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Printing for dyslexics   The anatomy of dyslexia   Obesity 1    Obesity 2    Obesity 3    Obesity 4    Trans fats   Some myths are true   Phonological awareness    Alzheimers news   More Alzheimers News    Recognize Stroke  Yes or no to breakfast    Protein Diagrams  

Printing for dyslexics
For some time people have been working on typefaces and typesetting that helps dyslexics to read and they have had success.  The recommendations of the British Dyslexia Association include optimizing the size and type of font, page layout, headings, type of paper, and line spacing:

Dyslexia Style Guide
1. Dyslexia Friendly Text.
The aim is to ensure that written material takes into account the visual stress experienced by some dyslexic people, and to facilitate ease of reading.
Adopting best practice for dyslexic readers has the advantage of making documents easier on the eye for everyone.
Paper should be thick enough to prevent the other side showing through.
Use matt paper rather than glossy. Avoid digital print processing which tends to leave paper shiny.
Avoid white backgrounds for paper, computer and visual aids. White can appear too dazzling. Use cream or a soft pastel colour. Some dyslexic people will have their own colour preference.
Use a plain, evenly spaced sans serif font such as Arial and Comic Sans. Alternatives include Verdana, Tahoma, Century Gothic, Trebuchet.
Font size should be 12-14 point. Some dyslexic readers may request a larger font.
Use dark coloured text on a light (not white) background.
Avoid green and red/pink as these are difficult for colour-blind individuals.
Headings and Emphasis.
Avoid underlining and italics: these tend to make the text appear to run together. Use bold instead.
AVOID TEXT IN BLOCK CAPITALS: this is much harder to read.
For Headings, use larger font size in bold, lower case.
Boxes and borders can be used for effective emphasis.
Use left-justified with ragged right edge.
Avoid narrow columns (as used in newspapers).
Lines should not be too long: 60 to70 characters.
Avoid cramping material and using long, dense paragraphs: space it out.
Line spacing of 1.5 is preferable.
Avoid starting a sentence at the end of a line.
Use bullet points and numbering rather than continuous prose.
Writing Style.
Use short, simple sentences in a direct style.
Give instructions clearly. Avoid long sentences of explanation.
Use active rather than passive voice.
Avoid double negatives.
Be concise.
Increasing accessibility.
Flow charts are ideal for explaining procedures.
Pictograms and graphics help to locate information.
Lists of 'do's and 'don'ts' are more useful than continuous text to highlight aspects of good practice.
Avoid abbreviations if possible or provide a glossary of abbreviations and jargon.
For long documents include a contents page at the beginning and an index at end.
Checking Readability.
To set your spell checker in Word 2003 to automatically check readability, go to Tools, Options, Spelling, and Grammar, then tick the Readability request. Word will then show your readability score every time you spell check.
In Word 2007 Click the Microsoft Office Button, and then click Word Options. Click Proofing. Make sure Check grammar with spelling is selected. Under When correcting grammar in Word, select the Show readability statistics check box.
Check long documents in sections, so that you know which parts are too hard.
Flesch Reading Ease score: Rates text on a 100-point scale; the higher the score, the easier it is to understand the document. For most standard documents, aim for a score of approximately 70 to 80.
Flesch-Kincaid Grade Level score: Rates text on a U.S. grade-school level. For example, a score of 5.0 means that a fifth grader, i.e. a Year 6, average 10 year old, can understand the document. For most standard documents, aim for a score of approximately 5.0, by using short sentences, not by dumbing down vocabulary.
2. Accessible Formats
It is important that documents and publications are prepared to be accessible in alternative formats for people with visual impairments or reading difficulties. These should include availability in electronic format which can be read by screen reading software.
Printed documents are created in computers, so it should be possible to issue the electronic files. Some documents will only be available electronically.
Word files are the easiest for individual viewing preferences and for listening.
Portable Document Format (PDF) files keep the presentation better than Word files, but are not as easy to use.
We suggest offering both the source Word files and derived PDF files where possible.
Publicise availability of accessible formats.
Preparing a document for text-reading software:
Listening to a document using a text reader will take longer than visual reading.
Put full stops after headings to make the voice drop and pause; a pale tint similar to the background colour will make the dots less visually distracting.
Put semi-colons, commas, or full stops after bullet points to make a pause.
Use Styles in Word to organise headings and formatting.
Avoid automatic numbering as some text readers will not read these. Use manual.
Contents Page listings should be hyperlinked to the relevant section to aid navigation. Number menu items.
Use internal and external hyperlinks for ease of navigation.
Avoid text in capital letters in mid-line, as they may be read as single letters.
Include as few signs and symbols as are absolutely necessary, e.g. asterisks or dashes (both short and long), as these will be spoken.
Long dashes should be avoided: use colons to make the voice pause.
Use straight quotation marks. Curly or slanting ones may be read out as ‘back quote’ by some screen readers.
Avoid Roman Numerals and No. for number.
Consider whether abbreviations and acronyms need full stops.
Text readers may have difficulty with tables in Word and may not automatically move on to the next cell without manual use of the Tab key.
Avoid text in images. Listeners cannot hear it. Repeat in the main text.
Use hyphens in compound words to aid text reading pronunciation.
Chunk phone numbers to avoid being read as millions or hundreds of thousands.
3. Website design
Website design must consider all the above factors together with the following points.
Research shows that readers access text at a 25% slower rate on a computer. This should be taken into account when putting information on the web. When a website is completed, check the site and information for accessibility by carrying out these simple checks.
Navigation should be easy. A site map is helpful.
Use graphics, images, and pictures to break up text, while bearing in mind that graphics and tables may take a long time to download.
Very large graphics make pages harder to read.
Offer alternate download pages in a text reader friendly style.
Where possible design web pages which can be downloaded and read off-line.
Moving text creates problems for people with visual difficulties. Text reading software is unable to read moving text.
Contents links should show which pages have been accessed.
Most users prefer dark print on a pale background. Colour preferences vary.
Some websites offer a choice of background colours.
Encourage the use of hyperlinks at the end of sentences.
Avoid green and red/pink as these are difficult for colour-blind individuals.
Make sure that it is possible for users to set their own choice of font style and size, background and print colours.

That is the advice...BUT... there is no mention of letter spacing which may be the most important aspect of all. Dyslexic children were found to be 20% faster and twice as accurate when reading text which has extra space between letters. This impressive result was obtained without any prior training whatsoever. 'Crowding' effects the reading of everyone, but especially dyslexics.

The anatomy of dyslexia
corpus callosumThe two hemispheres of the brain are connected by a large group of nerves running between them called the corpus callosum. Some years ago, there was an operation used for intractable epilepsy where this large nerve tract was severed so that epileptic fits could not spread through the whole brain but stayed in one hemisphere. Surgeons were surprised that patients could live normally after the operation. They only suffered “disconnection syndrome”. These patients are unable to compare sensory information presented to the different hemispheres. They are unable to name objects felt with the left hand, sounds heard with just the left ear, and odors perceived by only the left nostril. But they had no confusion or problems carrying on with their lives.

There are people born without a corpus callosum, but those without other malformations of the brain, have practically no symptoms, not even the “disconnection syndrome”. This is thought to be because the brain uses other roundabout ways to communicate between the hemispheres with other, smaller, more ancient nerve tracts across the divide. This change in communication is possible in babies and very young children but not in adolescents or adults – too late for large changes then. There are also people born with parts of the corpus callosum missing and the rest of it normal. These conditions are called agenesis and partial agenesis of the corpus callosum.
No one knows that percentage of people are born with no corpus callosum or a partial one. This is because it is only diagnosed with a brain scan (or in autopsy). So it is not usually diagnosed unless there are other malfunctions of the brain that prompt a scan. Estimates of the frequency of normal people with faults in their corpus callosum vary of very low to surprisingly high – no figures are reliable at present.The corpus callosum is long in cross section and stretches from the front to the back of the brain, nestled between the two hemispheres fanning out into all of both hemispheres. At the front it connects the two frontal lobes, at the back it connects the primary optical areas. In between it connects every other pair of areas that have mirrored locations on the two hemispheres. With partial agenesis, it depends on which part of the corpus callosum is missing, which areas of the cortex are disconnected from their matching areas.
The place along the corpus callosum that is most interesting to me is near the middle and appears to be missing in dyslexia (at least the common phonologic type – the type I have). There is a question of what would be cause. It might be the lack of communication between the hemispheres by the corpus callosum fault or it may that the lack is in the cortex with the corpus callosum nerves being missing because there is nothing to connect.
cc nerves

