Friday, December 30, 2011

For the Herd’s Sake, Vaccinate!


West Hartford, Conn.

I HAVE chronic lymphocytic leukemia. Three months ago, I underwent an allogeneic stem-cell transplant, in which my wise, 52-year-old white blood cells were replaced by bewildered, low-functioning cells from an anonymous European donor. For the next seven months or so, until those cells mature, I have a newborn’s immunity; I am prey to illnesses like chickenpox, the measles and the flu.

These diseases are rarely fatal, unless you’re a newborn or someone with a suppressed immune system like me. My newborn buddies and I do have some protection, however: the rest of you.

Young babies, the immuno-compromised and people who get chemotherapy are not able to process most vaccinations. Live vaccines in particular, like those for measles and chickenpox, can make us sick. But if 75 percent to 95 percent of the population around us is vaccinated for a particular disease, the rest are protected through what is called herd immunity. In other words, your measles vaccine protects me against the measles.

It’s the reasoning of Clarence, the angel from “It’s a Wonderful Life”: If you are vaccinated, you won’t pass a disease on to someone else, who won’t pass it on to six more people, and on and on. To quote Clarence, “Strange, isn’t it? Each man’s life touches so many other lives.”

Unfortunately, vaccination rates for many diseases in Europe and in areas of the United States are falling. This is partly due to Andrew Wakefield, a British doctor who published a paper, now discredited, in 1998 in The Lancet tying childhood vaccines to autism. Celebrities like Jim Carrey have also taken a strong antivaccine view. As a result of these unwarranted fears, childhood diseases are returning. The rate of whooping cough cases has spiked over the past 20 years. In 1990, the incidence was 2 per 100,000 people; in 2000 it was 3; by last year, it had risen to nearly 10.

Measles cases are also increasing. For each year between 2001 and 2008, the median number of cases in the United States was 56. In the first six months of this year alone, there were more than 150 reported cases — the most since 1996. A vast majority of those who were sickened had not been vaccinated or had uncertain vaccination histories. Before the vaccine was introduced in 1963, 400 to 500 Americans died of measles every year.

During last year’s flu season there were 55,403 reported cases of influenza A and B; 116 children died of the disease. And now flu season is back.

The truth is, we should not get vaccinated for ourselves alone; we should do it for one another. Having cancer has taught me the value of living in a community. We assist the infirm, pay our taxes and donate to charity, and getting vaccinated — for the flu, for adult whooping cough, for pneumonia — is just another important societal responsibility. After all, we’re in the same herd.

Steven L. Weinreb, an internist who is certified in oncology and hematology, is on medical leave from his job at a private practice.

Saturday, December 24, 2011

A Drug That Wakes the Near Dead

The moment she saw him, Judy Cox knew her son was dead. It was an October morning in 2008, and she had just stepped out the door to run an errand when she found him lying faceup in the driveway, ghost white, covered in purple splotches. He wasn’t breathing, and when she couldn’t revive him, she ran screaming into the house where her husband, Wayne, was still asleep. “Chris is dead,” she cried. “Call 911!”

Wayne jumped out of bed and raced down to the driveway, where he knelt over his son’s limp frame and tried frantically to elicit a breath or a heartbeat. As he pumped Chris’s chest and scooped out the vomit that had collected in his mouth, Judy ran to the kitchen and steadied herself long enough to call for an ambulance.

Chris was 26. He had not been well. An A.T.V. accident the previous August left him with debilitating back pain that physical therapy did nothing to alleviate. His doctor had recently prescribed Oxycontin. His parents learned later that he had taken too much.

By the time the ambulance arrived, Chris’s heart had been still for at least 15 minutes. It took the paramedics another 15 to get it pumping again; even then, doctors had little hope he would survive. Brain cells begin dying off just five minutes after blood stops delivering oxygen. After 30 minutes, there is likely to be more dead tissue than living.

