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Kennedy led high quality of life up to his death, say doctors

August 27, 2009 By admin Leave a Comment

Washington, Aug. 27 (ANI): Senator Edward M. Kennedy maintained a very good quality of life after he was diagnosed with brain cancer.

He continued speaking in front of Congress and making public appearances almost up until the time of his death on Wednesday morning at his home on Cape Cod.

“For a man in his 70s, he did very, very well,” Fox News quoted Dr. Michael Gruber, professor of neurology and neuro-surgery at NYU School of Medicine and Director of the Brain Tumor Center in Summit, New Jersey.

“He was walking unassisted (up until the end), he was lucid,” Dr. Gruber added.

Dr. Suriya Jeyapalan, a neuroncologist at Beth Israel Deaconess Medical Center in Boston, said that Kennedy’s condition was treatable, but not curable.

More than 18,000 primary malignant brain tumors are diagnosed each year in the United States; about 9,000 of those are malignant gliomas, according to the National Cancer Institute.

In general, half of all patients die within a year.

However, patients with malignant gliomas often maintain a very good quality of life after their diagnosis, Gruber said.

Gruber said the fate of a brain tumor patient depends on the location of the tumor. For example, if the tumor is located on the frontal or temporal lobe, then the patient’s speech might be affected.

Since Kennedy’s tumor was on the left parietal lobe, he suffered seizures. Other brain tumor patients may lose the ability to walk, lose vision or lose comprehension skills, depending on where the tumor lies or if the tumor invades other parts of the brain.

Kennedy underwent targeted brain surgery on June 2, 2008 at Duke University Medical Center. The surgery lasted for about 3 1/2 hours and Kennedy spent some of that time awake.

Targeted brain surgery is a delicate balance – removing as much tumor as possible improves cancer control, but there’s also the risk of harming the healthy brain tissue that lets patients walk and talk.

This is why doctors keep patients awake and talking during the surgery to make sure they’re steering clear of delicate areas of the brain. The surgery, considered a success, was followed by months of chemo and radiation therapy.

Kennedy has suffered other health problems over the years.

In October 2007, doctors performed surgery to clean out a partially blocked neck artery, which left untreated, could have trigged a stroke.

In 1964, Kennedy suffered several fractured bones in his back, broken ribs, and internal bleeding after he was involved in a plane crash.

Two people died in that crash. (ANI)

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Tone-deaf people lack an important neural pathway

August 19, 2009 By admin Leave a Comment

Washington, Aug 19 (ANI): Researchers have found that the nerve fibres that link perception and motor regions of the brain are disconnected in tone-deaf people.

According to experts’ estimates, at least 10 percent of the population may be tone deaf – unable to sing in tune.

The new finding has pinpointed a particular brain circuit that is believed to be absent in these individuals.

“The anomaly suggests that tone-deafness may be a previously undetected neurological syndrome similar to other speech and language disorders, in which connections between perceptual and motor regions are impaired,” said Dr. Psyche Loui, of Beth Israel Deaconess Medical Center and Harvard Medical School, one of the study’s authors.

For the study, the researchers used an MRI-based technique called diffusion tensor imaging to examine connections between the right temporal and frontal lobes.

It is known that this region, a neural “highway” called the arcuate fasciculus, is involved in linking music and language perception with vocal production.

They took brain images of 20 people, half of whom had been identified as tone-deaf through listening tests.

The arcuate fasciculus was smaller in volume, and had a lower fibre count in the tone-deaf individuals.

Particularly, the superior branch of the arcuate fasciculus in the right hemisphere could not be detected in the tone-deaf individuals.

Thus, the researchers speculated that this could mean the branch is missing entirely, or is so abnormally deformed that it appears invisible to even the most advanced neuroimaging methods.

“The findings are clear. They show that the arcuate fasciculus, a structure long-known to join perceptual and motor areas, has reduced connectivity in individuals with tone deafness. Beyond improving our understanding of the anatomical underpinnings of tone-deafness, this study provides new insight into a person’s ability to detect pitch,” said Dr. Nina Kraus, at Northwestern University.

The findings add to previous work by the same researchers demonstrating that tone-deaf people could not consciously hear their own singing, and work by other researchers indicating abnormalities in brain regions that affect sound perception and production.

