Apr 20, 2014

Why is it so Hard to Kick the Smoking Habit

Brain scans showed nicotine withdrawal weakens parts of the brain tied to ability to control cravings
Nicotine withdrawal triggers changes to the brain that help explain why smokers have such a tough time quitting, a new study suggests.

Up to 80 percent of smokers who try to quit eventually start smoking again. This latest finding might lead to new ways to identify smokers who are at high risk for failure when they try to quit, the researchers said. The study might also lead to more intensive treatment to help smokers quit for good.

The researchers used fMRIs to scan the brains of 37 smokers, aged 19 to 61, immediately after they smoked and again after they had been smoke-free for 24 hours and were experiencing nicotine withdrawal.

The researchers discovered that nicotine withdrawal weakens brain connections associated with the ability to control cravings for cigarettes, according to the study, which was published in this week's issue of the journal JAMA Psychiatry.

Specifically, they have trouble shifting from an inward-focused brain network to one that helps them have more control over their desire for cigarettes and focus on quitting smoking, the researchers said.

"Symptoms of withdrawal are related to changes in smokers' brains, as they adjust to being off of nicotine," study co-leader Caryn Lerman, head of the Brain and Behavior Change Program at the University of Pennsylvania, said in a university news release. "This study validates those experiences as having a biological basis."

"The next step will be to identify in advance those smokers who will have more difficultly quitting and target [them with] more intensive treatments, based on brain activity and network connectivity," she added.



Fatty acid Metabolism : Regulation of Fatty Acid Oxidation (Part 2)

Fatty acyl CoA formed has two fates one, it can undergo β oxidation and the other is it is converted to Tg and phospholipid in the cytosol.

Malonyl CoA (first intermediate in the cytosolic biosynthesis of long-chain fatty acids from acetyl-CoA) inhibit the carnitine acyltransferase I ensures that FA oxidation is inhibited when liver is amply supplied with glucose as fuel and is actively making Tg from excess glucose.

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When NADH/[NAD+] ratio is high (energy sufficiency), β-hydroxyacyl-CoA dehydrogenase is inhibited; in addition, high concentrations of acetyl-CoA inhibit thiolase.

During vigorous muscle exercise or during fasting [ATP/AMP] ratio decreases, this activates Protein Kinase (AMPK) which phosphorylates and deactivates acetyl-CoA Carboxylase; this lowers the concentration of malonyl-CoA, relieving the inhibition of fatty acyl-carnitine transport to mitochondria and allow β oxidation to replenish the supply of ATP.

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Transcription factors turn on the synthesis of proteins for lipid catabolism

PPAR or PPARα (Peroxisome proliferator-activated receptors) these are transcription factors. During increase demand for energy from fat catabolism, during fast between meals, long starvation. They turn on genes essential for fatty acid oxidation.

In fetus the principle fuels are glucose and lactate, but in the neonatal heart, fatty acids are the main fuel, so during transition from fetus to neonate, its activation, activates the genes essential for fatty acid metabolism.

Endurance training increases PPARα expression in muscle, leading to increase levels of fatty acid oxidizing enzymes.

Glucagon, in low blood glucose, can act through cAMP and the transcription factor CREB to turn on genes for lipid catabolism.

β Oxidation in Peroxisomes

One difference between the Peroxisomal and mitochondrial pathways is in the chemistry of the first step. In peroxisomes, the flavoprotein acyl-CoA oxidase that introduces double bond directly passes electrons to O2 producing H2O2 and this is cleaved by catalase. But in mitochondria electron are transferred to ETC, producing ATP and water. In peroxisomes energy is released as heat. Another difference is mitochondrial NADH is regenerated but in peroxisomes NADH cannot be regenerated. The Peroxisomal system is active on very long chain fatty acids as hexacosanoic acid and on branched chain fatty acids like phytanic acid and pristanic acid. Peroxisomal beta oxidation shortens the side chain of cholesterol in bile acid formation. Peroxisomes also take part in the synthesis of glycerolipids, cholesterol; and dolichol. They do not contain carnitine palmitoyltransferase.

The inability to oxidize these compounds is responsible for several serious human diseases. Individuals with Zellweger syndrome are unable to make peroxisomes.

In mammals, high concentration of fats in the diet results in increased synthesis of enzymes of Peroxisomal beta oxidation in the liver also the hypolipidemic drug like clofibrate. Liver peroxisomes do not contain the enzymes of CAC and cannot catalyze the oxidation of acetyl-CoA to CO2.