Nonetheless, the emergency-room staff members at the local hospital did their best. They hooked Chris up to a tangle of tubes and machines and injected him with drugs to stabilize his heart rate. Wayne and Judy watched helplessly from the hallway. After four hours, a doctor finally summoned them to a secluded corridor.

Chris was in a coma, the doctor said, and in all likelihood had suffered severe, irreversible brain damage. He was breathing only with the help of a ventilator and would probably have a series of heart attacks in the night.

“First they asked us to let them pull the plug,” Judy recalled one recent afternoon, as we sat in the living room of the Coxes’ house in a Memphis suburb. “Then they tried getting us to sign a do-not-resuscitate order.” Without one, the doctor explained, hospital staff would be forced to revive Chris each time he started slipping away, which could mean cracking his ribs and shocking him with electricity. Even if they managed to keep his body alive, what was left of his brain would surely die in the days ahead.

Wayne and Judy refused to sign. “This is not some dog we’re talking about putting down,” Wayne shouted. “This is our son.” Chris still lived with his parents. He was a good kid, a joker, but bashful, especially around girls. He liked playing basketball and fishing in the pond near his house. He was planning to take over the family repo business when Wayne retired in a few years. Before the A.T.V. accident, he’d never given them much trouble at all. He deserved every chance the hospital could give him.

The heart attacks never came. Four days later, Chris woke up.

It was not the awakening of Hollywood movies in which the patient comes to, just as he was, speaking full sentences and completely mobile. Three years later, Chris still cannot talk. Although he breathes on his own, his lungs battle a steady barrage of infections; a feeding tube provides all his sustenance, and his muscles have contracted into short, twisted knots. He can move only the slightest bit — his fingers and eyelids twitch, but his arms and legs remain mostly immobile — and his neck is not quite strong enough to hold up his head, which leans against a crescent-shaped support around his wheelchair headrest.

Still, Wayne and Judy say that his cognition is improving. On good days, they say, he can respond to basic commands — blink his eyes for yes, wiggle his finger for no, give a thumbs up when asked. Doctors agree that Chris has progressed beyond a vegetative state, to a hazy realm known as minimal consciousness. What that means — what it says about his experience of the world around him or his prospects for further recovery — is something they are still trying to figure out.

Convinced that the son they know and love is still “in there,” Chris’s parents have spent the past three years searching for a way to bring him back out. So far, their best hope has come from an unlikely source: Ambien. A growing body of case reports suggests that the popular sleep aid can have a profound — and paradoxical — effect on patients like Chris. Rather than put them to sleep, both Ambien and its generic twin, zolpidem, appear to awaken at least some of them. The early reports were so pronounced that until recently, doctors had a hard time believing them. Only now, more than a decade after the initial discovery, are they taking a closer look.

The first report of a zolpidem awakening came from South Africa, in 1999. A patient named Louis Viljoen, who, three years before, was declared vegetative after he was hit by a truck, had taken to clawing at his mattress during the night. Thinking he was suffering from insomnia, his family doctor suggested zolpidem to help him sleep. But 20 minutes after his mother ground the tablet up and fed it to him through a straw, Viljoen began to stir. His eyes, which normally wandered the room, vacant and unfocused, flickered with the light of consciousness. And then he began to talk (his first words were “Hello, Mummy”), and move (he could control his limbs and facial muscles). A few hours later he became unresponsive. But the next day, and for many days after that, zolpidem revived him, a few hours at a time.

Here was a case worthy of Hollywood: three years was well past the point at which doctors would expect any sort of spontaneous recovery. Viljoen awoke with the ability to speak in complete sentences. Not only did he recognize his mother, but he also recognized the voices of people who had spoken to him only when he was apparently vegetative. He remembered nothing of the mysterious realm he kept receding back into. When doctors asked him what it was like to slip away, he said he felt no changes at all. But he could recall conversations from the previous day’s awakening, along with bits and pieces of his former life: his favorite rugby team, specific matches he attended, players that he rooted for and against. As time passed, his cognition improved. He could laugh at jokes, and his awakenings stretched from a few hours to entire days. Eventually, he no longer needed zolpidem.