The study has been published in the latest issue of The Journal of Neuroscience. (ANI)

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Beef, chicken, fish may help treat stomach ulcers

May 16, 2009 By admin 1 Comment

Washington, May 16 (ANI): Beef, chicken, fish, eggs, dairy products and some fruits and vegetables could help keep stomach ulcers at bay, says a new study.

Bacteria known as Helicobacter pylori are known to cause such ulcers, and thus antibiotics are used a primary therapy for such infection. But today the bacteria are growing increasingly resistant to antibiotics.

And now, the study by scientists at Beth Israel Deaconess Medical Center (BIDMC) and the Massachusetts Institute of Technology, has shown that the amino acid glutamine, found in many foods as well as in dietary supplements, may prove beneficial in offsetting gastric damage caused by H. pylori infection.

The findings offer the possibility of an alternative to antibiotics for the treatment of stomach ulcers.

“Our findings suggest that extra glutamine in the diet could protect against gastric damage caused by H. pylori. Gastric damage develops when the bacteria weakens the stomach’s protective mucous coating, damages cells and elicits a robust immune response that is ineffective at ridding the infection,” says senior author Dr. Susan Hagen, Associate Director of Research.

She noted that eventually, years of infection result in a combination of persistent gastritis, cell damage and an environment conducive to cancer development.

Glutamine is a nonessential amino acid naturally found in certain foods, including beef, chicken, fish, eggs, dairy products and some fruits and vegetables. L-glutamine – the biologically active isomer of glutamine – is widely used as a dietary supplement by body builders to increase muscle mass.

In earlier studies, researchers had shown that glutamine protects against cell death from H. pylori-produced ammonia.

“Our work demonstrated that the damaging effects of ammonia on gastric cells could be reversed completely by the administration of L-glutamine. The amino acid stimulated ammonia detoxification in the stomach – as it does in the liver – so that the effective concentration of ammonia was reduced, thereby blocking cell damage,” explained Hagen.

Thus, they hypothesized that a similar mechanism might be at work in the intact stomach infected with H. pylori.

After testing the hypothesis on mice, researchers found that at six-weeks-post infection, the animals exhibited increased expression of three cytokines – interleukin 4, interleukin 10 and transforming growth factor-alpha mRNA.

“These all play an important role in the stomach’s ability to protect against damaging effects resulting from other responses to H. pylori infection,” explained Hagen.

The study results showed that in 20 weeks, H. pylori-infected mice, that were fed the L-glutamine diet exhibited lower levels of inflammation than did the mice that received the standard control diet.

“Because many of the stomach pathologies during H. pylori infection [including cancer progression] are linked to high levels of inflammation, this result provides us with preliminary evidence that glutamine supplementation may be an alternative therapy for reducing the severity of infection,” explained Hagen.

She added that studies in human subjects would be the next step to determine the relevance of this finding in the clinical setting.

The study was published in the latest issue of the Journal of Nutrition. (ANI)

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Common virus may cause high blood pressure

May 15, 2009 By admin Leave a Comment

Washington, May 15 (ANI): A common virus affecting 60 to 99 percent of adults worldwide can be a major cause of high blood pressure, finds a new study.
The research team from Beth Israel Deaconess Medical Center (BIDMC) showed that when combined with other risk factors for heart disease, the cytomegalovirus (CMV), can lead to the development of atherosclerosis, or hardening of the arteries.

“CMV infects humans all over the world,” said co-senior author Dr Clyde Crumpacker, an investigator in the Division of Infectious Diseases at BIDMC and Professor of Medicine at Harvard Medical School.

“This new discovery may eventually provide doctors with a whole new approach to treating hypertension, with anti-viral therapies or vaccines becoming part of the prescription,” Crumpacker added.

CMV affects all age groups and is the source of congenital infection, mononucleosis, and severe infection in transplant patients.

In the study using mouse models, the scientists examined four groups of laboratory mice.

Two groups of animals were fed a standard diet and two groups were fed a high cholesterol diet. After a period of four weeks, one standard diet mouse group and one high-cholesterol diet mouse group were infected with the CMV virus.

They found that CMV-infected mice had increased blood pressure compared with the uninfected group.

Moreover, 30 percent of the CMV-infected mice that were fed a high-cholesterol diet not only exhibited increased blood pressure, but also showed signs of having developed atherosclerosis.

