Science Weekly: On the pathologist’s slab

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Pathologists; a victory on the road to libel reform; the climate email scandal; and the latest thinking on geo-engineering

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High Altitude Metabolism – Mice Stay Slim and Healthy on High-Fat Diet

Mice that are missing a protein involved in the response to low oxygen stay lean and healthy, even on a high-fat diet (April 15 issue of the journal Cell Metabolism). While their normal littermates gain 1) ___, develop fatty livers and become resistant to insulin on a high fat diet, just like overweight humans do, the mutant mice suffered none of these ill effects. The protein, an enzyme called FIH, plays a key role in the physiological response to low levels of 2) ___ and could be a new target for drugs to help people who struggle with weight gain. Because the protein influences a wide range of 3) ___ involved in development, it was surprising that its deletion improved health. It was expected for the mice to die as 4) ___. The lean mice had a high metabolism, and a common check for insulin resistance, a symptom of diabetes, revealed a super sensitivity to 5) ___. The mice were fed with a very high 6) ___ diet of 60% fat just to see how they would respond. The mutants can eat a lot, but they didn’t gain a lot of weight. They are less fatty around their middles compared with their littermates. Obese people develop a “fatty liver,“ and so did the wild type littermates. The fat mice also developed high blood 7) ___ with elevated levels of the “bad“ type, LDL. In lean mutants, LDL increased much less. All of these observations support that the modified mice have better 8) ___ profiles. The genetic manipulations disabled the FIH gene entirely. In every tissue, in every cell, the 9) ___ was gone. But the authors wanted to know what part of the mouse physiology was responsible for the changes, so they created new mice in which the FIH protein was deleted only in specific tissues: the nervous system or the liver. Mice that were missing FIH only from their nervous system showed most of the same effects. Though smaller, the mutant mice ate and drank 30 to 40% more than wild-type mice. Where did the calories go? The calories caused heat generation and an increased 10) ___ rate. They also breathed heavily compared with normal mice, taking in 20 to 40% more air. According to the authors, this deep breathing is like exercise for them. The FIH protein is part of a wide system that responds to low levels of 11) ___. The mice behaved as if they are breathing thin air. When people travel to higher altitudes, they breathe heavily for a few days, then adjust by producing more oxygen-carrying blood cells. These mice never adjust to the apparent low oxygen but stay in this acute phase of hypoxic response their whole lives.

ANSWERS: 1) weight; 2) oxygen; 3) genes; 4) embryos; 5) insulin; 6) fat; 7) cholesterol; 8) metabolic; 9) protein; 10) heart; 11) oxygen

Ancient Egyptian Cosmetics May Have Been Medicine for Eye Disease

There’s more to the eye makeup that gave Queen Nefertiti and other ancient Egyptian royals those stupendous gazes and legendary beauty than meets the eye. Scientists in France are reporting that the alluring eye makeup also may have been used to help prevent or treat eye disease by doubling as an infection-fighter. Thousands of years ago the ancient Egyptians used lead-based substances as cosmetics, including an ingredient in black eye makeup. Some Egyptians believed that this makeup also had a “magical“ role in which the ancient gods Horus and Ra would protect wearers against several illnesses. Until now, this was largely dismissed since it is well known that lead-based substances can be quite toxic. In earlier research, 52 samples were analyzed from ancient Egyptian makeup containers preserved in the Louvre museum in Paris. Four different lead-based substances were found in the makeup. In the new study, it was found that the substances boosted production of nitric oxide by up to 240% in cultured human skin cells. Modern scientists recognize nitric oxide as a key signaling agent in the body. Its roles include revving-up the immune system to help fight disease. Eye infections caused by bacteria can be a serious problem in tropical marshy areas such as the Nile area during floods. Therefore, the ancient Egyptians may have deliberately used these lead-based cosmetics to help prevent or treat eye disease. Two of the compounds do not occur naturally and must have been synthesized by ancient Egyptian “chemists.“ The present data suggest that the eyes of Egyptians bearing the black makeup were presumably prone to immediately resist a sudden bacterial contamination with extreme efficiency through the spontaneous action of their own immune cells. It is well recognized today that in most tropical marshy areas, such as was the Nile area during floods, several bacterial infections are transmitted to humans following any accidental projection of contaminated water drops into one’s eye. The current data fully support that Horus’ and Ra’s protection that ancient Egyptians associated with this makeup, and particularly with its laurionite component, was real and effective. One cannot evidently go as far as to propose that laurionite was purposely introduced into the composition of the makeup because of any recognized antibacterial properties. Yet, one can presume that ancient Egyptian “chemists“ recognized empirically that whenever this “white precipitate“ was present in the makeup paste, their bearers were enjoying better health and thus decided to amplify this empirical protective function by specifically manufacturing laurionite. Many examples of such subtle observations and medical conclusions that would have a priori been surprising can be found even in our recent history. It is sufficient, for example, to think about the historical origin of penicillin, aspirin, or quinine. Whether or not the manufacture of these lead chlorides was deliberately connected to preventive health care by Egyptians, it is clear that such intentional production remains the first known example of a large scale chemical process. It is no wonder that “kemej,“ the Egyptian word that referred to the Egyptian land and to the black earth of the Nile valley, was handed to us via the Greeks and then the Arabs to eventually coin our present chemistry.