The diagram shows a map of the areas connected: F frontal, M motor, Ss somatosensory, A auditory, T/P temporal/pariental, V visual. The diameter (and speed) of the fibres in different areas is indicated be the size of the circles. The motor and sensory fibres tend to be myelinated and fast, the association areas less so and the executive areas have extremely fine, tightly packed, slow, unmyelinated fibres. Of course this is not to scale; there are several hundreds of thousand fibres to fan out to all parts of the cortex.
Identifying whether there are missing bits of the corpus callosum is not easy. It cannot be done by size. Size is not clearly related to the number of fibres or the size of the cortex. All the fibres that are going to be present are present at birth, during childhood they are myelinated to increase speed and also pruned to some extent. Attempts have been made to find size differences in dyslexia but there is no pattern. The bundle is often bigger than normal but also often smaller. But it has been noticed that it has an unusual shape. Looking at this shape change has allow the missing part to be identified. The researchers took an average of some normal and some dyslexic corpus callosums; they scaled the results to be the same size at the two end sections (see a); they then found the part that needed to be added to make the two conform as well as they could (see b).
cc comparison

The missing bit is in the area usually called the posterior midbody/isthmus junction. This is the posterior midbody area where auditory areas connect and also the isthmus where the language areas in the superior temporal gyrus (Wernickes’ area, planum temporale) connect. This study was done with only right-handed subjects and controls. The area was identified on the average profile. Comparing back to the original shapes it was found the the posterior midbody gap was the most diagnostic of the extent of dyslexia. The posterior corpus callosum is massively myelinated during the time that normal readers learn to read and write. This does not happen in dyslexics and in children who remain illiterate for other reasons such as lack of schooling. Today we cannot decide whether the less developed corpus callosum is a cause for or a consequence of developmental dyslexia. It may even be either or both depending on the child.
It is thought that dyslexia as due to failure of acoustic discrimination – simply not hearing the fast changes characteristic of individual consonants, but instead relying on the slower changes characteristic of whole syllables.Another aspect is the asymmetry between the hemispheres. As well as communication between the hemisphere there is also a function of the corpus callosum in establishing asymmetry between the two sides. One hemisphere can suppress activity in the other and interfere with the development of some areas. This seems to happen in right-handed people so that the non-dominant hemisphere is smaller; in the left-handed the two hemispheres are more equal in size and function. This equality is found in a number of other conditions that have been found to involve problems with the corpus callosum. A left-handed dyslexic is likely to be different from a right-handed one.

Obesity 1
Most serious researchers disagree with much that is published in the mass media about obesity. The journalistic articles are popular with readers and they appear to be helpful to those trying to control their weight – but they mostly are not helpful and can even be harmful.
It is not being overweight that people die of – it is a number of conditions that are associated with being overweight – metabolic syndrome, diabetes, heart disease and many more. But some people are healthy as well as fat. It is also not clear how much metabolic syndrome causes obesity and how much obesity causes metabolic syndrome (probably both). It is not clear whether the association should be between obesity and disease or between inactivity and disease. Do joints get bad because of the weight they carry; or is the weight the result of lack of exercise on painful joints? The message that getting thin means getting health is generally wrong because losing weight the wrong way is more dangerous than staying fat. People should be being advised to lose weight very slowly and not by low calorie dieting alone. There should be smart eating, exercise, good sleep patterns and other changes as well.
In the press generally there is an undercurrent of moral disapproval of the overweight. In the extreme version, the fat have transgressed and must be punished. They offend by being ugly, lazy and undisciplined. They should be guilty, they should hide. They are probably the only people left in the world that it is politically correct to discriminate against and to publish hate language about.

Basic ignorance:
There is an idea that weight gain is a simple idea (calories in – calories out = calories stored). I have even heard someone say that it had to be true because it is the first law of thermodynamics. Nothing biological is that simple! Like Clinton we have to say, it depends on the definition of 'calorie', it depends on the definition of 'in', of 'out', and of 'stored'.
I have read this story from a number of sources. It is like other stories of mathematicians leaving the simplicity of physics for more complicated subjects. Here is highlights of Micheal Moyer's version:
...Carson Chow, a researcher at the National Institute of Diabetes and Digestive and Kidney Diseases, had no experience in the health sciences before he came to study the problem of why so many Americans are overweight. “I didn’t even know what a calorie was,” he says. … Chow relates the story of starting work at the institute—a division of the National Institutes of Health—and finding a mathematical model created by a colleague that could predict “how body composition changed in response to what you ate.” The problem, as Chow describes it, was that the model was complicated: “hundreds of equations. [We] began working together to boil it down to one simple equation. That’s what applied mathematicians do.” And what did Chow’s simple model reveal about the nature and causes of obesity? Basically, that we eat too much. “The model shows that increase in food more than explains the increase in weight.” Food in, fat out. Simple enough to be captured in a single equation. Unfortunately Chow’s outsider’s perspective on the obesity crisis isn’t really an outsider’s perspective at all: it is the physicist’s perspective. Physicists have a long history of marching into other sciences with grand plans of stripping complex phenomena down to the essentials with the hope of uncovering simple fundamental laws.... Chow’s conclusion is not just obvious—it’s a tautology.”
It was useless and explains nothing, because he didn't take into account that all calories are not the same, and many other not too subtle subtleties. So forget this idea. We are not talking about the difference between calories in and out. “The obesity crisis isn’t rocket science. It’s complicated.”
It is not just mathematicians that have too simple ideas – there are the nutritionists. In most countries the title 'nutritionist' is not a professional designation that implies any education or training. It is not protected by any legal professional regulating body. The term 'dietitian' is more restricted but there is no international convention about the nature of each countries use of the title (unlike doctor, nurse, surgeon, radiologist, medical technologist and so on, who get approximately the same education and job description everywhere). dietitians can have very little knowledge in some places.

