choco-chip Butter Cookies (Courtesy of Anna -- I'm her biggest fan)

      1/2 cup butter (1 stick), very soft or slightly melted and creamy (I should've used MORE)
      1/4 cup sugar
      1 teaspoon vanilla
      1 teaspoon almond extract
      4 eggs
      1/2 cup garbanzo bean flour
      1/2 cup almond meal/flour
      1/2 cup oat flour
      1/2 cup unsweetened grated coconut: fine, coarse or combination

      1/2 cup gluten-free tiny-sized semi-sweet chocolate chips (or up to 1 cup)

      Makes 24 cookies
      Preheat oven to 425°F (Convection; or 400°F regular). Cover cookie sheet with aluminum (or Silpat silicone mat).

      Mix together soft butter and sugar. Add eggs and vanilla and almond extract; mix well.

      Add all flours and grated coconut; mix well.

      Drop cookie dough by spoonfuls or dough scoop onto pan one inch apart (cookies don't spread).

      Bake 425°F (convection) for 15-18 minutes until golden brown. Remove to wire rack immediately to cool.



      Menu
      Pineapple Teriyaki Chicken
      Gluten-free Hawaiian Pizza (frozen cooked shells from Whole Foods)
      BBQ Wings
      Organic Turkey Hotdogs (no they're not nitrate-free)
      Italian Tuna and Olives (in cupcake papers)
      Snap Peas
      Corn on the Cob
      Olives
      Garlic Mushrooms

      Desserts
      Almond Lemon Birthday Cake (gluten-free at Whole Foods)
      Whipped Cream in Chocolate Shells (Whole Foods)
      Cherries and Strawberries


      (I said Paleo... not low-carb!)