Targeting the Blood-Brain Barrier May Delay Progression of Alzheimer’s Disease (AD)

The blood-brain barrier separates the brain from circulating blood, and it protects the brain by removing toxic metabolites and proteins formed in the brain and preventing entry of toxic chemicals from the blood. Alzheimer’s disease (AD) is an irreversible, progressive brain disease that slowly destroys memory and thinking skills, and eventually disrupts function of major organs. Estimates vary, but experts suggest that as many as 2.6 million to 5.1 million Americans may have AD. One hallmark of AD is the deposition of beta-amyloid protein in the brain. This protein clumps to form plaques that destroy neurons and lead to cognitive impairment and memory loss in Alzheimer patients. According to an article published in the Molecular Pharmacology (2010 77:715-723), using a mouse model of disease, it was demonstrated that by targeting the blood-brain barrier, it was possible to slow the accumulation of a protein associated with the progression of AD. What was shown is that it was possible to reduce the accumulation of beta-amyloid protein in the brain by targeting a certain receptor in the brain known as the pregnane X receptor. The study demonstrated that when 12-week-old genetically modified mice expressing human beta-amyloid protein are treated with a steroid-like chemical that activates PXR, the amount of beta-amyloid protein in the brain is reduced. The activation of the PXR was found to increase the expression of a blood-brain barrier protein known as P-glycoprotein, which transports beta-amyloid out of the brain. The results show several new findings:

1.     P-glycoprotein plays a pivotal role in clearing beta-amyloid from the brain

2.     P-glycoprotein levels are reduced in the blood-brain barrier

3.     AD mice treated with the chemical to activate PXR were able to reduce their beta-amyloid levels to that of mice without Alzheimer’s

According to the authors, it is also likely that reduced P-glycoprotein expression at the blood-brain barrier may be an early indicator of AD, even before the cognitive symptoms appear. Going forward, a study is planned where the AD mice will be fed a PXR-activating compound in their diet for 12-18 months. The cognitive skills of the animals will be monitored regularly, along with their P-glycoprotein levels, to determine whether the feeding regimen delays the onset of cognitive impairment.


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Even Mild Sleep Apnea Puts Men in Danger to Increased Risk of Stroke

Stroke is the second leading cause of death worldwide. Although several risk factors for stroke – such as age, high blood pressure and atrial fibrillation, and diabetes – there are still many cases in which the cause or contributing factors are unknown. Obstructive sleep apnea is a common disorder in which the upper airway is intermittently narrowed or blocked, disrupting sleep and breathing during sleep. More than 12 million American adults are believed to have sleep apnea, and most are not diagnosed or treated. Treatments to restore regular breathing during sleep include mouthpieces, surgery, and breathing devices, such as continuous positive airway pressure, or CPAP. In people who are overweight or obese, weight loss can also help. According to an article published online in the American Journal of Respiratory and Critical Care Medicine (25 March 2010), obstructive sleep apnea is associated with an increased risk of stroke in middle-aged and older adults. Results from the Sleep Heart Health Study (SHHS) show that the risk of stroke appears in men with mild sleep apnea and rises with the severity of sleep apnea. Men with moderate to severe sleep apnea were nearly three times more likely to have a stroke than men without sleep apnea or with mild sleep apnea. The risk from sleep apnea is independent of other risk factors such as weight, high blood pressure, race, smoking, and diabetes. The study also reports for the first time a link between sleep apnea and increased risk of stroke in women. The SHHS is the largest and most comprehensive prospective, multi-center study on the risk of cardiovascular disease and other conditions related to sleep apnea. In the latest report, stroke risk was studied over nine years in 5,422 participants aged 40 years and older without a history of stroke. At the start of the study, participants performed a standard at-home sleep test, which determined whether they had sleep apnea and, if so, the severity of the sleep apnea. During the course of the study, 85 of 2,462 men and 108 out of 2,960 women had a stroke. After adjusting for several cardiovascular risk factors, it was found that the effect of sleep apnea on stroke risk was stronger in men than in women. In men, a progressive increase in stroke risk was observed as sleep apnea severity increased from mild levels to moderate to severe levels. In women, however, the increased risk of stroke was significant only with severe levels of sleep apnea. The authors suggest that the differences between men and women might be because men are more likely to develop sleep apnea at younger ages. Therefore, they tend to have untreated sleep apnea for longer periods of time than women. According to the authors, the findings provide compelling evidence that obstructive sleep apnea is a risk factor for stroke, especially in men and that the increased risk of stroke in men with sleep apnea is comparable to adding 10 years to a man’s age. Importantly, it was found that increased stroke risk in men occurs even with relatively mild levels of sleep apnea. The new results support earlier findings that have linked sleep apnea to stroke risk where it was reported that untreated sleep apnea is associated with an increased risk of high blood pressure, heart attack, irregular heartbeats, heart failure, and death from any cause. Other studies have also linked untreated sleep apnea with overweight and obesity and diabetes. It is also linked to excessive daytime sleepiness, which lowers performance in the workplace and at school, and increases the risk of injuries and death from drowsy driving and other accidents.