In the years that followed, a steady trickle of similar reports emerged — some from doctors who tried zolpidem after hearing about the Viljoen case, others from those who discovered its benefits accidentally, as Viljoen’s doctor had. The drug did not work for everyone, and even when it did, its effects typically wore off after an hour or two. But for a lucky few, those effects were profound. People who seemed vegetative for years were waking up.

There are roughly 200,000 patients in the United States trapped in the borderlands between consciousness and oblivion. Until recently, most doctors believed that recovering from this condition was not possible. Vegetative states were considered permanent after three months if the injury was caused by oxygen deprivation, or one year if it was caused by blunt trauma. And since minimally conscious patients did not fare much better than those who were vegetative, most doctors did not bother to draw the distinction.

But in the past decade, a series of developments have coalesced into a far more complicated picture than previously imagined. In 2003, an Arkansas man named Terry Wallis emerged, after 19 years, from a minimally conscious state. Neuroimaging suggested that his brain had essentially reconfigured itself — surviving neurons bypassed dead ones and forged new connections to one another. In a 2007 Nature paper, Nicholas Schiff, a neurologist from Weill Cornell Medical College, and his colleagues showed that deep brain stimulation — surgically implanting a “brain pacemaker” that sends electrical impulses to specific regions of the brain — can help some severely injured patients recover the ability to speak and eat, years after the injury. And just this month, Adrian Owen, a British neuroscientist, reported in the journal The Lancet that the brains of some patients who seemed vegetative responded to basic commands: their bodies didn’t move, but distinct patterns of neuronal firing were detected on EEG scans when these patients were told to make a fist (which triggered one region of the premotor cortex) or wiggle their toes (which triggered another).

This year, scientists at Moss Rehabilitation Research Institute and at the University of Pennsylvania, both in the Philadelphia area, began the first large-scale clinical study of zolpidem as a treatment for disorders of consciousness. (Amantadine, a drug used to treat Parkinson’s disease, and the anti-anxiety medication Ativan also show promise in increasing awareness in minimally conscious patients.) So far, the evidence suggests that less than 10 percent of brain-injured patients will experience the drug’s paradoxical effects, and that among those, only a few will respond as profoundly as Viljoen did. For families like the Coxes, such odds provide a tortured kind of hope. For doctors, they bring questions. Why does a sleeping pill induce awareness in some patients but not others? And what can these bizarre awakenings tell us about the brain’s ability to heal?

Two weeks after Chris first emerged from the coma, he began tracking objects with his eyes. At one month, he could follow simple commands. “His friends would come in the room, and there’d be two or three on each side of the bed,” Judy recalled. “And eventually, when they’d say, ‘Look at Jim,’ or ‘Look at Bob,’ he’d fix his eyes on the right guy.” Wayne and Judy asked for a follow-up M.R.I., but their neurologist said it would be pointless. Chris’s behaviors were entirely reflexive, he said; they were produced by his brainstem, which regulates basic functions like breathing and body temperature, not by his cortex, the region responsible for higher-order thinking. That Chris’s friends and family saw him following commands was proof of their denial, not of Chris’s recovery.

“Every couple days, the doc would stop in the doorway and shout Chris’s name to see if Chris responded,” Judy said. “But he wouldn’t come in the room and look at Chris up close. So one day, I practically grabbed his arm and dragged him into the room, over to Chris’s bed.” She told Chris to blink his eyes. He did. Then she made the doctor walk across the room and told Chris to keep his eyes on the doctor. He did. Finally, with the doctor standing across the room, eyes fixed on Chris, she asked Chris to give her a thumbs up. When he wiggled his thumb, just the tiniest bit, the doctor’s jaw dropped. Chris was not in a vegetative state after all. He was minimally conscious.

Still, there was little that the community hospital could do for him. It had neither the resources nor the expertise to tease out a prognosis or chart a course of therapy. The same was true of local nursing homes, which is where many patients like Chris end up.