When we read what a nutritionist says, we should also look at their actual qualifications and experience and judge their advice accordingly. This is also pretty good advice for anyone talking about food. Listener beware. and
 Not only may the authors of food advice be somewhat ignorant, they may also be bought. The American group Academy of Nutrition and Dietetics has a surprising list of benefactors: ConAgra, the National Cattlemen’s Beef Association, Kellogg’s, Mars, the National Dairy Council, Coca-Cola, Kraft Foods, Nestlé, PepsiCo, Cargill, MacDonalds, General Mills, Corn Refiners Association, the Sugar Association, the Meat Board. Many of the 74,000 members are not happy with this situation and feel the the sponsors are shaping the activities of the AND.
This situation is unfortunate because good advice on diet is needed now like never before.
When paleolithic skeletons are looked at they are tall, with good teeth and only rare signs of disease. Then when agriculture started we became shorter, with bad teeth and with signs of ill health and repetitive work. But not signs of overweight. In the industrial age, some of us got healthier and some didn't but still only a few very rich people became obese. Sometime shortly after the second world war there was a change and we have been getting heavier ever since, and with increasing speed. What happened in the early 50s? I would guess it was more cars, home heating/cooling, and cheap refined sugar. It simply took much less energy to live our lives and more processed food was available. But there were also other changes: pollution, lights into the night/less sleep, advertising of food and so on. It is likely that those that were genetically disposed to gain weight were the first to become obese. But today almost everyone is running the risk. The cure is not just to lose weight. Even after successful weight loss, there are still problems. Some obese people can't fully recover. Something has changed in their metabolism. What has changed is the immune system and its interaction with metabolism. Fat cells have come to produce inflammation and inflammation damages organs.
The science
One thing that has been shown scientifically over and over is that most people can lose weight on a variety of diets, this is not the problem. The problem is that this weight is almost always regained, with a little more for good measure. How weight is gained, lost or maintained is very complex: it involves many biochemical pathways, many genes, many hormones, many parts of the body. It is not fully understood but there are some signposts.
I have just been going through all the reports I had collected on obesity to cut down on computer space and get some order. I am sharing the results in two goes. Here, first I am avoiding the diet and exercise area and giving a look at some other scientific papers.
Timing of eating & biological clock
   Eating during the rest period (night-eating syndrome) causes weight gain. (Stunkard 1955)
   When the time of eating is inappropriate, the fatty acids EPA and EHA (ie fish oil unsat fats) are low and therefore do not signal the hypothalamus and brain's control of fat storage fails. (G Paschos 2012)
   Scientists have synthesized a pair of small molecules that dramatically alter the core biological clock in animal models through REV-ERB, highlighting the compounds' potential effectiveness in treating a remarkable range of disorders -- including obesity, diabetes, high cholesterol, and serious sleep disorders. (L. Solt 2012)
   Insulin action shows a circadian rhythm and mice are most resistant to insulin during their inactive phase. Disruption of the circadian clock redisposes animals to obesity. (S Shi 2013)
   People working shifts have more difficult weight control problems.
Quitting smoking
   Quitting smoking increases weight. After 3 months gain is 4-22%, after 6 months 5-35%. Quitters show increase insulin secretion and an unconscious increase in carbohydrate intake. Insulin resistance is seen in the first 3 months but not by 6 months. These changes probably explain the immediate weight gain but not the long term increase. (M. Stadler 2012)
   Meta-analysis of 62 studies estimates the average weight gain in the year after quitting was about 10 pounds, approximately half in the first two months. Those taking action about weight gain, had less gain in the first months but the same amount by one year. People using bupropion, nicotime replacement, varenicline gained the same weight as those not treated with pharmacotherapy. (H Aubin 2012)
Gut flora
  Obese people tend to have different microbes in their intestines. In animal tests, the microbes from obese animals were shown to increase food intake, weight gain and obesity. They changed the actions of the intestinal nutrient sensors and levels of some gut peptides resulting in changes in response to eating. So the animal gains more weight from what it eats, eats more if available and does not sense and respond to food properly. (F. Duca 2012)
   26 species of gut bacteria are linked to obesity, metabolic syndrome, increases in blood triglyceride, cholesterol, glucese, C-reactive protein. Direction of causation was not established, just correlation. (M Zupancic 2012)
  Organotins and endocrine disruptors are environmental obesogens by interfering with nuclear receptor signaling. (F Grun 2006).
   Environment chemicals contributes to obesity and diabetes. Exposure to obesogens especially when young can influence fat distribution, the use of fat, and the synthesis of fat. (K Thayer 2012)
   Obesogens affect fat metabolism: organotins (marine paints, plastics, pesticides), bisphenol A (plastics), phthalates (plastics), perfluoroalkyll compounds (water repellant fabrics, stain preventing treatment) byproducts of smoking, pharmaceuticals. (K Thayer 2012)
   When studying endocrine-disrupting chemicals and lab animals got unusually fat. Endocrine Society definition “An endocrine-disrupting substance is a compound, either natural or synthetic, which through environmental or inappropriate developmental exposures alters the hormonal and homeostatic systems that enable the organism to communicate with and respond to its environment." Obesogens mimic hormones. Studies link exposure during fetal or infant development to later weight. (W Holtcamp 2012)
   Smoking during pregnancy linked to obesity in children (Oken 2008).
   Some evidence for an endocrine-disrupting chemicals on adult weight (Tang-Peronard 2011)
   Found in: medical devices, some canned foods, cash register receipts, designer handbags, items made of Gore-tex(TM), wallpaper, vinyl blinds, tile, and vacuum cleaner dust, air fresheners, laundry products, personal care products, items with Scotchgard(TM) (e.g. carpets, furniture, and mattresses), non-stick cook-ware, and microwaveable food items. There are also potential dietary obesogens including phytoestrogens (soy) (Diamanti-Kandarakis 2009)
  Effects from MSG, monosodium glutamate. (Holtcamp 2012)
  Note: the link between these chemicals and obesity is not yet proven but only indicated/correlated.
   Debate: Frayling says body mass index is strongly genetic (up to 70%). One gene variant has stronger effect on sedentary people. Genetic factors may operate largely through appetite control. "If true, plans based on changing our environment, such as banning the sale of supersized sugary drinks, may be more successful than plans to increase awareness through education." Wilding says there is a genetic role but the rapid increase in obesity recently cannot be due to genetics. The environmental change is overwhelming. Both agree that changes to the environment are the only way to tackle the problem.(Frayling and Wilding debate 2012)
In a study of animals living around humans: lab animals, feral animals, pets, urban wildlife, totaling 20,000 animals, it was found that all 24 sets of records were becoming heavier. Some sets could be due to food or exercise but not all of them and the results were consistent across the sets. What could be the same for all these animals and humans? Light pollution, chemical pollution etc. Obesity is likely to have many causes. (Y. Klimentidis 2010)
  Animals exposed to the fine-particulate air pollution had larger and more fat cells in their abdominal area and higher blood sugar levels than did animals eating the same diet but breathing clean air. Fine particulates directly cause inflammation and changes in fat cells, both of which increase the risk for Type 2 diabetes. (X Xu 2010)
   Exposure to tolylfluanid, a common anti-fungicide, induced insulin resistance in fat cells, which play a critical role in regulating the body's blood glucose and fat levels. It also resulted in more fat storage in the cells (Endocrine Society 2012)
   A great number of studies are now showing that people with high concentrations of persistent organic pollutants in their body are developing metabolic syndrome. These are people live ordinary lives so there is likely to be a combined "cocktail effect". Safe limits are too high. ( Research Council of Norway 2012)
From about 30 onwards some hormone levels change and progressively favour weight gain. (Culler 2012)

Obesity 2
I have not had time recently to finish my ordering of information of obesity (I will finish it soon). But I have read an interesting article about theories of obesity. In essence he says we should, just for once, look at an alternative hypothesis – we get fat because our metabolism is protecting fat accumulation; therefore we are undernourished for other energy uses; therefore we are hungry and lethargic – and it is likely that the effect of carbohydrates in the diet on insulin levels is the basic cause of the protection of fat accumulation. Here is the ScienceDaily review of the Gary Taubes' essay that appeared in the British Journal of Medicine.
What Really Makes Us Fat? Article Questions Our Understanding of the Cause of Obesity
The science of obesity: what do we really know about what makes us fat? If we are to make any progress in tackling the obesity crisis, we have to look again at what really makes us fat, claims a new article.
Gary Taubes, co-founder of the Nutrition Science Initiative, argues that our understanding of the cause of obesity may be incorrect, and that rectifying this misconception is "absolutely critical" to future progress.
"What we want to know," he says, "is what causes us to gain weight, not whether weight loss can be induced under different conditions of semi-starvation."
The history of obesity research is a history of two competing hypotheses of energy balance and endocrinology, writes Taubes. Since the 1950s, conventional wisdom on obesity has been that it is caused by a positive energy balance -- in other words we get fat because we overeat. The alternative hypothesis -- that obesity is a hormonal or regulatory disorder -- was dismissed after the second world war as being unworthy of serious attention.
But Taubes believes that the wrong hypothesis -- energy balance -- won out and that it is this hypothesis, along with substandard science, that has fuelled the obesity crisis and the related chronic diseases.
He argues that attempts to blame the obesity epidemics worldwide on increased availability of calories "typically ignore the fact that these increases are largely carbohydrates" and, as such, these observations "shed no light on whether it's total calories to blame or the carbohydrate calories."
Nor do they shed light on the more fundamental question of whether people or populations get fat "because they're eating more, or eat more because the macronutrient composition of their diets is promoting fat accumulation … in effect, driving an increase in appetite."Taubes also points to "substandard" research that is "incapable of answering the question of what causes obesity."
As a result, he has co-founded the Nutrition Science Initiative, a not-for-profit organisation to "fund and facilitate rigorously well controlled experimental trials, carried out by independent, sceptical researchers." Our hope, he says, is that these experiments will answer definitively the question of what causes obesity, and help us finally make meaningful progress against it.
If we are to make progress in the struggle against obesity and its related chronic diseases, he believes we must accept the existence of alternative hypotheses of obesity, refuse to accept substandard science, and find the willingness and the resources to do better.
"With the burden of obesity now estimated at greater than $150bn (£100bn; €118bn) a year in the US alone, virtually any amount of money spent on getting nutrition research right can be defended on the basis that the long term savings to the healthcare system and to the health of individuals will offset the costs of the research by orders of magnitude," he concludes.

