Inhibiting an enzyme known as Sirt1 in a particular region of the brain helps reduce food intake, according to scientists at Brown University. The discovery could open the door to new pharmacologic options for the management of obesity.

Sirt1 is found in many tissues including the liver and pancreas.

Earlier studies had shown that Sirt 1 had a fundamental role in cell differentiation, aging and death.

In these studies, both fasting and the antioxidant compound resveratrol-which is found in red wine–activated Sirt1 in peripheral tissues. This phenomenon was associated with improved exercise capacity, improved glucose control and prolonged survival in rats.

The Brown study, conducted by Eduardo Nillni and colleagues, is the first to study Sirt1 activity in the hypothalamus, a region of the brain known to be associated with appetite. 

Nillni’s team used 2 methods to inhibit hypothalamic Sirt1 activity: pharmacological inhibition and RNA transcription blockade. Both approaches resulted in reduced food intake and weight loss.

The scientists also found that fasting increases hypothalamic expression of the Sirt1 gene, which makes it even more likely that Sirt1 plays a central role in moderating appetite and hunger in mammals.

Nillni now plans to study how obesity affects Sirt1 activity in the brain.

The write-up is in PloS One.

Asthma is common in first world nations, unheard of in the developing world and rising quickly in countries making the transition.

Many theories have been posited to explain this association. They range from the idea that clean living somehow revs-up the immune system to a belief that swimming pool chemicals bring on the allergy-mediated condition.

The common denominator is that environmentally mediated phenomena associated with economic development are directly triggering asthma.

Shadmehr Demehri and colleagues at Washington University in St. Louis have postulated an indirect link, in which environmental factors trigger eczema, a benign though annoying skin condition, and the distressed skin cells create chemical signals that in turn trigger asthma. 

Eczema is also linked to economic development. Nearly 17% of US children have it, and nearly 70% of children with eczema develop asthma, even though the prevalence of the letter condition in the general population is only 4-8%.

Demehri’s team believes the culprit is thymic stromal lymphopoietin (TSLP), an immune-stimulating molecule released by skin cells when they are damaged, as by eczema. TSLP, they theorize, causes lung tissue to over-react to allergens, which leads to asthma.

The team wrote-up the results of 3 experiments in the Public Library of Science Biology that provide support for its hypothesis.

First, the scientists showed that mice genetically engineered to develop eczema were prone to develop asthma. Then they deleted the gene coding for the TSLP receptor in the bronchial tissue of such mice and voila, the new editions did not develop asthma.

In the third step, the scientists created mice that over-produced TSLP in the absence of skin problems. These mice wheezed up the wazoo.

Case closed, at least in mice. Eczema is easily treated, by the way, with low-dose topical steroids.

In the brains of patients with Alzheimer’s disease, A-beta proteins stick together to form plaques that are at least associated with, and may actually precipitate the clinical syndrome.

A-beta proteins are formed when enzymes known as secretases digest a larger protein known as amyloid precursor protein.

Knowing this, drug designers have tried to find something that inhibits the secretases, but so far the search has been fruitless.

Malcolm Leissring and a team at Mayo Clinic, Florida have taken a different approach. They searched for compounds that hasten the destruction A-beta proteins, and they may have hit paydirt.

In a report published in PLoS ONE, the scientists used in vitro procedures to isolate 2 chemicals that stimulate insulin-degrading enzyme or IDE, which chews up A-beta proteins faster than Owen and Jen’s white Lab Marley could dismantle a sofa.

Almost immediately after the chemicals were added to IDE, more than 99 percent of the A-beta was destroyed.
 
“This study describes the first examples of synthetic small-molecule activators of IDE, showing that activation of this enzyme is achievable,” Leissring told BurrillReport.

“If it is possible to generate drugs for human use that stimulate the activity of IDE, these agents might offer therapeutic benefit for treating and preventing Alzheimer’s disease.”
 
IDE is shaped like a clamshell that opens and shuts, like Pac-Man.

When IDE is open, A-beta fits snugly inside. The protease then closes like a Venus-fly trap and digests the A-beta.

IDE’s primary role is to digest excess insulin in the body, so small molecule activators like the ones uncovered by Leissring’s group might prove to be useful in managing diabetes one day as well.

The compounds are years away from human testing.

For decades, scientists theorized that aging was caused by oxidative stress, a phenomenon in which cellular damage is caused by free radicals and nasty oxygen-based molecules that build up over time as byproducts of normal biological processes.

According to the theory, the cellular defense against the culprits-which are enzymes known as superoxide dismutases-gets overwhelmed by the accumulating bad guys and the next thing you know, cells are looking like Methuselah.

From the theory sprung an entire industry hawking antioxidant therapies from Vitamin A to Coenzyme Q which supposedly boosted the body’s ability to water-cannon the free radicals.

Alas clinical trials have never shown them to work and now McGill University scientists are raising doubts about the validity of the oxidative stress theory itself.

Siegfried Hekimi and colleagues disabled one-by-one, 5 genes coding for superoxide dismutases in a worm that goes by the unassuming name C. elegans.

The successive gene deletions did not shorten the worms’ lifespan; in fact in one instance, the altered critters outlived the wild-types.

The report is in PloS Genetics.

Come to think of it, the evidence supporting the oxidative stress theory is circumstantial, Hekimi told BurrillReport.

And oxidative stress could be the result of aging rather than its cause.

“It is true that the more an organism appears aged, whether in terms of disease, or appearance or anything you care to measure, the more it seems to be suffering from oxidative stress. (But) people think correlation is causation,” he told BurrillReport.
 
Hekimi’s not saying oxidative stress is actually a good thing. It clearly interferes with normal cellular functioning. But it’s a stretch, he says, to say that oxidative stress causes aging.