So Wayne and Judy took over their son’s care, bringing him first to a premier brain-injury center in Atlanta (where Chris had a device implanted in his spine, which releases drugs to help with spasticity) and then to a clinic in Destin, Fla. (where he tried an experimental treatment known as hyperbaric oxygen therapy). They had just made their way back home to Tennessee when a friend told them about the Ambien paradox and the clinical trial in Philadelphia.

One hallmark of the minimally conscious state is a rapid fluctuation between levels of awareness. Spend 10 or 20 minutes with Chris Cox, and you might conclude that there is nothing going on upstairs. But spend a full hour, and at some point you’ll see his puppy-dog eyes come into focus. They will appear to search for one of his parents, or to settle quizzically on the new person in the room. Ask him to say something, and he’ll smack his lips frantically before leaning forward and tapping his feet in apparent frustration. You’ll swear that he is there with you and that only his physical infirmities (he cannot quite swallow or control his jaw) prevent him from describing the netherworld from which he has just emerged.

And then, a few minutes later, he’ll slip away again.

This fluidity makes diagnosis a challenge. “If a patient follows every command you give them, you know that,” says Dr. John Whyte, director of the Moss Institute and lead investigator on the zolpidem trial. “If a patient has never, ever followed a command, you know that too. But if you tell a patient to wiggle their finger, and they do it occasionally — which is the case for most of these folks — how do you figure out if that ‘occasionally’ means something or not?”

Whyte has spent his entire career trying to answer this question. His first job after his residency was at a facility with a large number of vegetative patients. While working there, he was struck by the amount of contention over diagnoses. For all their experience with this population, clinicians could not seem to agree on whether any given patient was actually conscious. Family members also argued, with one another and with staff, over the meaning of every wince, twitch and eye flutter.

It turned out that a lot of people — staff members included — were drawing their conclusions from pure coincidence. Whyte told me about one mother who insisted that her son would point down toward his feeding tube to indicate that fluid was leaking onto his stomach, causing irritation. “He did it while I was there,” Whyte says. “And she lifted his shirt and said: ‘See, doctor, there’s the liquid. He’s communicating with us.’ And I said: ‘How often do you look under there when he isn’t pointing like this? Never? Not even once?’ ” It was possible that the pointing corresponded to the leak, Whyte explained. But it was also possible that the leaking was constant and the pointing was random. There were countless other examples. “Behaviors would be exceptions if they happened at the wrong time, and evidence if they happened at the right time,” Whyte says.

To help eliminate this bias, Whyte developed what he calls the single-subject assessment, in which doctors design a set of tests specific to each patient’s idiosyncrasies to determine whether the patient is vegetative or minimally conscious. It is painstaking work, but the information it yields is significant. “Patients who achieve minimal consciousness early tend to have a better prognosis,” Whyte says. “And you can at least try to build a communication system with them, because you have a foundation to work from.”

With a reliable assessment method in place, he began searching for ways to build on that foundation. Then the curious Ambien awakenings caught his attention.

It’s not entirely surprising that Ambien would arouse instead of sedate. The pill has long been linked to reports of bizarre sleepwalking behavior (not to mention sleepeating, sleeptalking, even sleepdriving). Some scientists call this phenomenon “paradoxical excitation.” So far, none of the accepted determinants of prognosis — age, overall health, the nature of the initial injury or the extent of brain damage as determined by an M.R.I. — have proved useful in predicting which brain-injured patients will experience it and which won’t. To begin answering that question, Whyte says, you need to study both responders and nonresponders in an unmedicated state.

One morning this past March, I met Chris, Wayne and Judy at the University of Pennsylvania’s main hospital, where they had been flown in from Tennessee, at the study’s expense, so that Chris could be tested in an unmedicated state. From the corner of a small hospital room, we watched as Whyte’s research assistant, Andras Szeles, attached dozens of tiny electrodes to Chris’s face and scalp, then fitted him with a large headset. The electrodes would measure Chris’s brain activity as Szeles administered a series of cognitive tests.