Obesity 3
Does obesity cause cardiac problems? Strong associations have been found previously, but it has not been clear whether it was overweight as such that was the cause, or if the overweight was just a marker of another underlying cause. Or even whether the cardiac problems cause the overweight. This is not easy to resolve. The association is clear – obesity is a risk factor for cardiac problems – but it is not clear if it is a direct cause of heart disease. This sort of question can not be answered easily by experimental random trials on humans for ethical reasons. Epidemiological studies can only give evidence of association and not cause. There is another way called Mendelian randomization studies.
First the researchers have to find a gene variant that effects obesity but does not also do anything directly to cardiac health. Assumptions are made about the gene variant being random in the population and not associated with any other gene variant or life style etc. that could associate it indirectly with cardiac health. Then the researchers simply measure the association of the gene variant with heart disease. As the heart disease cannot be the cause of the gene variant, and the assumptions have ruled out an association between the gene variant and heart disease, therefore if there is an association it must be the gene variant causing obesity and obesity causing the heart disease. Confidence in this method depends on whether the assumptions can be trusted.
I find this somewhat wooly. We know less about the genetics of either obesity or heart disease than we do about their physiology (and that is a pool of ignorance). That does not make me very confident. This is a study that looks impressive with over a 130 authors on the paper from all over the world and 200,000 subjects tested in 35 separate studies. The scientists studied whether a gene variant in the FTO gene, which regulates the appetite and thereby increases the individual's BMI, is also linked to a series of cardiovascular diseases and metabolism. They conclude that obesity contributes causally to heart failure, increases in liver enzymes, higher insulin values, higher blood pressure, worse cholesterol values, increased markers of inflammation, increased risk of diabetes. The question is – do they know exactly how the gene regulates appetite and whether that is the only thing it does? The authors say, “we acknowledge that although FTO (the gene) is one of the most well-studied obesity loci, and there are credible hypotheses for its action on adiposity (obesity) by increasing the appetite, the precise mechanism of the FTO polymorphisms (the effects of different variants) is still unclear, and potential pleiotropy (multiply functions of a gene) cannot completely be ruled out. It has, however, been demonstrated previously that FTO is not associated with the most obvious potential confounders, such as smoking and drinking habits, income, or education.” So there we have it: causal contribution indicated but not proven.
At more or less the same time as this study was published, so was another. This was a long-term study of heart disease in people with type2 diabetes. The question was would weight loss decrease the incidence of heart failure? In this case 16 locations study 5000 people for over 11 years. The subjects were divided randomly into two groups: one was giving intensive support in losing weight and the other was give other support. The group that was coached to lose weight did so and maintained the loss while the control group did not.
The study reached the definite conclusion that there were no differences between the two groups in cardiovascular disease rates. The failure of weight loss to reduce the risk of heart disease in obese diabetic subjects was clear. Perhaps the weight loss was not enough (it averaged 6%) or the damage to the heart was already done or perhaps the obesity and the heart disease are not causally related. That applies to only a very small subset of the population. So the lack of a causal contribution was indicated but not proven especially for the general population.
The whole area is still up in the air. There is an association between a number of conditions involving the heart, liver, insulin, fat etc. - they occur together. The number of things involved in the regulation of these systems is enormous and the relationships are complex. What causes what under what conditions is still a mystery.

Obesity4 – Fat and immunity
This is based on some interesting observations by Lucas Tafur on the relationship between fat and immunity:
Obesity is a metabolic disease. It is the result of a positive energy balance for a prolonged time – that is its proximate cause but not its ultimate cause. Obesity can be eliminated by restricted calories and/or increased exercise. But this loss of weight does not solve the cause of obesity in the first place – that is its ultimate cause. The metabolic dysfunction remains in previously obese people and some can never fully recover. Obesity is just an obvious symptom of pathological insulin resistance and leptin resistance. It has now been found that the immune system is involved in the effects of obesity – there is an interplay between immunology and metabolism and this interplay is important in preventing and treating both metabolic and immune disorders.
Fat tissue (adipose tissue) is an organ of immunity. Here is a table of some of the chemicals produced primarily by fat cells.

Adipocytokine Effect on Inflammation Levels in obesity & Metabolic Effects
Adiponectin Anti-inflammatory
(decrease: NfkB, TNF, phagocytic activity, IFN-gamma; increase: IL-10, IL-1RA)
Decrease in obesity
(decrease: hyperglycemia, FFA, SREBP1c; increase: insulin sensitivity, beta-oxidation, AMPK)
Leptin Pro-inflammatory
(increase: TNF, IL-6, IL-12, CCL2, Th-1, IL-2, IFN-gamma, ROS, Chemotaxis, NK-cell function, lymphopoiesis, Thymocyte survival, T-cell proliferation; decrease: The, IL-4)
Increased in obesity
(increase: energy expenditure, satiety, insulin sensitivity)
Resistin Pro-inflammatory
(increase: NfkB, TNF, IL-6, IL-1, IL-12, CCL2, VCAM1, ICAM-1)
Increased in obesity
(increase: hepatic insulin resistance)
Visfatin Pro-inflammatory
(increase: IL-6, IL-8, IL-1beta, TNF, ICAM-1, IL-10, IL-1RA)
Increased in obesity
(decrease: insulin resistance)
Other cytokines secreted by adipocytes but not primarily by them: TNF-alpha, IL-6, IL-1, CCL2, PAI-1 Pro-inflammatory Increased in obesity

The immune cell types in adipose tissue have led to the proposal that fat is an ancestral immune organ and some T cells represent an evolutionary and functional bridge between the innate and adaptive immune systems.
The immune system affects the fat cells too. The cells differ with distance from lymph nodes and the ones nearest (perinodal cells) are smaller, contain more polyunsaturated and less saturated fatty acids, provide energy to the lymph nodes, are much more sensitive to cytokines and noradrenaline then other fat cells.
The fatty acid composition of diet affects the relationship between fat and lymph nodes.
There are innate immune cells in fat tissue and, in fact, adipocytes and macrophages are similar cells that arise from the same precursors. Fat tissue can therefore produce both adipocytes and macrophages.
Immature and mature fat cells have receptors for recognition of pathogens and other patterns. The receptors trigger the secretion of IL-6 and other inflammatory chemicals. Mutant mice without these receptors are protected for obesity and insulin resistance.
There are two types of macrophages: M1 have an inflammatory response and M2 stimulate tissue repair. Thin people have more type 2 macrophages and obese people have more type 1. TH2 cytokines control the ratio of M2:M1. There are also changes in natural killer cells and natural killer T cells (in both number and activity) in obesity.
Take away thought: obesity is not simply or easy to cure; and, obesity and immune disease can be closely linked.

fat shapes
Trans fats
Trans fats have a different shape then other unsaturated fats. The shape is closer (but not identical to saturated fats.) Unsaturated cis fats have a kink which makes them more mobile and liquid. Saturated fats are straight and can pack together more easily and so they tend to be solids. Unsaturated trans fats also tend to be solid.
Saturated fat has no double bonds; unsaturated fats have one or more double bonds with the missing hydrogen atoms on the same side of the bond; trans fats have one or more double bonds with at least one with the missing hydrogen atoms on the opposite side of the bond. Trans fat are made chemically in a factory with no control over the placement of the added hydrogens. Natural unsaturated fats are made by enzymes in biological cells and control the placement of the hydrogens. (There are some specific trans fats found in low amounts in some natural foods.)
The problem with trans fats is that they are not easily broken down by ordinary enzymes. This is why they resist going bad and are so handy for the food industry. But they are not good for our bodies and we should avoid them. Avoid anything containing trans fat or the phrase 'partially hydrogenated fat'. Really - saturated fat is much better than trans fat. Natural (cis) unsaturated fat is much better yet.
cholesterol graphLook at what trans fat does to cholesterol – bad cholesterol goes up and good cholesterol goes down as trans fat replaces cis fat. (Saturated fat does a similar thing with bad cholesterol but actually increases the good cholesterol.) Trans fat has been associated with clogged arteries, heart attack and stroke. It is also suspected in female infertility, depression, obesity, liver disease, diabetes, breast cancer and alzheimers. They are difficult for the body to burn for energy.
I remember when there was first a scare about butter and my mother tried to convince me to use soft margarine instead of butter. She changed but I never did. I reasoned that something made in a reaction vessel was not going to be as good as something made in a dairy from milk. Instead I just used less butter when I used it, and replaced it with vegetable oil where possible. But I did not realize until a few years ago that I had to stop eating cookies and the like that had a long shelf life because they tended to contain trans fats. Best to forget about cookies, read the labels carefully, or make your own.

Some food myths are true
There seems to be a rash of articles on the web with titles like “Food Myths...” and the first myth they are anxious to bust is that there is a problem with high fructose corn syrup. The message is given in more or less the same words. I suspect that the HFCS producers have distributed a message to people who write about food/nutrition. The message is the same (1) HFCS is the same as sucrose (2) fructose does not act any different in the body to other sugars (3) it is calories and not specific foods that causes obesity and insulin resistance (4) HFCS is a 'natural' food.
This is misleading. (1) sucrose is glucose and fructose that is chemically bonded together while HFCS is free glucose and fructose often (but not always) in approximately the same ratio. So goes the myth busters – sucrose and HFCS are the same. The difference is that sucrose has to be digested into glucose and fructose before they can be absorbed into the blood stream; sucrose does not enter the blood stream. Therefore the sugars in HFCS are absorbed faster and over a short time then the sugars in sucrose which is digested over a period of time. This means that HFCS has a higher glycemic index. This is an important difference. HFCS is also more soluble and therefore can be used in higher concentrations and it can be made to taste sweeter (but producers say it isn't but is formulated to be exactly the same sweetness as sucrose – so they say). (2) Indeed, the absorbing and metabolizing of fructose is similar to glucose. However more fructose goes into making fats and less into glycogen giving higher blood lipids. Fructose also has a different effect on insulin, leptin and ghrelin. So it is different in its effect on the amount of lipids, insulin resistance and appetite. (3) it is definitely not the amount of calories that determines weight gain – this is the real 'myth'. (4) whether HFCS is natural depends on what is meant by natural. It is as natural is most things on the market, but that doesn't mean it is OK in large amounts.
There has been a problem with the science. Many experiments show the HFCS increases abdominal fat, and causes insulin resistance in animals and humans. But there are also experiments that show it has no effect. The results depend on a lot of things: whether eating is limited to some calorie value or not, how much HFCS is used and the fructose % in the HFCS; the length of the experiment; what the control group eats; the amount and type of exercise; and the like.
Finally someone is shining some light on the subject. A team of 20 researchers at Colorado University have just published a paper in Nature. They show that we also make our own fructose in the liver as well as getting it from what we eat. When we eat glycemic foods (foods that result in a fast rather than slow rise in blood glucose) the liver converts much of the glucose into fructose (presumably to dampen the rise in glucose). Both the fructose from food and the fructose made in the liver have the effect of causing insulin resistance and that resistance causes obesity and other aspects of metabolic syndrome. It is also a cause of fatty liver and high blood lipids. It increases the appetite. This it is why refined sugars and carbohydrates cause obesity – they are very glycemic. Fructose itself is not very glycemic (even thought HFCS is). But fructose is damaging in large amounts and even if we do not eat much of it, we can still make enough to do damage. Its damage leads to weight gain and other problems.
The take home message is first to avoid high glycemic index foods, second avoid additional fructose, third avoid high calorie intake. Some 'myths' are true.