“This strongly suggests that the CMV infection and the high-cholesterol diet might be working together to cause atherosclerosis,” said Crumpacker.

A second analysis found that infection of a mouse kidney cell line with murine CMV led to an increase in expression of the renin enzyme, which has been known to activate the renin-angiotensin system and lead to high blood pressure. (ANI)

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iet prescribed to reduce BP may also lower women’s heart failure risk

May 12, 2009 By admin Leave a Comment

Washington, May 12 (ANI): The DASH (short for Dietary Approaches to Stop Hypertension) diet prescribed to help patients lower their blood pressure may also significantly reduce women’s risk of developing heart failure, a new study has suggested.

The study led by investigators at Beth Israel Deaconess Medical Center (BIDMC) demonstrates that a diet high in plant foods and low in sugar and saturated fats is good for health.

“High blood pressure is always of concern because it has the potential to lead to major adverse events, including strokes, heart attacks and heart failure,” said senior author Emily Levitan, ScD, a research fellow in the Cardiovascular Epidemiology Research Center at BIDMC.

Therefore, she and her colleagues hypothesized that the DASH diet would also reduce a woman’s risk of heart failure through its blood pressure lowering effects as well as its secondary effects on cholesterol and other heart-disease risk factors.

The DASH diet is plentiful in fruits, vegetables, low-fat dairy products and whole grains.

“These foods are high in potassium, magnesium, calcium and fiber, moderately high in protein, and low in saturated fat and total fat,” said Levitan.

For the study, Levitan analyzed data from women participants in the Swedish Mammography Cohort, in which women aged 48 to 83 who had no evidence of heart failure were invited to participate.

In the fall of 1997, 36,019 women completed food frequency questionnaires to determine how closely their diets matched the DASH guidelines. Participants were given a ‘score’ based on their diet’s similarity to the DASH diet.

“We then used records from the Swedish national healthcare system to determine whether the women went on to be hospitalized or to die from heart failure. We compared women with diets most similar to the DASH diet to women with diets that were not similar and found that those women whose diets most closely resembled DASH had the lowest risk of heart failure,” said Levitan.

The study is published in issue of the Archives of Internal Medicine. (ANI)

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Delirium hastens memory decline in Alzheimer’s patients

May 5, 2009 By admin Leave a Comment

Washington, May 5 (ANI): An episode of delirium rapidly accelerates cognitive decline and memory loss in Alzheimer’s patients, according to a study by researchers at Beth Israel Deaconess Medical Center (BIDMC) and Hebrew Senior Life.

Elderly patients often develop delirium during hospitalisation or serious illness, and this acute state of confusion and agitation has for long been suspected to be linked to Alzheimer’s disease and other dementias.

Alzheimer’s disease is an irreversible, progress form of dementia that gradually destroys a person’s ability to carry out even the simplest of tasks,

Delirium, on the other hand, is a potentially preventable condition that often develops following a medical disturbance, surgery or infection, and is estimated to affect between 14 percent and 56 percent of all hospitalized elderly patients.

“The cognitive rate of decline was found to be three times more rapid among those Alzheimer’s patients who had had an episode of delirium than among those who did not have such a setback,” according to lead author Dr. Tamara Fong.

Fong added: “In other words, the amount of decline you might expect to see in an Alzheimer’s patient over the course of 18 months would be accelerated to 12 months following an episode of delirium.”

The researchers conducted a secondary analysis of data gathered from 408 patients, examined between 1991 and 2006 at the Massachusetts Alzheimer’s Disease Research Center (MADRC).

Over this 15-year period, MADRC staff conducted a number of memory tests on patients, which was done on at least three occasions, separated by intervals of approximately six months.

They observed that 72 participants developed delirium during the course of the study.

In the final analysis, the researchers found that among patients who developed delirium, the average decline on cognitive tests was 2.5 points per year at the beginning of the study.

After an episode of delirium, decline nearly doubled to 4.9 points per year.

Fong said: “Although each dementia patient declines at his or her own individual rate, the results of our study tell us that this rate can increase three-fold following an episode of delirium.

“Older patients may be at greater risk of developing delirium – particularly in the hospital setting – because they tend to have less ‘reserve’ or ability to compensate in settings of increased stress. Consequently, infections, new medications and other stressors put the patient at risk for delirium.”