For one test, Szeles placed a rubber glove on Chris’s right hand. A voice coming through the headset told Chris to either “squeeze glove” or “squeeze bare,” several times over. Chris did not seem to be responding at all, but Szeles explained that the electrodes would measure what the naked eye could not. “We’re not so interested in whether or not Chris can squeeze,” he said. “We just want to know if he’s trying to squeeze.” Different neurons fire when you move your left hand versus your right hand. They also fire if you imagine moving it, prepare to move it or start to move it but stop, all of which the electrodes would detect.

“The term ‘consciousness’ can be a real can of worms,” Szeles said. “There are degrees of awareness, and it’s not always clear what the threshold should be. What we’re really looking for here is evidence of comprehension and will.” If Chris understood the words “squeeze” and “glove,” knew that this very specific thing was being asked of him, and possessed, at the most basic level, the will to respond, a distinct pattern of brain waves would show up in the results.

After Whyte and his team have tested 80 patients, they will compare the results of zolpidem responders to those of nonresponders and look for clues that might help explain the difference — maybe a specific brain region that lights up unexpectedly, or a pattern of neuronal firing common to one group but not the other. Any such discovery could light a path not only through the labyrinths of Chris’s fractured mind but to a better understanding of consciousness itself.

Wayne and Judy have a more immediate question: they want to know their son’s long-term prognosis. Has he reached the pinnacle of his cognitive recovery? Or is it a launching pad from which greater heights might be reached?

“Once a patient progresses to minimal consciousness, we can’t predict what’s going to happen,” says Dr. Joseph J. Fins, chief of medical ethics at Weill Cornell Medical College and author of a coming book, “Rights Come to Mind: Brain Injury, Ethics and the Struggle for Consciousness.” Some patients have recovered full consciousness, but many more remain stuck in limbo. The only way to know the outcome is to give the patient time.

But offering time is a complex proposition. “Early on, when families have the option to pull the plug, it’s almost impossible to tell what the long-term prognosis will be,” says Dr. Soojin Park, a neurointensivist at the University of Pennsylvania Hospital, and an investigator on the zolpidem trial. “And then later, when we have the certainty — that this is as good as it’s going to get — that option is gone. Because by then, the patient is breathing on their own. There’s no more plug to pull.” At that point, families who want to end a loved one’s suffering must either have the feeding tube removed, or agree to let the next bacterial infection win out, unhindered by antibiotics. Many families find choosing these deaths much more difficult than turning off a ventilator. It’s an instinct reinforced by religious edicts that forbid the withholding of basic sustenance but allow, for example, unplugging artificial respirators.

It is not uncommon for doctors to assume the worst and advise family members to withdraw care early. They do so in part because they see their duty as helping loved ones face reality. But Fins argues that this is a cop-out. “It’s glossing over all the unknowns for the sake of a quicker, cleaner solution,” he says. “It’s wrong to be so uniformly fatalistic so early on, especially with all the data emerging about the prospects for later-stage recovery.”

According to several studies, about 40 percent of patients who have been declared vegetative are actually minimally conscious. Other studies have shown that a surprising number of vegetative and minimally conscious patients made huge strides toward recovery much later than conventional wisdom would predict.

Park says that more doctors are trying drug therapy on vegetative and minimally conscious patients, but for the most part, they are groping in the dark. “We still don’t understand which drugs should work on which patients, or at what dosage, or at what point in their recovery,” she says. “And that makes it tough for families to know when they should fight and when they should give up.”