α- and ῳ-oxidation

This occurs in some vertebrates and other species. α-oxidation removes the one carbon from carboxyl end and seen in brain tissue. It does not require CoA and does not generate energy. This occurs when beta position is occupied by methyl group e.g. in phytanic acid which cannot undergo beta oxidation.

ῳ-oxidation is brought about by cytochrome P450 and electron donor NADPH in ER of liver and kidney. In mammalian this is minor but when beta oxidation is defective this comes into play. This is also a type of mixed function oxidase reaction. The –CH3 is converted to –CH2OH that is oxidized to –COOH, forming dicarboxylic acid. This is beta oxidized to adipic (C6) and suberic (C8) acids, and excreted in urine.

Ketone body formation

Ketone bodies are acetoacetate, D(-)-3hydroxybutyrate (β-hydroxybutyrate) and acetone (spontaneous decarboxylation of acetoacetate. They are produced in the liver.

 

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The ratio of 3-hydroxybutyrate/acetoacetate in blood varies between 1:1 and 10:1 in blood.

Formation, utilization, and excretion of ketone bodies. Solid arrow indicates the main pathway.

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Enzymes for ketogenesis are located in mitochondria. C2 units formed in β-oxidation condense to form acetoacetate. This may occur by inhibition of thiolase. Acetoacetyl-CoA is the starting material for ketogenesis which may arise by β-oxidation or by condensation of 2 acetyl-CoA. 3-hydroxybutyrate is the predominant ketone body present in the blood and urine in ketosis.

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Utilization of ketone bodies

In the liver cytosol it is a precursor of cholesterol synthesis. Before utilization, Acetoacetate is activated as Acetoacetyl-CoA involving succinyl-CoA and the enzyme succinyl-CoA-acetoacetate CoA transferase.

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Ketone bodies are oxidized in extrahepatic tissue. If the blood level is raised, oxidation increases until, until a concentration is approximately 12 mmol/L, where they saturate the oxidative machinery. Ketonemia is the increased production of ketone bodies and decreased utilization in extrahepatic tissues.

Regulation of ketogenesis

1. Control in adipose tissue: Free fatty acids produced by lipolysis of TAG in adipose tissue are the precursors of ketone bodies in the liver. The liver both in fed and in fasting condition can extract 30% of FFA passing through it.

2. Carnitine palmitoyltransferase-I (CPT-1): Regulates the entry of long chain fatty acyl groups into mitochondria prior to β-oxidation. Its activity is low in fed state, leading to depression of fatty acid oxidation, and high in starvation, allowing fatty acid oxidation to increase. During fed state Malonyl-CoA formed inhibits CPT-1, so fatty acids entering liver are esterified as acylglycerols and transported out of liver as VLDL. As the concentration of FFA increases with starvation, acetyl-CoA carboxylase is inhibited by acyl-CoA, and malonyl-CoA decreases, releasing the inhibition of CPT-1 and thus more FFA are oxidized. These events are reinforced in starvation by decrease in the [insulin]/ [glucagon] ratio. This cause inhibition of acetyl-CoA carboxylase in liver by covalent phosphorylation. Thus, β-oxidation is controlled by CPT-1 gateway into the mitochondria, and those not oxidized is esterified.

3. Regulation of partition of acetyl-CoA between the ketogenic pathway and pathway of oxidation to CO2. The partition of acetyl-CoA between the ketogenic pathway and the pathway of oxidation to CO2 is so regulated that the total free energy captured in ATP which results from the oxidation of free fatty acids remains constant. Here the complete oxidation of 1 mol of palmitate involves a net production of 129 mol of ATP via β-oxidation and CO2 production in the citric acid cycle, whereas only 33 mol of ATP are produced when acetoacetate is the end product and only 21 mol when 3-hydroxybutyrate is the end product. Thus, ketogenesis may be regarded as a mechanism that allows the liver to oxidize increasing quantities of fatty acids within the constraints of a tightly coupled system of oxidative phosphorylation without increasing its total energy expenditure. Also increased [NADH]/ [NAD+] ratio caused by β-oxidation caused the decrease in the concentration of oxaloacetate; this can impair the ability of the CAC to metabolize acetyl-CoA.