New Genes Associated With Age-Related Macular Degeneration

Age-related macular degeneration AMD is a leading cause of visual impairment and blindness in older Americans. Previously discovered genes that account for a significant portion of AMD risk have been identified through genome-wide association studies (GWAS). These studies scan the entire DNA of individuals to uncover genetic variations related to certain diseases. According to a study published online in the Proceedings of the National Academy of Sciences (12 April 2010), a large genetic study of AMD has identified three new genes associated with this blinding eye disease. Two of the genes are involved in the cholesterol pathway. The strongest AMD genetic association found in the study was in a region on chromosome 22, near a gene called metalloproteinase inhibitor 3 (TIMP3). Mutations in the TIMP3 gene were previously found to cause Sorsby’s fundus dystrophy, a rare inherited early-onset form of macular degeneration. Although further research is needed, it is likely that the genetic region pinpointed influences the expression of TIMP3. The study has also shed light on a new biological pathway for AMD disease development, by uncovering two genes associated with AMD risk in the high-density lipoprotein (HDL) cholesterol pathway: human hepatic lipase (LIPC) and cholesterol ester transfer protein (CETP). The study identified two additional genes, lipoprotein lipase (LPL) and ATP binding cassette transporter 1 (ABCA1), that may be involved in the cholesterol pathway as well, but more research is needed to confirm these findings. HDLs are among a family of lipoproteins that transport essential fats, such as cholesterol, through the bloodstream. It is believed that early stages of AMD are affected by accumulation of oxidation products of cholesterol and other lipids in the retinal pigment epithelium, a layer of cells in the back of the eye. However, the relationship between HDL cholesterol levels in the blood and AMD is still unclear. The authors suspect that since these genetic variations found in the cholesterol pathway impact the retina differently from the circulatory system, cholesterol levels in the blood may not provide meaningful information about AMD risk. The authors added that a major biochemical pathway has been identified that may be a target for future AMD treatments.

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The recently signed health reform law, more formally the Patient Protection and Affordable Care Act (PPACA) has codified the approval pathway for “biosimilars.“ Biosimilars are generic competitors for complex protein molecules synthesized in biological systems. Since these medicines cannot be precisely replicated, they present challenges to established standards for introducing generic competitors. In addition, the law defines and protects “interchangeable“ products, specific biosimilars that “may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.“ The new law provides for 12 years of exclusivity for the reference (innovator) product from the time of its initial licensing. The rules for resolving patent challenges are complex, and therefore the practical consequences of the legislation will, (as is typically the case) reveal themselves only over time as specific procedures are implemented. However, the reactions of certain stakeholders are instructive. So far, PhRMA (representing large pharmaceutical companies) and BIO (representing the biotechnology companies) have been positive about key components of the law, while the Generic Pharmaceutical Association has been less enthusiastic. While “bending“ the cost curve through generic competition is an important, in fact a critical goal for the long term economic health of the nation; it is likewise true that both the economic and physical health of Americans is enhanced by the presence of a robust, innovative biotechnology industry. The protection provided for reference biologics in the new law seems intended to provide the proper balance of 1) predictability for the innovative biotechnology industry and 2) a clear pathway for generic competition. The balance strikes us as reasonable, with the potential to benefit all.

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