There is also the matter of cost. Treating and monitoring patients like Chris — designing and performing single-subject assessments that can discern random twitches from deliberate behavior, managing the host of medical complications that can stymie brain recovery and continually evaluating progress — is significantly more expensive than placing them in nursing homes, where they receive basic care but have no access to brain-injury specialists. Proponents argue that the measures will save money in the long run — if the patient is able to go home, for instance. Still, it’s unclear whether even the most aggressive care will make much difference for many patients. “The payers need a better sense of what the likely outcome is for any given patient,” says Tom Smith, program director at Moss, “so that they can say with confidence which patients are likely to benefit from treatment, and how significant that benefit is likely to be. And I hate to sound this way, but then it’s basically: ‘Am I going to invest this amount of money to get this outcome? Is that worth it?’ And that is a tough, tough question to answer.”

When Chris first returned from the hospital, the Coxes’ house was flooded with well-wishers. A former teacher brought a quilt that Chris and his classmates made in grade school. Old girlfriends, acquaintances and childhood pals visited regularly. His high-school friends even held a fund-raiser to help pay for some of his therapy. But as time wore on, and it became clear that he would neither die nor fully recover, the guests dwindled. Besides Chris’s sister, Amber, who visits often, Wayne and Judy are now mostly on their own.

The couple surrendered their bedroom, which is on the ground floor of their split-level house, to Chris. They take turns sleeping there, on a small cot in the corner of the room, surrounded by medical equipment: a hospital bed with a queen-size air mattress that helps prevent bed sores, a special chair called a “sit-stand,” which can be cranked into an upright position and is supposed to help ease muscle contractions. A mechanical lift. A breathing machine.

Judy is especially keen to show me Chris’s latest gadget, a device called an Eyegaze, that looks a bit like an iPad, and which Chris is learning to use to communicate. She mounts it to a handlebar on Chris’s wheelchair. At first, Chris’s eyes move rapidly across several rows of icons — words with pictures, partial sentences like “I want” or “I like,” and cartoon images of friends and family members with their names in bold. Tracking his eyes, the computer reads: “Green. Brit. I want.” And then, “Brit–Brit–Brit–Brit–Brit.” Brit is his cousin. It’s unclear if he’s asking for her, or if his eyes are just not cooperating.

Judy puts the computer away. He still needs practice, she says. When they first tried it, in February, during outpatient rehab, the therapist asked Chris what color went with Valentine’s Day, and he was able to look at the “red” icon. But so far, “I want a drink,” is the only full sentence he has managed.

Each day begins with the same routine: Judy helps Chris up, forcing him to sit on the edge of the bed, without neck or back support, for several minutes. The goal is to strengthen his neck muscles so that one day he can hold his own head up. A nurse helps her bathe him and then lift him into his chair, so that he can be wheeled into the living room or taken outside. Three times a week, a van delivers mother and son to a rehab center, where a therapist works to stretch and stimulate Chris’s contracted muscles. And almost as often, either Wayne or Judy spends several hours on the phone, battling Chris’s insurance company, which they say has covered private nursing and weekly therapy but denied an extended stay at a brain-injury rehab center. The couple arrange their schedules so that their son is never without at least one parent.

The Coxes have surrounded themselves with a new group of friends — other parents with children like Chris. The families in this informal group share strategies and trade information on emerging research and experimental treatments. They also talk of weariness and isolation. “At the end of the day, you feel like you’re a thousand years old,” Judy says. “And you have no idea how you’re going to get up and do it all over again tomorrow.” Both Wayne and Judy admit to being frustrated by the slow pace of Chris’s progress. But he’s come this far; they can’t help hoping that he might come further still. “I know that some people, even people who loved Chris, think maybe he should have just died,” Wayne says. “But he didn’t die. He lived. And as long as he’s still breathing, we have to do the absolute best we can for him.”

The reports on zolpidem are still mixed. Viljoen and a few others have improved steadily over time; some of them are now fully conscious on their own, without medication. (Viljoen is confined to a wheelchair and has cognitive disabilities but has improved over the years.) But such improvement is rare. According to Whyte, most responders fall into one of two categories: those who can take zolpidem daily, with no appreciable loss of efficacy, and those for whom the “awakenings” wane with continued use. The latter type, he says, may be the most common.