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Regulation of ketogenesis

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Regulation of long-chain fatty acid oxidation in the liver

CLINICAL ASPECTS

a) Carnitine deficiency: Particularly in newborn and especially in preterm infants owing to inadequate biosynthesis or renal leakage. There are episodic periods of hypoglycemia owing to reduced gluconeogenesis resulting from impaired fatty acid oxidation in the presence of raised plasma FFA, leading to lipid accumulation with muscular weakness. Treatment is by oral supplementation of carnitine.

b) Inherited carnitine palmitoyltransferase-I deficiency: Affects only the liver, resulting in reduced fatty acid oxidation and ketogenesis with hypoglycemia.

c) Carnitine palmitoyltransferase-II deficiency: Affects skeletal muscles (weakness and necrosis with myoglobinuria) and more severely the liver.

d) Acute fatty liver of pregnancy: Deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase.

e) Jamaican vomiting sickness: Caused by eating the unripe fruit of the akee tree, which contains a toxin hypoglycin that inactivates medium and short-chain acyl-CoA dehydrogenase.

f) Dicarboxylic aciduria: Excretion of C6-C10 omega dicarboxylic acids and by non-ketotic hypoglycemia. Caused by lack of mitochondrial medium-chain acyl-CoA dehydrogenase.

g) Refsum’s disease: Rare neurological disorder caused by accumulation of phytanic acid, formed from phytol, a constituent of chlorophyll, this occurs due to defect in α-oxidation.

h) Zellweger’s (cerebrohepatorenal) syndrome: There is inherited absence of peroxisomes in all tissues. They accumulate C26 –C38 polyenoic acids in brain tissue, they also have impaired bile acid and ether lipid synthesis.

i) Ketoacidosis: This occurs during starvation, due to depletion of carbohydrate coupled with mobilization of FFA, this process is exaggerated during diabetes mellitus. This also occurs in high fat diet and severe exercise in the postabsorptive state.

Fatty acid contains a long hydrocarbon chain and a terminal carboxylate group. Fatty acids have four major physiological roles.

1. Stored as triacylglycerols (neutral fats) – used as energy reserve

2. FA are building blocks of phospholipids and glycolipids – component of biological membrane.

3. FA covalently attaches protein and modifies them and targets them to membrane locations. E.g. attachment of soluble proteins to membrane by attaching to palmitoyl group, farnesyl group and glycosylphosphatidylinositol group.

4. Fatty acid derivatives serve as hormones and intracellular messengers.

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FATTY ACID SYNTHESIS AND DEGRADATION MIRROR EACH OTHER CHEMICALLY BUT DIFFER MECHANISTICALLY.

Triacylglycerols are highly concentrated stores of metabolic energy because they are reduced and anhydrous. The yield from the complete oxidation of fatty acids is about 9 kcal g-1 (38 kJ g-1), in contrast with about 4 kcal g-1 (17 kJ g-1) for carbohydrates and proteins. The basis of this large difference in caloric yield is that fatty acids are much more reduced. Furthermore, triacylglycerols are nonpolar, and so they are stored in a nearly anhydrous form, whereas much more polar proteins and carbohydrates are more highly hydrated. In fact, 1 g of dry glycogen binds about 2 g of water. Consequently, a gram of nearly anhydrous fat stores more than six times as much energy as a gram of hydrated glycogen, which is likely the reason that triacylglycerols rather than glycogen were selected in evolution as the major energy reservoir. Consider a typical 70-kg man, who has fuel reserves of 100,000 kcal (420,000 kJ) in triacylglycerols, 25,000 kcal (100,000 kJ) in protein (mostly in muscle), 600 kcal (2500 kJ) in glycogen, and 40 kcal (170 kJ) in glucose. Triacylglycerols constitute about 11 kg of his total body weight. If this amount of energy were stored in glycogen, his total body weight would be 55 kg greater. The glycogen and glucose stores provide enough energy to sustain biological function for about 24 hours, whereas the triacylglycerol stores allow survival for several weeks.

FFA, monoacylglycerol transported to intestine and absorbed into plasma membrane

In mucosal cells TAG and MAG are resynthesized and packaged into chylomicrons along with apo-B48.

Chylomicrons released into blood via lymph

Action of lipoprotein lipase in adipose tissue and muscle tissue breaks TAG into fatty acids

TAG resynthesized and stored or used as energy

Difference between Fatty acid synthesis and Degradation.

1.Synthesis takes place in the cytosol, in contrast with degradation, which takes place

primarily in the mitochondrial matrix.