Phonological awareness
Here is the material from a phonological awareness test used to assess and follow the progress of children who may have a problem with reading. It is interesting that it puts a clear finger on the problems that dyslexics have with individual sounds. It illustrates the problem well.
“The 2000 report of the National Reading Panel defines phonemic awareness as the ability to focus on and manipulate phonemes in spoken words. The Put Reading First publication describes phonological awareness as a broad term that includes phonemic awareness. Phonological awareness activities can involve work with phonemes, rhymes, words, syllables, and onsets and rimes. ”
The test is given orally and so can be used for pre-school children as well as children that are learning to read. Remember when you look at this tests that the child being tested probably has perfectly normal oral language (listening, understanding and speaking) and yet may fail this test badly. If you can understand this then you can imagine what the dyslexic is dealing with. This test on pre-schoolers is a very good predictor of dyslexia found later. And these are exactly the skills that dyslexics need to learn in order to overcome their problem.
In the tests and remedial instruction for older, schooled children there is an introduction of written elements, but these do not identify the root of the problem. They do help with reading and writing preformance:
Graphemes—Given a printed letter, say the sound the letter(s) represents (consonants, vowels, consonant blends, consonant digraphs, r-controlled vowels, vowel digraphs, and diphthongs).
Decoding—Generalize knowledge of sound/symbol correspondences to blend sounds into unknown words.
Invented Spelling (optional)—Write words to dictation to show encoding ability but not conventional spelling ability.