Fong further said that all elderly patients, but particularly patients who have already been diagnosed with Alzheimer’s disease, could benefit from a number of preventive measures if they are hospitalized.

“Our current study now shows that delirium can also adversely impact the state of cognitive decline in patients with Alzheimer’s disease. Because up to 40 percent of delirium episodes can be prevented, taking steps to avoid delirium could result in significant improvements,” said Fong.

The findings have been reported in the latest issue of the journal Neurology. (ANI)

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80-mln yr old protein found in bones and tissues of duck-billed dino

May 3, 2009 By admin Leave a Comment

Washington, May 1 (ANI): A new study has confirmed that ancient protein dating back 80 million years to the Cretaceous geologic period has been preserved in bone fragments and soft tissues of a hadrosaur, or duck-billed dinosaur.

Led by scientists at Beth Israel Deaconess Medical Center (BIDMC) and North Carolina State University (NCSU), the new findings support earlier results from analyses suggesting that collagen protein survived in the bones of a well preserved Tyrannosaurus rex, and offer robust new evidence supporting previous conclusions that birds and dinosaurs are evolutionarily related.

“With this new paper, we hoped to show that our T. rex discovery was not a unique occurrence,” said John Asara, Director of the Mass Spectrometry Core at BIDMC, who is also an Instructor in Pathology at Harvard Medical School.

“This is the second dinosaur species we’ve examined and helps verify that our first discovery was not just a one-hit wonder. Our current study was the collaborative effort of a number of independent laboratories, whose findings collectively add up to a robust conclusion,” he added.

At the heart of the controversy is the idea that ancient protein can exist at all.

When an animal dies, protein immediately begins to degrade and, in the case of fossils, is slowly replaced by mineral, a substitution process assumed to be complete by 1 million years.

But, with this latest evidence, it appears that some proteins do indeed have real staying power.

“We wound up identifying nearly double the number of amino acids we recovered in the T. rex study,” said Asara. “The sequences displayed high spectral quality and the interpretations were of high confidence,” he added.

The two scientists had decided to collaborate again after Schweitzer and paleontologist Jack Horner of Montana State University’s Museum of the Rockies recovered the 80-million-year-old Brachylophosaurus canadensis femur bone in the summer of 2007 and observed that it appeared to be even better preserved than the original T. rex fossil.

Schweitzer’s initial laboratory analyses confirmed this observation.

After being subjected to demineralization, the B. canadensis bone fragments showed marked preservation of original tissues and molecules, with microstructures resembling soft, transparent vessels, cells and fibrous matrix – even though the fossil was much older than the T. rex sample.

Chemical extractions of bone and vessel were subsequently sent to the laboratories of BIDMC scientists Lewis Cantley, PhD, and Raghu Kalluri, where immunoblots and immunochemistry analyses were conducted to determine the presence of collagen protein in the samples.

The results confirmed the existence of protein. (ANI)

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Study: BMI and waist size influence heart failure risk

April 9, 2009 By admin Leave a Comment

According to a new study related to belly fat and heart failure, the body mass index (BMI) and the waist size of people influence their risk of being hospitalized with the heart failure condition or even death from the same.

The findings of the study indicated that each additional BMI point increased the risk of heart failure hospitalization or death by 3 percent in women and 7 percent in men; while a waist-size increase of 10 centimeters furthered the risk by 19 percent in women and 30 percent in men.

Heart failure does not mean that the heart has ceased functioning; it means that the organ is not robust enough to pump blood competently through a person’s body; causing difficulty in breathing, and fatigue.

Lead researcher Dr. Emily B. Levitan, of Boston’s Beth Israel Deaconess Medical Center, said: “Obesity has effect on blood pressure and lipids and increases the risk of heart disease,” by increasing the “workload of the heart. The bigger someone’s body, the harder the heart has to work to pump the blood around!”

For the Swedish study spanning six years, the researchers observed 36,873 women, aged 48 to 83 years, and 43,487 men, aged 45 to 79 years. The follow up of these people revealed that as many as 382 women and 718 men were either hospitalized for heart failure or died from the ailment.

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Big belly raises heart failure risk

April 8, 2009 By admin 1 Comment

Washington, Apr 8 (ANI): Carrying an extra four inches of fat around the waist can increase a person’s risk of being hospitalised with heart failure, warn researchers.