2. Intermediates in fatty acid synthesis are covalently linked to the sulfhydryl groups of an

acyl carrier protein (ACP), whereas intermediates in fatty acid breakdown are covalently

attached to the sulfhydryl group of coenzyme A.

3. The enzymes of fatty acid synthesis in higher organisms are joined in a single polypeptide

chain called fatty acid synthase. In contrast, the degradative enzymes do not seem to be

associated.

4. The growing fatty acid chain is elongated by the sequential addition of two-carbon units

derived from acetyl CoA. The activated donor of two carbon units in the elongation step is

malonyl ACP. The elongation reaction is driven by the release of CO2.

5. The reductant in fatty acid synthesis is NADPH, whereas the oxidants in fatty acid

degradation are NAD+ and FAD.

6. Elongation by the fatty acid synthase complex stops on formation of palmitate (C16).

Further elongation and the insertion of double bonds are carried out by other enzyme

systems.

Fatty acid Metabolism Notes (Part 1)

Fatty acid catabolism includes the complete oxidation (β oxidation) of fatty acid to yield acetyl CoA which has different fates. Fatty acids are hydrocarbons with energy of complete oxidation (about 38 kJ/g) more than twice that for the same weight of carbohydrate or protein. To overcome the stability of C-C bonds in a fatty acid, the carboxyl group at C-1 is activated by attachment to coenzyme A, which allows stepwise oxidation of the fatty acyl group at the C-3, or β position – hence the name β oxidation.

How to be successful in learning: 6 Steps

You are probably one of the people who believe in the power of knowledge, and who understand that humans could solve their problems if they understood the world better. More and more people in the world suffer from Information Fatigue Syndrome - stress from too much information.

This text shows you how to manage information and knowledge. There are no fantastic miracles. Everything in this article is based on facts and science.
For 18 years, Dr Wozniak has been working on the problem of effective learning. As a student of molecular biology, he understood how he could improve the quality of his actions if he could remember more. He needed to improve his ability to remember what he studied for exams (and not only for exams).

Now, he wants to share his experience with you. He wants many people to enjoy the power of knowledge. He believes that we can build a better world, if we can learn and understand more. He represent a commercial company, but you don't need to spend a penny. You can improve your learning ability by reading this article. Spend 20 minutes on this article and you will learn how to learn more effectively.
The first three points may be obvious to you. Please don't stop reading.
1.     Get hungry for knowledge! If your motivation to learn is weak, you can stop reading this text, this advice will not work. Your motivation cannot be shallow. For example, if you only want to pass an exam or impress your boss, then your motivation is shallow. You must see the connection between knowledge and the value that it brings to life. Do you like science programs? Do you want to know how your computer works? Do you look for news on the Internet? If the answer is yes, you are probably on the right way. Can you spend more than 30 minutes talking about something unimportant, or being lazy doing nothing? If so, you will have a problem with learning. The hunger for knowledge grows as you learn. The more you know, the more you want to know, and you also notice how little you know. If you need motivation to learn, simply start learning and you will soon want to know more, and your motivation will grow. Scientists discovered that strong motivation is more important than IQ
2.     Find what you really need. You must know which areas of knowledge are most important to you. There is much more to learn than you can learn in your life. If you understand this, you will see that sometimes three pieces of knowledge, which are carefully chosen, can be more valuable than a whole textbook of facts. You must decide how much time you can spend on learning. Most people cannot learn more than an hour a day. If you are one of them, the problem of choosing what to learn, is very important. Do not choose only one subject to learn. You need much general knowledge about health, sociology, history, natural sciences, etc. Only people with wide education can be truly successful
3.     Find sources of information. If you are not a student, you probably cannot spend much time reading whole books. Did you discover the power of the Internet? You can find many answers on the net. There are many articles like this: short, free, and, I hope, inspiring. TV, news magazines and libraries are still useful. See also Reading the Internet to learn more about how to use the Internet to get knowledge
4.     Formulate your knowledge in such a way that you can repeat it actively. This is the first point on the list that I need to defend. You may not agree with it at first: you must review your material regularly in order to learn effectively. If you don't review, you will forget. Do not believe in theories saying that you can remember something for ever without repeating it! Everything that you remember is repeated from time to time, even if you do not notice the repetition. This is how your memory works. You must repeat to remember. Active recall is the name for the method of formulating knowledge that lets you repeat your knowledge actively. When you repeat, your brain must generate the answer to a question. Repetition cannot be passive. It is not enough to read that George Washington was the first US president. You need a question! For example, Who was the first US president? Most sources of information in the world do not use active recall! Usually, you will have to formulate your knowledge for active recall yourself. You will gather your knowledge from many sources, for example CNN, the Internet, Newsweek, encyclopedias, business journals, science journals, etc. They are only sources for information. This information is not formulated for active recall. You will have to reformulate it. The time you spend on formulating your knowledge will be returned in the future. You will see that it's not a waste of time, but an investment. To better understanding the relationship between knowledge and remembering, see: The 20 rules of formulating knowledge in learning
5.     Repeat the material at proper times. This point can improve your learning ability even if you are already a very good learner. As I said earlier, you must repeat the material if you want to keep it in memory. The problem is: when to repeat, how often to repeat, and what to repeat. This problem is solved for you. The solution is called SuperMemo. SuperMemo is the name of the method of choosing the time for repetitions. The name means "super memory". You can start using SuperMemo even today. You have three options (two are free):
        you can read Using SuperMemo without a computer and start using the method today
        you can download older versions of SuperMemo freeware
        if you have a credit card, you can order and download the newest version for Windows in minutes (there are also versions for Windows CE and Palm)
If you learn how to use SuperMemo, you will never have a problem with remembering your knowledge. You can tell the computer what part of your knowledge you want to keep in memory (you can choose any number between 90% and 99%)
6.     Keep managing your knowledge. Constantly pay attention to the knowledge you have in your SuperMemo collection. Your needs will change. Maybe after some time, you will need to change parts of your collection. You should do repetitions every day. This should become your habit. You will spend your time effectively if all the facts in your collection are worthy. They should be useful, up-to-date, and they should be properly formulated. You can save 70-90% of your time if you delete the most difficult 5% of your material.
In this article, I described an effective approach to learning. This method requires spending some time before you can see the results. To use this method you will have to change your ways of thinking about learning. You will have to have a different attitude. Maybe you don't believe that this method works. Maybe you have the following doubts:
  • Is knowledge so important in my life?
  • Is active recall so important in learning? Is it important to reformulate everything I learn? Isn't this a waste of time?
  • Do I have to use the SuperMemo method? Maybe my current methods are good enough?
Reading articles, learning new methods, installing new software, and spending money can be reasons for you not to try. Maybe you will find it hard to do regular repetitions every day?