Fifteen percent of all hospitalized patients experience at least one adverse drug reaction during their stay, and each ADR adds about 0.25 days onto the length of stay, according to Munir Pirmohamed and colleagues at the University of Liverpool.

To reach this conclusion, the scientists tracked the hospital stays of 3,695 consecutive patients admitted to 12 hospital wards during a 6-month stretch in 2005.

They reviewed charts to assess causality, severity and preventability, and performed multivariate analysis to identify ADR risk factors.

In all, 545 patients experienced at least one ADR. The report is in Plos One. 
 
The most common ADRs included bleeding, constipation, confusion, renal problems, and nosocomial infections involving Clostridia, Staph and other potentially life-threatening bacteria.  Half of all ADRs were felt to be definitely or possibly preventable.

The most commonly offending drugs were narcotic analgesics, anticoagulants and diuretics.
 
The number of drugs being taken by a patient turned out to be the most significant predictor of ADRs, with each additional medication multiplying the risk by about 14%.

Elderly people, who tend to be taking many medications, were therefore found to be at high risk for ADRs.
 
“Our results show that the overall burden of ADRs on hospitals is high and therefore new methods of intervention are needed to reduce this,” Pirmohamed told BurrillReports. 
 
“We are currently looking at…ways of improving the safety of medicines, including increased monitoring…and identification of genetic factors that increase the risk of…adverse effects,” he added.

Other groups, particularly Boston’s Institute for Healthcare Improvement have made progress in this area. Even so, IHI estimates there are as many as 15 million incidents of medical harm each year in US hospitals.

A recent study from McMaster University revealed that medicalized terms carry a weightier, more serious connotation than corresponding lay terms for the same condition, but only if they had recently entered the lexicon.

How good are you at deciphering ridiculous medical jargon? Let’s find out!

Match the normal words on the left with the fancy ones on the right. Note that the medical terms corresponding to the normal words 1 to 8 had, according to the McMaster scientists, entered the lexicon years hence, so they don’t carry a more ominous connotation.

It’s the medicalized terms for 9-16 that are the troublemakers.

Normal words                          Medicalized terms
1. High blood pressure                a. Hypercortisolism
2. Lou Gehrig’s disease               b. Hypertrichosis
3. Stroke                                           c. Erectile dysfunction disorder
4. Gall bladder disease                d. Seborrheic dermatitis
5. Sore throat                                 e. Amyotrophic lateral sclerosis
6. Cushing’s disease                      f. Myocardial infarction
7. Celiac disease                            g. Hypertension
8. Heart attack                               h. Pharyngitis
9. Impotence                                  i. Gluten enteropathy
10. Male pattern baldness           j. Androgenic alopecia
11. Chronic fatigue syndrome  k. Myalgic encephalomyelitis
12. Skin tags                                    l. Cerebrovascular accident
13. Excessive sweating              m. Gastroesophageal reflux
14. Dandruff                                   n. Cholecystitis
15. Impotence                              o. Hyperhydrosis
16. Excessive hairiness             p. Acrochordon

Answers: 1-g, 2-e, 3-l, 4-n, 5-h, 6-a, 7-I, 8-f, 9-c, 10-j, 11-k, 12-p, 13-0, 14-d, 15-c, 16-b

Where do you fit?

Number Correct   Your Title
16                                   Einstein
14-15                             Ivy League
12-13                             Specialist
10-11                             Med Student
8-9                                 Politician
<8                                  Wall Street

How would you feel if your physician said you have heartburn, male pattern baldness or excessive sweating?

Now, how would you feel if she said you have gastroesophageal reflux disease, androgenic alopecia or hyperhydrosis?

The terms are synonymous but the medicalized ones carry different connotations, according to scientists at McMaster University.
 
To investigate the impact of medical terminology on perceptions of disease, Meredith Young and colleagues asked college students to rate medical and lay terms for several medical conditions.

When a condition was given a fancy medical label, students perceived it to be more serious, more legitimate as a disease, and less prevalent than when labeled using a lay term. The perceptions were not impacted by severity of the condition.

Thus a patient told she has gastroesophageal reflux disease is likely to think she is sicker than had she been told she has heartburn.  The authors speculate the difference can impact a patient’s sense of well-being and willingness to comply with care plans among other things.

The differences were observed only in conditions that had been recently medicalized (see post later today on this matter).

“A simple switch in terminology can result in a real bias in perception,” Young told the Journal of Life Sciences. The study co-author added, “These findings have implications for many areas, including medical communication with the public, corporate advertising and public policy.”

Karin Humphres, another co-author said “This is particularly important when you have…conditions that have become medicalized… through the influence of pharmaceutical companies, who want to make you think that you have a disease that will need to be treated with a drug.”

Nearly 60% of the clinical trials that the FDA reviewed during its approval processes for new drugs between 1998 and 2000 were not published in peer reviewed journals within 5 years after the drugs went to market, according to research published in PLoS Medicine. 

24% of the non-published studies were “pivotal” trials focusing on safety and effectiveness in humans. Within this cohort, the PLoS study revealed publication bias: trials showing significant benefits for a new drug were more likely to be published than those showing no benefit.

Pharmaceutical companies sponsor the studies in question and they get to decide whether to pursue publication of trial results or squelch them.

PLoS study investigators concluded that Big Pharma’s failure to publish the results of all trials amounted to “scientific misconduct” that “harms the public good” because it prevents physicians from making informed decisions on behalf of their patients.

Things may be about to change at least a little however. The 2007 FDA Amendments Act mandated that substantial detail from all trials used in support an FDA approval process must be posted on the NIH clinical trials site. This is a good step, but maybe not enough. Clinicians may or may not recognize the unique value of the newly informed NIH site, much less use it. And it doesn’t address the problem with publication bias at all.