Phonological Awareness – Rhyme Identification
Directions: This test should be administered individually to students. The teacher could introduce the test by saying, “Two words rhyme when they sound alike at the end. I am going to read two words; I want you to tell me if they rhyme or do not rhyme.”
Practice Items: Help the student identify when two words rhyme by using the following practice items. Create additional practice items as needed.
sit – bit
boy – chair
Test Items: Read each pair of words. Mark those items that the student answers correctly. Create additional lists as needed.
1. bed – fed _____ (yes)
2. top – hop _____ (yes)
3. run – soap _____ (no)
4. hand – sand _____ (yes)
5. funny – bunny _____ (yes)
6. girl – giant _____ (no)
7. lid – hid _____ (yes)
8. mess – yell _____ (no)
9. fell – fun _____ (no)
10. skip – hip _____ (yes)
Phonological Awareness – Rhyme Production
Directions: This test should be administered individually to students. The teacher could introduce the test by saying, “I am going to tell you a word and I want you to tell me a word that rhymes with it.” (The answers may be real or nonsense words)
Practice Items: Help the student identify when two words rhyme by using the following practice items. Create additional practice items as needed.
sun... __________
cat... __________
Test Items: Read each word and allow the student to respond. Write the word that the student responds with on the line. Mark those items that the student answers correctly with a rhyming match. The answer may be a real word or a nonsense word. Create additional lists as needed.
1. pain __________
2. cake __________
3. hop __________
4. see __________
5. dark __________
6. candy __________
7. fun __________
8. hair __________
9. row __________
10. sip __________
Phonological Awareness – Syllable Blending
Directions: This test should be administered individually to students. The teacher could introduce the test by saying, “I am going to say a word in a funny way. I want you to put the parts together and say the whole word.”
Practice Items: Help the student identify syllable blending with the following practice items. Create additional practice items as needed.
ro-bot : “robot”
out-side : “outside”
Test Items: Read the parts of the word with a pause between each syllable. Mark those items that the student answers correctly. Create additional lists as needed.
1. black - board _____
2. rain - bow _____
3. pop - corn _____
4. side - walk _____
5. pen - cil _____
6. hon - ey _____
7. pic - ture _____
8. pa - per _____
9. riv – er _____
10. can - dle _____
Phonological Awareness – Syllable Segmentation
Directions: This test should be administered individually to students. The teacher could introduce the test by saying, “I am going to say a word and I want you to break it into parts or syllables.”
Practice Items: Help the student identify how to break a word into syllables by saying a word normally and then clapping out the parts of a word while saying each part. Use the following practice items. Create additional practice items as needed.
cowboy (cow - boy)
candy (can - dy)
Test Items: Read each word. Allow the student to clap each syllable in the word. Mark those items that the student answers/claps correctly. Create your own or additional lists as needed.
1. sometime _____ (2)
2. basket _____ (2)
3. bedroom _____ (2)
4. kite _____ (1)
5. bag _____ (1)
6. carpet _____ (2)
7. computer _____ (3)
8. sunflower _____ (3)
9. fantastic _____ (3)
10. helicopter _____ (4)
Phonological Awareness – Syllable Deletion
Directions: This test should be administered individually to students. The teacher could introduce the test by saying, “We are going to play a word game. Say CUPCAKE (allow the student to respond). Now say it again, but don’t say CUP.”
Practice Items: Help the student identify how to delete a syllable from a word by saying a word normally and then asking them to say it again but don’t say ___. Use the following practice item. Create additional practice items as needed.
Say AIRLINE. Now say it again, but don’t say AIR.
Test Items: Read each item and allow the student to respond. Mark those items that the student answers correctly. Create your own or additional lists as needed.
1. Say DOWNTOWN. Now say it again, but don’t say TOWN. (down) _____
2. Say INSIDE. Now say it again, but don’t saw SIDE. (in) _____
3. Say FORGET. Now say it again, but don’t say FOR. (get) _____
4. Say BASKET. Now say it again, but don’t say BAS. (ket) _____
5. Say AFTER. Now say it again, but don’t say AF. (ter) _____
6. Say SKATEBOARD. Now say it again, but don’t say BOARD. (skate) _____
7. Say PERFUME. Now say it again, but don’t say FUME. (per) _____
8. Say CANDY. Now say it again, but don’t say DY. (can) _____
9. Say COWBOY. Now say it again, but don’t say COW. (boy) _____
10. Say BOWTIE. Now say it again, but don’t say TIE. (bow) _____
Phonological Awareness – Phoneme Identification
Directions: This test should be administered individually to students. The teacher could introduce the test by saying, “I am going to say some words; I want you to tell me the sound that is the same in all the words.”
Practice Items: Help the student identify the same sound found in each word with the following practice items. Create additional practice items as needed.
cat, car, cap : “What sound is the same in all the words? I hear /c/ in all three words.”
hop, sip, lap : “What sound is the same in all the words? I hear /p/ in all three words.”
Test Items: Read the list of words and allow the student to respond. Mark those items that the student answers correctly. Create your own or additional lists as needed.
1. fix, fall, fun _____ /f/
2. me, milk, mom _____ /m/
3. ship, shop, share _____ /sh/
4. dig, dog, do _____ /d/
5. fit, mat, lot _____ /t/
6. lip, flap, cap _____ /p/
7. chair, cheese, chalk _____ /ch/
8. see, bee, me _____ /ee/
9. like, click, sick _____ /k/
10. fish, crash, dish _____ /sh/
Phonological Awareness – Phoneme Isolation (initial)
Directions: This test should be administered individually to students. The teacher could introduce the test by saying, “I am going to say some words; I want you to tell me the first sound that you hear in the word.”
Practice Items: Help the student identify the initial sound of a word with the following practice items. Create additional practice items as needed.
dog – “The first sound that I hear in the word dog is /d/.”
Test Items: Read each word and allow the student to respond. Mark those items that the student answers correctly. Create additional lists as needed.
1. big _____ /b/
2. land _____ /l/
3. farm _____ /f/
4. apple _____ /a/
5. desk _____ /d/
6. ship _____ /sh/
7. man _____ /m/
8. help _____ /h/
9. then _____ /th/
10. truck _____ /t/
Phonological Awareness – Phoneme Isolation (final)
Directions: This test should be administered individually to students. The teacher could introduce the test by saying, “I am going to say some words; I want you to tell me the last sound that you hear in the word.”
Practice Items: Help the student identify the final sound of a word with the following practice item. Create additional practice items as needed.
dog – “The last sound that I hear in the word dog is /g/.”
Test Items: Read each word and allow the student to respond. Mark those items that the student answers correctly. Create your own or additional lists as needed.
1. pick _____ /k/
2. ran _____ /n/
3. fill _____ /l/
4. bug _____ /g/
5. same _____ /m/
6. tooth _____ /th/
7. fish _____ /sh/
8. hop _____ /p/
9. case _____ /s/
10. jar _____ /r/
Phonological Awareness – Phoneme Blending
Directions: This test should be administered individually to students. The teacher could introduce the test by saying, “I am going to separate the sounds of a word and I want you to tell me what word it is.”
Practice Items: Help the student identify how to blend phonemes with the following practice items. Create additional practice items as needed.
“/s/ /i/ /t/ is what word? SIT”
“/s/ /t/ /o/ /p/ is what word? STOP”
Test Items: Read the sounds of a word and allow the student to respond. Mark those items that the student answers correctly. Create additional lists as needed.
1. /m/ /ee/ _____ (me)
2. /b/ /e/ /d/ _____ (bed)
3. /h/ /a/ /t/ _____ (hat)
4. /m/ /u/ /s/ /t/ _____ (must)
5. /sh/ /o/ /p/ _____ (shop)
6. /p/ /l/ /a/ /n/ /t/ _____ (plant)
7. /s/ /t/ /o/ /p/ _____ (stop)
8. /f/ /l/ /ow/ /er/ _____ (flower)
9. /l/ /u/ /n/ /ch/ _____ (lunch)
10. /s/ /t/ /r/ /a/ /n/ /d/ _____ (strand)
Phonological Awareness – Phoneme Segmentation
Directions: This test should be administered individually to students. The teacher could introduce the test by saying, “I am going to say a word; I want you to tell me all of the sounds that you hear in that word.”
Practice Items: Help the student identify how to segment phonemes in a word with the following practice item. Create additional practice items as needed.
“DIM, I hear the sounds /d/ /i/ /m/.”
Test Items: Read each word and allow the student to respond. Mark those items that the student answers correctly. Create additional lists as needed.
1. in /i/ /n/ _____ (2)
2. at /a/ /t/ _____ (2)
3. name /n/ /ae/ /m/ _____ (3)
4. ship /sh/ /i/ /p/ _____ (3)
5. sock /s/ /o/ /k/ _____ (3)
6. chin /ch/ /i/ /n/ _____ (3)
7. sand /s/ /a/ /n/ /d/ _____ (4)
Phonological Awareness – Phoneme Deletion
Directions: This test should be administered individually to students. The teacher could introduce the test by saying, “I am going to say a word and then have you say that word without one of the sounds.”
Practice Items: Help the student identify how to delete phonemes in a word by using the following practice item. Create additional practice items as needed.
“Say GOAT. Now say it again without the /t/.” (go)
Test Items: Read each item and allow the student to respond. Mark those items that the student answers correctly. Create additional lists as needed.
1. Say ROSE, now say it again without /z/ _____ (row)
2. Say TRAIN, now say it again without /n/ _____ (tray)
3. Say GROUP, now say it again without /p/ _____ (grew)
4. Say SEAT, now say it again without /t/ _____ (sea)
5. Say BAKE, now say it again without /k/ _____ (bay)
6. Say INCH, now say it again without /ch/ _____ (in)
7. Say SMILE, now say it again without /s/ _____ (mile)
8. Say FEET, now say it again without /f/ _____ (eat)
9. Say BOAT, now say it again without /b/ _____ (oat)
10. Say LAKE, now say it again without /l/ _____ (ache)
Phonological Awareness – Phoneme Addition
Directions: This test should be administered individually to students. The teacher could introduce the test by saying, “I am going to say a word and then have you say that word with one extra sound.”
Practice Items: Help the student identify how to add phonemes to a word by using the following practice item. Create additional practice items as needed.
“Say PARK, now say it again with /s/ in front of it.” (SPARK)
Test Items: Read each item and allow the student to respond. Mark those items that the student answers correctly. Create additional lists as needed.
1. Say TOP, now say it again with /s/ in front of it _____ (stop)
2. Say LIP, now say it again with /f/ in front of it _____ (flip)
3. Say EAT, now say it again with /m/ in front of it _____ (meat)
4. Say LAP, now say it again with /c/ in front of it _____ (clap)
5. Say TRAP, now say it again with /s/ in front of it _____ (strap)
6. Say RUST, now say it again with /t/ in front of it _____ (trust)
7. Say LAY, now say it again with /p/ in front of it _____ (play)
8. Say EAT, now say it again with /sh/ in front of it _____ (sheet)
9. Say ROBE, now say it again with /p/ in front of it _____ (probe)
10. Say LOT, now say it again with /s/ in front of it _____ (slot)
Phonological Awareness – Phoneme Substitution
Directions: This test should be administered individually to students. The teacher could introduce the test by saying, “I am going to say a word and some sounds to switch, then I want you to say the new word.”
Practice Items: Help the student identify how to substitute phonemes in a word with the following practice item. Create additional practice items as needed.
“Say BUG, now change /g/ to /n/. What is the new word?” (BUN)
Test Items: Read each item and allow the student to respond. Mark those items that the student answers correctly. Create additional lists as needed.
1. Say MAN, now change /m/ to /c/ _____ (can)
2. Say PIG, now change /p/ to /d/ _____ (dig)
3. Say SACK, now change /s/ to /t/ _____ (tack)
4. Say WELL, now change /w/ to /f/ _____ (fell)
5. Say BED, now change /b/ to /r/ _____ (red)
6. Say SHOP, now change /sh/ to /ch/ _____ (chop)
7. Say HOT, now change /h/ to /p/ _____ (pot)
8. Say TAP, now change /t/ to /c/ _____ (cap)
9. Say LIVER, now change /l/ to /r/ _____ (river)
10. Say MILE, now change /m/ to /p/ _____ (pile)