A study led by investigators at Beth Israel Deaconess Medical Center (BIDMC) has found that larger waist circumference is associated with increased risk of heart failure in middle-aged and older populations of men and women.

The findings, published online in the April 7 Rapid Access Report of the journal Circulation: Heart Failure, showed that increased waist size was a predictor of heart failure even when measurements of body mass index (BMI) fell within the normal range.

A life-threatening condition that develops when the heart can no longer pump enough blood to meet the body’s needs, heart failure (also known as congestive heart failure) is usually caused by existing cardiac conditions, including high blood pressure and coronary artery disease.

Heart failure is characterized by such symptoms as fatigue and weakness, difficulty walking, rapid or irregular heartbeat, and persistent cough or wheezing.

To reach the conclusion, researchers examined two Swedish population-based studies, the Swedish Mammography Cohort (made up of 36,873 women aged 48 to 83) and the Cohort of Swedish Men (43,487 men aged 45 to 79) who responded to questionnaires asking for information about their height, weight and waist circumference.

Over a seven-year period between January 1998 and December 2004 the researchers reported 382 first-time heart-failure events among the women (including 357 hospital admissions and 25 deaths) and 718 first-time heart-failure events among men (accounting for 679 hospital admissions and 39 deaths.)

Their analysis found that based on the answers provided by the study participants, 34 percent of the women were overweight and 11 percent were obese, while 46 percent of the men were overweight and 10 percent were obese.

“By any measure – BMI, waist circumference, waist to hip ratio or waist to height ratio -our findings showed that excess body weight was associated with higher rates of heart failure,” explains Emily Levitan, ScD, the study’s first author and a Research Fellow in the Cardiovascular Epidemiology Research Unit at BIDMC.

Further breakdown of the numbers showed that among the women with a BMI of 25 (within the normal range), a 10-centimeter higher waist measurement was associated with a 15 percent higher heart failure rate; women with a BMI of 30 had an 18 percent increased heart failure rate. In men with a BMI of 25, a 10-centimeter higher waist circumference was associated with a 16 percent higher heart failure rate; the rate increased to 18 percent when men’s BMI increased to 30.

Furthermore, adds Levitan, among the men, each one-unit increase in BMI was associated with a four percent higher heart failure rate, no matter what the man’s waist size. In women, she adds, BMI was only associated with increased heart failure rates among the subjects with the largest waists. Finally, the authors found that the association between BMI and heart-failure events declined with age, suggesting that the younger the person, the greater the impact of weight to heart health.

“This study reinforces the importance of maintaining a healthy weight,” says Levitan. (ANI)

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Warm weather can trigger migraines

March 10, 2009 By admin 1 Comment

Washington, Mar 10 (ANI): If you blame changes in the weather for your headaches, well, then you’re absolutely right. According to a new study, high temperatures and low air pressure trigger migraines.

A study of more than 7,000 patients, led by researchers at Beth Israel Deaconess Medical Center (BIDMC), provides some of the first large-scale data on how environmental conditions.

According to the study, which has been published in journal Neurology, higher temperatures, and to a lesser degree, lower barometric pressure, contribute to severe headaches.

“Migraine headaches affect a large proportion of the population,” notes Kenneth Mukamal, MD, MPH, the study’s first author and a physician in the Division of General Medicine and Primary Care at BIDMC.

Knowing that migraines can be set off by “triggers,” including certain foods, alcohol, stress and hormones, Mukamal and his coauthors decided to study whether environmental factors were also acting as headache triggers.

“Air temperature, humidity and barometric pressure are among the most frequent reasons that people give for their headache pain,” explains Mukamal, who is also an Associate Professor of Medicine at Harvard Medical School.

“But none of these reasons have been consistently verified. We wanted to find out if we could verify this ‘clinical folklore.’ We also wanted to determine whether air pollutants trigger headaches, much as they have been found to trigger strokes,” the expert added.

To reach the conclusion, Mukamal and his coauthors designed a “case crossover” study, which directly compares levels of pollutants and meterological variables at the time of the patient’s hospital visit with corresponding levels on preceding days and subsequent weeks.

The study looked at 7,054 patients who went to the emergency room of Beth Israel Deaconess Medical Center between May 2000 and December 2007 and were discharged with a primary diagnosis of headache (2,250 diagnosed with migraine; 4,803 diagnosed with tension or unspecified headache).