With no way of knowing which type of responder Chris might be, the Coxes play it safe. They give Chris Ativan every day; it has a similar though less profound effect on his behavior. But zolpidem they hoard like pixie dust, giving it only on special occasions, when friends and family can be there.

They gave him some when I visited, so I could see how it works.

A few minutes after receiving the zolpidem, Chris opened his eyes and smiled. Judy sat on the bed, facing him. “Hey, buddy!” she said. “Can I have a kiss?” She leaned in, cheekward, but he turned his head up in what looked like a deliberate slight. “Chris!” she admonished, playfully. He smiled and grunted. He was teasing her. Just as she pulled away, he thrust forward and grazed her cheek with puckered lips. Confident that he was there with us, Judy took out a marker and some paper and wrote one command after another, each of which Chris followed: Stick out your tongue, give me five, give me a thumbs up. And then, “Show us your Elvis grin.” Chris curled his upper lip into a sneer. When Judy ran out of commands, Chris began smacking his lips and moving his tongue. “Talk to us, buddy,” Wayne said. “Say, ‘Mom,’ ” Judy said. After several moments, Chris managed a loud, slow “Maaaa.”

Monday, December 12, 2011

Led by the child who simply knew

The twin boys were identical in every way but one. Wyatt was a girl to the core, and now lives as one, with the help of a brave, loving family and a path-breaking doctor’s care.
Jonas and Wyatt Maines were born identical twins, but from the start each had a distinct personality.

needs hair
accessories, clothes, shoes . . . likes to wear bikinis, high heels,

Jonas was all boy. He loved Spiderman, action figures, pirates, and swords.

Wyatt favored pink tutus and beads. At 4, he insisted on a Barbie birthday cake and had a thing for mermaids. On Halloween, Jonas was Buzz Lightyear. Wyatt wanted to be a princess; his mother compromised on a prince costume.

Once, when Wyatt appeared in a sequin shirt and his mother’s heels, his father said: “You don’t want to wear that.’’

“Yes, I do,’’ Wyatt replied.

“Dad, you might as well face it,’’ Wayne recalls Jonas saying. “You have a son and a daughter.’’

That early declaration marked, as much as any one moment could, the beginning of a journey that few have taken, one the Maineses themselves couldn’t have imagined until it was theirs. The process of remaking a family of identical twin boys into a family with one boy and one girl has been heartbreaking and harrowing and, in the end, inspiring - a lesson in the courage of a child, a child who led them, and in the transformational power of love.

Wayne and Kelly Maines have struggled to know whether they are doing the right things for their children, especially for Wyatt, who now goes by the name Nicole. Was he merely expressing a softer side of his personality, or was he really what he kept saying: a girl in a boy’s body? Was he exhibiting early signs that he might be gay?Was it even possible, at such a young age, to determine what exactly was going on?

Until recently, there was little help for children in such situations.But now a groundbreaking clinic at Children’s Hospital in Boston - one of the few of its kind in the world - helps families deal with the issues, both emotional and medical, that arise from having a transgender child - one who doesn’t identify with the gender he or she was born into.

The Children’s Hospital Gender Management Services Clinic can, using hormone therapies, halt puberty in transgender children, blocking the development of secondary sexual characteristics - a beard, say, or breasts - that can make the eventual transition to the other gender more difficult, painful, and costly.

Founded in 2007 by endocrinologist Norman Spack and urologist David Diamond, the clinic - known as GeMS and modeled on a Dutch program - is the first pediatric academic program in the Western Hemisphere that evaluates and treats pubescent transgenders. A handful of other pediatric centers in the United States are developing similar programs, some started by former staffers at GeMS.

It was in that clinic, under Spack’s care, that Nicole and her family finally began to have hope for her future.

The Maineses decided to tell their story, they say, in order to help fight the deep stigma against transgender youth, and to ease the path for other such children who, without help, often suffer from depression, anxiety, and isolation.