Alzheimers news
The pharmaceutical industry has spent billions of dollars on futile clinical trials directed at treating Alzheimer's disease by ridding brains of a substance called amyloid plaque. After the disappointment of the drug tests and the weakening of the theories behind these drugs, there seems to be a change of course. Many new theories are being investigated and perhaps some will yield treatments. The main source of the new theories are publicly funded pure science labs. Here is a sample.
Unfolded protein response
One theory is that the production of misfolded proteins causes all protein production to stop (the UPR or unfolded protein response). UPR is a defense against viral diseases where it is an advantage for cells infected with virus to die before a lot of virus particles are made in the cell. But in the case of diseases like Alzheimers (prion and prion-like diseases), the misfolding continues with the protein already made and therefore the UPR continues so that all the actually needed normal proteins are not made and the cell dies. An enzyme PERK is a key part of the UPR so interfering with PERK allows protein synthesis to continue and the cell to continue living. Researchers (GlaxoSmithKline & a Leicester Univ team) are looking at drugs to do this without side-effects etc. If this pans out it would be useful in other diseases too like Creuzfeldt-Jakob disease and Parkinsons. It doesn't stop the disease (not a cure) but stops one of the worst symptoms, cell death, and would be a continuous treatment.
Immunotherapy without full antibodies
One of the trials that was abandoned in its early stages was an antibody treatment to get rid of amyloid plaques. The problem was inflammation of the brain. By using only part, the most efficient part of the antibody molecule and one tailored for the oligomers rather than plaque, it seems that the inflammation can be avoided. The partial antibody works in tissue culture and in mice, protecting against cell death and clearing amyloid B oligomers. Researchers in the university in Barcelona, developed the theory and are working on improvements to the therapy.
Excessive pruning
Just stopping cell death is not going to protect cells from losing function, but blocking axon breakdown has a great benefit. Without the axon and dendrite branches there can be no signal communication between cells. Researchers at McGill in Montreal have looked at protecting the axons. There is a mechanism for pruning axons that is used in early development and neurodegenerative disease appears to reactivate this pruning. Key proteins in pruning are the executioner caspases and they are inhibited by XIAP. The researchers are trying to find therapies that reduce caspase-dependent degeneration occuring during neurodegenerative disease.
Alzheimers starts far earlier than thought
One of the reasons that previous attempts to remove plaque have not been successful is that the damage is being done long before there is any plaque. The theory is that beta-amyloid destroys synapses before it clumps. Wholesale loss of synapses in the disease gives a parallel deterioration in function, particularly memory. Beta-amyloid is not harmful as a single molecule or in large clumps (plaques). But in small soluble freely moving clumps it binds to a receptor on nerve cells and starts a process that destroys synapses. Stanford researchers using mice showed that beta-amyloid cluster binds to PirB (in humans the protein is called LilrB2) protein on the surface of the neurons close to synapses. This binding causes loss of synapses long before there are symptoms of memory loss or plaques. The mechanism may be an increase in the enzyme cofilin; colfilin breaks down actin a building-block of synaptic structure (and cellular transport); without actin, the synapses disappear. They found abnormal levels of cofilin in human Alzheimer brains on autopsy. They are looking at ways to stop the binding of beta-amyloid to the receptor.
Earlier diagnoses of Alzheimers is needed
It seems unlikely that Alzheimers can be successfully treated or cured unless it is caught early – before there are clear symptoms. New tests are needed. Here are three.
Cornell researchers have found a memory test that differentiates alzheimers from aging. Healthy aging has declines in recollective memory (words, events) while Cognitive impairment and Alzheimers has declines in reconstructive memory (piecing together clues to recall a word or event).
INRS researchers have developed a EEG protocol for differentiating between healthy individuals, those with mild Alzheimers and those with moderate disease. It is being tested and improved.
Researchers at Washington U at St. Louis compared the changes in spinal fluid that are reliable early indicators of Alzheimers (a rise in beta amyloid and a drop in tau) with fMRI scans of resting patients. Changes in the default network happen at the same time as changes in the spinal fluid. The scans are less invasive.
Too much excitation of synapses
Another theory was developed by researchers at the Salk and the Sanford-Burnham Institutes. They showed that in mice, binding of beta-amyloid to alpha7Rs receptors gave detrimental effects similar to Alzheimers. One of the signalling chemicals at synapses is glutamate - it is an excitatory neurotransmitter involved in learning and memory. Other brain cells, astrocytes, can also release glutamate. When beta-amyloid binds to alpha7 nicotine receptors it triggers astrocyes to release additional glutamate into synapses which over-excites them. This triggers eNMDARs to depress synaptic activity which is overdone. The depressed synapses lead to memory loss and confusion. A Lipton drug NitroMemantine may block the action of eNMDARs.
Blocking glutamate receptor with old drug
Beta-amyloids couple with prion proteins on neuron surfaces and this activates a messenger molecule, Fyn. A Yale group found a link in the chain was a glutamate receptor mGluR5 and when this was blocked by an existing drug (for Fragile X syndrome) the symptoms were reduced in a Mouse model of Alzheimers. The drug may have to be modified for human Alzheimers.
Defective trash-disposal
A Stanford team has compared microglia (the brain's equivalent of white blood cells) and found that those in Alzheimers patients are defective in trash disposal. The microglia have phagocytic receptors on their surface which recognize detritus, dead cells and toxins such a beta-amyloid, and the microglia eats this trash to remove it. In this process, the receptors are not destroyed by returned to the surface of the cell by a complex called retromer. Deficiencies in a protein called beclin impairs retromer. Beta-amyloid is cleared quickly from normal mice but takes much longer in beclin-deficient mice. Also, it was recently discovered that a rare mutation in a key phagocytic receptor that binds to beta-amyloid confers a three to four-fold additional risk for Alzheimer's disease.
Separately researchers from Rochester have connected copper levels with the efficiency of beta-amyloid removal. High levels of copper in the brain accelerates Alzheimers. Normally beta amyloid can be removed by a protein, LRP1, which lines the capillaries that supply the brain. LRP1 binds beta amyloid and escorts it into the blood vessels and away from the brain. High levels of blood copper can accumulate in the cellular walls of the capillaries of the brain – these cells normally prevent copper from entering the brain. The copper in the capillary walls disrupts the function of LRP1 and inhibites the removed of beta amyloid from the brain. This can go further and the capillary walls can become leaky (breakdown of the brain-body barrier) allowing copper to enter the brain. It then stimulates the creation of beta-amyloid. Copper is however an essential part of the diet and cannot be lowered too much.
Genetic markers indicate complexity
It may seem that only one of these theories could be right, but that is not so. The causes of the disease could be multiple and the course of it could be complex and varied. This is shown in the genetic data. Between 2009 and 2012, there were 10 genes identified that related to Alzheimers risk. Recently a huge program with contributors from around the world identified more – 11 new genes and 13 possible genes (now being verified) in addition to the 10 already known. The probable functions of these genes are interesting. “Some of the newly associated genes confirm biological pathways known to be involved in AD, including the amyloid (SORL1, CASS4 ) and tau (CASS4 , FERMT2 ) pathways. The role of the immune response and inflammation (HLA-DRB5/DRB1 , INPP5D , MEF2C ) already implied by previous work (CR1, TREM2) is reinforced, as are the importance of cell migration (PTK2B), lipid transport and endocytosis (SORL1 ). New hypotheses have also emerged related to hippocampal synaptic function (MEF2C , PTK2B), the cytoskeleton and axonal transport (CELF1 , NME8, CASS4) as well as myeloid and microglial cell functions (INPP5D).”

There is more news on Alzheimers theories that I will put in a later month.

More Alzheimers news
The problem with Alzheimers is getting critical. The average age at which people get the disease is falling and the percentage of people who get it at any age is rising. It is not an easy disease to live with, there are no effective treatments/cures, and it is very expensive for families and health systems. Here are some more new ideas to add to last month's.
Normal DNA repair disrupted
DNA damage of the type 'double-strand break' is part of the learning/memory process in neuron cells. But it is very tightly controlled and immediately repaired. Researchers at Gladstone Institutes found that beta amyloid increases the number of neurons with double-strand breaks and delays their repair. Mice with an Alzheimers-like condition have higher numbers of unrepaired DSBs then normal mice after a learning session. They found that levetiracetam, an anti-epileptic drug, deceased the DSBs in mice. Also mice without the gene for tau did not have excessive DSBs.
It is an epidemic
Pritchard of Bournmouth Univ thinks the cause is environmental – his group have been studying the stats world-wide. "This has to be speculative but it (the rise) cannot be genetic because the period is too short. Whilst there will be some influence of more elderly people, it does not account for the earlier onset; the differences between countries nor the fact that more women have been affected, as their lives have changed more than men's over the period, all indicates multiple environmental factors. Considering the changes over the last 30 years -- the explosion in electronic devices, rises in background non-ionising radiation - PC's, micro waves, TV's, mobile phones; road and air transport up four-fold increasing background petro-chemical pollution; chemical additives to food etc. There is no one factor rather the likely interaction between all these environmental triggers, reflecting changes in other conditions. For example, whilst cancer deaths are down substantially, cancer incidence continues to rise; levels of asthma are un-precedented; the fall in male sperm counts -- the rise of auto-immune diseases -- all point to life-style and environmental influences. These `statistics' are about real people and families, and we need to recognise that there is an `epidemic' that clearly is influenced by environmental and societal changes."
Tracking Tau
Researchers in Ohio are developing a way to image the buildup of tau in the brain. The chemical they are creating would attach to tau in the living brain and allow it to be see in scans. There are a number of conditions where tau accumulates but the buildup is in different places for different dementias. This would improve diagnosis, both accuracy and earliness. It would help with the development of drugs aimed to tau.
Early disruption of energy metabolism
Neurons in Alzheimers have difficulty with sugar, fat and calcium metabolism because the mitochondria do not function correctly and this leads to cell death. Mitochondria need to connect with the endoplasmic reticulum though an area called the MAM. Faulty proteins in the MAM stop the mitochrondria from delivering energy and the cell dies. Researchers at Karolinska Institute have found that normal neurons when they were exposed to beta amyloid increased in the number of contact points between the mitochondria and the ER, causing more calcium to be transferred from the ER to the mitochondria. The resulting over-accumulation of calcium is toxic to the mitochondria and affects their ability to supply energy to the nerve cell. This energy starvation would happen in the very early stages of Alzheimers.
Brain activity changes beta amyloid ratios
Beta amyloid comes in two types, called 40 and 42. Beta amyloid 42 is the dangerous type. Some brain activity can affect the ratio of 40 to 42. Tel Aviv Univ researchers have found that the transmission of 'spikes', high-frequency bursts of electrical activity in the hippocampus improves the 40/42 ratio. This sort of activity is needed in plasticity, information processing and memory encoding. This may be the reason for the 'use it or lose it' aspects of aging and Alzheimers. The change in ratio seems to involve the protein presenilin.
Dysfunction of the cell's transport system
Presenilin has been fingered before, as the 'classic' cause of Alzheimers. It is involved in producing beta amyloid and mutations in the presenilin gene are common in Alzheimers. It can snip off a 40 or a 42 length of beta amyloid.
It has further activities. Researchers in Buffalo have found that presenilin works with an enzyme, GSK-3beta, to control how fast materials move through the cells. Cargo is moved in little 'motorized' vesicles along tracks in the cell. Dyneins are the motors that carry vesicles towards the center of the cell and kinesins are the motors that carry them to the periphery of the cell. GSK-3beta attaches the motors to the track and switches them on. When the level of GSK-3beta is right, the traffic moves smoothly. When GSK-3beta levels are high, too many motors attach, leading to slow movement as motor activity loses coordination. Low GSK-3beta levels appear to have the opposite effect, causing fast, uncontrolled movement as too few motors latch on. The level of presenilin controls the GSK-3beta levels and therefore presenilin has to be just right, not too high or too low. This idea that the cause is the transport system in the cell is all fairly old – the 'classic' tau theory.
Hygiene Hypothesis
Cambridge researchers using carefully corrected statistics have shown that the relationship between cleaner environments and risk of autoimmune diseases (which is well established) can be extended to the risk of Alzheimers. This would imply that Alzheimers may be an autoimmune condition.
Stress affects on tau
Researchers from S Florida U have looked at why depression and anxiety accelerate Alzheimers. They found the stress related protein FKBP51 partnered with a chaperone complex prevents the clearance from the brain of the abnormal and toxic tau protein found in Alzheimers.
APP and BACE-1 convergence theory
California researchers wondered why we all don't have Alzheimers. They find that the enzyme and the protein that would cause Alzheimers if they came together, are kept apart. Understanding how the 'gunpowder and match' are separated would give ways to stop the disease. The signs of Alzheimers are beta-amyloid plaques outside the neurons and tau tangles inside. To make beta-amyloid the precursor (APP) has to be cut by an enzyme (BACE). Both these proteins are normally found in ample quantities in the brain. The APP and BACE-1 are normally segregated into distinct compartments as soon as they are made and do not contact one another. An increase in neuronal electrical activity (which is known to increase beta-amyloid) leds to an increase in APP-BACE contact.
Pre-diabetes in early Alzheimers
Many people with early Alzheimers have high blood sugar at pre-diabetic levels Georgetown researchers found. It is not clear which causes which or if they are both the result of some other condition (like high inflammation).
Some nutritional news
Plant sterols – Saarland Univ found that phytosterols, especially stigmasterol, inhibits proteins with a role in Alzheimers & lowers cholesterol. (nuts, seeds and plant oils)
Red wine – Bucks Institute found that resveratrol increases SirT1 which prevents the action of ApoE4 including the production of beta amyloid and phospho-tau.
Zinc – Madison researchers have found (in yeast) that low levels of zinc promotes mis-folding of proteins.
Iron – UCLA researchers are looking at accumulation of iron in the hippocampus which may be a risk factor in Alzheimers.
Aluminium – Shanxi Univ researchers have found that aluminium increases cell death in aging and neural degeneration.
Cinnamon – Cinnamaldehyde and epicatechin in cinnamon reduce tau tangles that are found in Alzheimers and are signs of the malfunction of the cell's transport system. They are also anti-oxidants.