Using meterological and pollutant monitors, they then compared measurements of a number of environmental factors – air temperature, barometric pressure, humidity, fine particulate matter, black carbon, and nitrogen and sulfur dioxides-during the three days previous to patients’ hospital visits and then again at corresponding dates to determine whether these factors trigger severe headaches.

The findings showed that of all of the environmental factors considered, higher air temperature in the 24 hours prior to the patient’s hospital visit was most closely associated with headache symptoms, with a 7.5 percent higher risk of severe headache reported for each temperature increase of 5 degrees Celsius (approximately 9 degrees Fahrenheit).

To a lesser degree, lower barometric pressure 48 to 72 hours prior to patients’ emergency room visits also appeared to trigger headache.

The researchers found no evidence that air pollutants influenced the onset of headache, but could not rule out a smaller effect similar to that previously seen for stroke. (ANI)

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New mammalian genes that play roles in health, disease identified

February 2, 2009 By admin Leave a Comment

London, February 2 (ANI): Scientists at the Broad Institute of Harvard and MIT and Beth Israel Deaconess Medical Center have announced the discovery of a vast new class of previously unrecognised mammalian genes that do not encode proteins, but instead function as long RNA molecules.

The researchers describe their discovery as a novel class of “large intervening non-coding RNAs” (lincRNAs).

According to them, these genes play critical roles in both health and disease, including cancer, immune signalling and stem cell biology.

“We’ve known that the human genome still has many tricks up its sleeve. But, it is astounding to realize that there is a huge class of RNA-based genes that we have almost entirely missed until now,” Nature magazine quoted Eric Lander, founding director of the Broad Institute, as saying.

The researchers say that, in comparison with standard “textbook” genes, the newly discovered lincRNAs are thousands of bases long.

Because only about ten examples of functional lincRNAs were known previously, they seemed more like genomic oddities than critical components.

The team said that the new find demonstrates that there are actually thousands of such genes, and that they have been conserved across mammalian evolution.

“The challenge in finding these lincRNAs is that they have been hiding in plain sight,” said John Rinn, a Harvard Medical School assistant professor at Beth Israel Deaconess Medical Center and an associate member of the Broad Institute of Harvard and MIT.

“The human and mouse genomes are already known to produce many large RNA molecules, but the vast majority show no evolutionary conservation across species, suggesting that they may simply be ‘genomic noise’ without any biological function,” he added.

During their study, the researchers looked not at the RNA molecules themselves but at telltale signs in the DNA called chromatin modifications or epigenomic marks.

The scientific team looked for genomic regions that have the same chromatin patterns as protein-coding genes, but do not encode proteins.

Upon the survey of the genomes of four different types of mouse cells, including embryonic stem cells and cells from various tissue types, the researchers found an astounding 1,586 such loci that had not been previously described.

The study also showed that the vast majority of these genomic regions are transcribed into lincRNAs, and that these are conserved across mammals.

“The epigenomic marks revealed where these genes were hiding. Analysis of their sequence then revealed that the genes are highly conserved in mammalian genomes, which strongly suggested that these genes play critical biological functions,” said Mitch Guttman, a MIT graduate student working at the Broad Institute.

The scientists correlated the expression patterns of lincRNAs in various cell types with the expression patterns of known critical protein-coding genes in those same cells, and found that lincRNAs likely play critical roles in helping to regulate a variety of different cellular processes, including cell proliferation, immune surveillance, maintenance of embryonic stem cell pluripotency, neuronal and muscle development, and gametogenesis.

Their observations were verified by further experimental evidence from several of the identified lincRNAs.

In their study paper, the researchers say that the stringent experimental conditions imposed by them in identifying the 1,600 lincRNAs during the study suggest that it is likely that there are many more lincRNA genes hiding in plain sight in the genome, as well as other RNA-encoding genes that are as important to genome function as their better-recognized protein-coding counterparts. (ANI)

Filed Under: Science News Tagged With: beth israel deaconess, beth israel deaconess medical, beth israel deaconess medical center, critical roles, deaconess medical center, eric lander, evolutionary conservation, genomic regions, harvard medical school, hiding in plain sight, human genome, israel deaconess medical center, john rinn, mammalian evolution, mammalian genes, mouse genomes, novel class, rna molecules, stem cell biology, telltale signs