Dr Wozniak has spent all his professional life promoting the presented method. He designed it and improved it over many years. I guarantee good results. If you really want to try and and if you are really determined to continue, then you will see good result for sure.

If you have any doubts, please write to: Michal Ryszard Wojcik


(Source: www.supermemo.com)

Apr 19, 2014

Wider Waistline May Mean Shorter Lifespan

Having a big belly means big trouble when it comes to your health, researchers warn.

They analyzed data from 11 studies that included more than 600,000 people worldwide and found that people with large waist circumferences were at increased risk of dying younger and dying from conditions such as heart disease, lung problems and cancer.

Men with waists of 43 inches or more had a 50 percent higher risk of death than those with waists less than 35 inches. This equated to a three-year lower life expectancy after age 40, according to the study.

Women with waists of 37 inches or more had an 80 percent higher risk of death than those with waists of 27 inches or less, which equated to a five-year lower life expectancy after age 40.

The larger the waist, the greater the risk, the researchers said. For every 2 inches of increased waist circumference, the risk of death increased 7 percent in men and 9 percent in women, according to the study, which was published in the March issue of the journal Mayo Clinic Proceedings.

Although the review found an association between larger waist size and risk of death at a younger age, it didn't prove a cause-and-effect relationship.

The link between a big belly and increased risk of death was seen even among people whose body-mass index (BMI) was within the healthy range, the researchers found. BMI is an estimate of body fat based on height and weight.

"BMI is not a perfect measure," study lead author Dr. James Cerhan, an epidemiologist at the Mayo Clinic, said in a journal news release. "It doesn't discriminate lean mass from fat mass, and it also doesn't say anything about where your weight is located. We worry about that because extra fat in your belly has a metabolic profile that is associated with diseases such as diabetes and heart disease."

When assessing patients, doctors need to consider both waist size and BMI.

"The primary goal should be preventing both a high BMI and a large waist circumference," Cerhan said. "For those patients who have a large waist, trimming down even a few inches -- through exercise and diet -- could have important health benefits."



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