Signs of stroke
There is a new test in the identification of stroke by friends, relatives and bystanders. The normal advice is called STR.
  1. Ask the person to smile. Should be symmetrical.
  2. Ask the person to TALK and speak a simple sentence. Should not be blurred.
  3. Ask them to raise both arms. Should be able to raise both together.
  4. (New) Ask the person to stick out their tongue. Should be straight and symmetrical.

If the person cannot do one of the tests, then phone emergency services immediately and describe the symptoms.

Yes or no to breakfast
Here is some advice from a website with good medical credentials. The things they are saying are backed up with research. But they are very conventional in their advice in general:
“But there's ample evidence that the simple act of eating breakfast -- every day -- is a big part of losing weight, lots of weight.”
"People skip breakfast thinking they're cutting calories, but by mid-morning and lunch, that person is starved. Breakfast skippers replace calories during the day with mindless nibbling, bingeing at lunch and dinner. They set themselves up for failure."
“Another research group analyzed government data on 4,200 adults. They found that regular breakfast eaters were more likely to exercise regularly. And women who ate breakfast regularly tended to eat fewer calories overall during the day.”.
“Eating early in the day keeps us from "starvation eating" later on. But it also jump-starts your metabolism. When you don't eat breakfast, you're actually fasting for 15 to 20 hours, so you're not producing the enzymes needed to metabolize fat to lose weight." (I would dispute the statement about not making enzymes during fasting – nutty.)
“breakfast eaters are usually those who have lost a significant amount of weight. They also exercise.”
“As for sugary cereals, it's better than nothing. Some breakfast is better than no breakfast. The last thing anyone should do is skip breakfast. Otherwise, you'll be eating something even worse later on - candy bars and potato chips -- because you're starving."
This is the yes-to-breakfast case. And I have some reservations about the science, for instance it is often funded by cereal companies and the like, but that is not too important – there is a lot of different data. If you are relatively young, active and healthy and not actually obese – than I am sure they are right, it is better to eat breakfast even if you are trying to loss weight. However, the message is not one the fits me.
The no-to-breakfast case is more limited:
For patients with diabetes, it is better to eat a single large meal than several smaller meals throughout the day. This is the result of a current dietary study at Linköping University in Sweden.
In the study the effect on blood glucose, blood lipids and different hormones after meals were compared using three different macronutrient compositions in patients with type 2 diabetes. The three diets were a low-fat diet, a low-carbohydrate diet and a Mediterranean diet. The scientists included 21 patients that tested all three diets in a randomized order. During each test day blood samples were collected at six time points. The total calorie intake for the day was the same for all the diets, but the Mediterranean diet had a breakfast that was a cup of black coffee only and a larger lunch than the other two. The ratio of carbohydrate to fat for the Mediterranean diet was between the other two diets, but the fat is from olive and fatty fish. Some of the calories in the Mediterranean diet came from red wine. All the participants were on all the diets for some period of time in random order. After meals blood glucose, blood lipid and hormones were tested. The results was (if you are type 2 diabetic or pre-diabetic) it is better to eat a single large Mediterranean meal later than have several smaller meals starting with a breakfast.
Now this in the only no-to-breakfast case as far as I know in the literature, but I have heard people who like me cannot do well on breakfasts. Even taking diabetics and pre-diabetics there is variation - when and what you eat also depends on what medication you are taking and when in the day you have to be active etc. etc. From my own experience, I do not get hungry, unless I eat something, until mid afternoon. During the morning I have more energy and drive than the rest of the day. If I eat breakfast I can forget about getting much done that day because I have so little energy and I am so ravenously hungry that I can barely concentration on anything but food. I would also have a be dragged to any exercise; unlike without breakfast when I am active. It is OK to have a big breakfast Christmas morning because I can do nothing for the rest of the day but munch on nuts. If I am losing weight I absolutely must have no breakfast or a very small one. Those people who say that EVERYONE who wants to lose weight should eat breakfast are doing a disservice to some of the people who need to lose weight the most, those on the road to obesity through diabetes and pre-diabetes.

structureProtein diagrams
Proteins have a complex structure that is diagrammed in a convention that makes that structure visible and produces some lovely designs. There are at least 4 stages in a protein getting to its final structure.
Primary structure: the bonded string of amino acids in the order specified by the gene for that protein – It would be like a mess of spaghetti. There can be little additions and connections between some amino acids other than the straight long string but they are all strong covalent bonds.
Secondary structure: The units of amino acid can form a couple of structures using hydrogen bonding which is weaker than covalent. The most common secondary structure types are alpha helix and beta sheets. There are higher order structures made out of these two structures that have names.
Tertiary structure: Some amino acids repel water and others attract water. The protein, which is quite flexible in its secondary structure, folds so that the water loving parts are on the outside and the lipid loving parts on the inside. This structure is not made with chemical bonds at all, but can have some bonds added to keep it in that structure. Many proteins have a 'mold' called a chaperon to fold against if they need a little help to reach the right structure.
Quaternary structure: many functional proteins are made from several proteins acting together. The proteins are held together by the separation of water repelling and attracting surfaces and a few stronger bonds. Sometimes they hold metal ion within their structure.
In the end they are little machines that can join things, break things, form locks and keys, gates, levers, rotors and whatever a cell needs to do its work. There diagrams of them are very beautiful I think. Chick (twice if necessary) to enlarge.

A number of diseases are thought to be caused by misfolding proteins and by the elimination of proteins that are misfolded. A new type of drug is being looked for that will refold a protein and by doing so treat the disease. This sort of drug could give very specific and effective treatments. They will be called pharmacoperones.