“We told our kids you can’t create change if you don’t get involved,’’ says Wayne, 53, sitting in the living room of their comfortable home in a southern Maine community they do not want identified.

They have good reason for caution. Their journey has included a lawsuit to protect their daughter’s rights, and a battle against bullying and insensitivity that led them to move to a new place and new schools.

It has been a hard road, but nothing that compares with the physical transformation of Wyatt into Nicole.

“I have always known I was a girl,’’ says Nicole, now 14. “I think what I’m aiming for is to undergo surgery to get a physical female body that matches up to my image of myself.’’

Early confusion

When Wyatt and Jonas were born, their father was thrilled. Wayne looked forward to the day when he could hunt deer with his boys in the Maine woods. The family lived in Orono, near the University of Maine campus, where Wayne is the director of safety and environmental management.

They had no preparation for what would come next.

When Wyatt was 4, he asked his mother: “When do I get to be a girl?’’ He told his father that he hated his penis and asked when he could be rid of it. Both father and son cried. When first grade started, Wyatt carried a pink backpack and a Kim Possible lunchbox.

His parents had no idea what was going on. They had barely heard the term “transgender.’’ Baffled, they tried to deflect Wyatt’s girlish impulses by buying him action figures like his brother’s and steering him toward Cub Scouts, soccer, and baseball.

When the boys were 5, Kelly and Wayne threw a “get-to-know-me’’ party for classmates and parents. Wyatt appeared beaming at the top of the stairs in a princess gown, a gift from his grandmother.

Kelly whisked him off and made him put on pants. Though she and Wayne were accustomed to his girly antics, they were afraid of what others might think.

To this day, she feels guilty about it. “I know she was totally confused and felt like she had done something wrong,’’ says Kelly, 50, who works in law enforcement.

“Even when we did all the boy events to see if she would ‘conform,’ she would just put her shirt on her head as hair, strap on some heels and join in,’’ Kelly says. “It wasn’t really a matter of encouraging her to be a boy or a girl. That came about naturally.’’

Kelly and Wayne didn’t look at it as a choice their child was making.

“She really is a girl,’’ Kelly says, “a girl born with a birth defect. That’s how she looks at it.’’

Fear of the unknown

After Wyatt began to openly object to being a boy, his mother started doing research on transgender children. There was little out there; it seemed they would have to find their way largely on their own.

During those early years, while Kelly was doing her research, Wayne was hoping that this was no big deal, that this was a stage Wyatt just had to go through.

“I felt it had nothing to do with how they would grow up,’’ he says.

But as they grew older, his concern grew. “I feared the unknown,’’ he says.

Even the family Christmas card became a challenge. They would write about Jonas’s affinity for sports and Wyatt’s “flair for the dramatic.’’

Their elderly pediatrician, nearing retirement, did not want to discuss the matter with them. Finally, Kelly picked another pediatrician out of the phone book. “I told her how it was, and it turned out that she understood and was very supportive.’’

When the twins were in the first grade, their parents found a therapist for Wyatt, who was starting to act out. In the third grade, before the GeMS Clinic was even open, Kelly heard about Dr. Spack and made an appointment with him.

“He told us everything,’’ Wayne says, recalling that first meeting. “I didn’t understand it all, but I saw the weight lift off Kelly’s shoulders and a smile in Nicole’s eyes. That was it for me. There were tons of challenges for us after that, but I knew my daughter was going to be OK, medically.’’

Elementary school changes

In elementary school, Wyatt told classmates that he was a “girl-boy.’’ In the fourth grade, he grew his hair longer and started talking about a name change. That same year, he drew a self-portrait as a girl, and in a class essay, wrote: “Wyatt needs hair accessories, clothes, shoes . . . likes to wear bikinis, high heels, mini-skirts.’’

Emma Peterson of Orono, a close friend from the elementary years at the Asa Adams School, recalls playing dolls with Nicole’s giant dollhouse, and the two of them putting on makeup. “Before Nikki started growing her hair out, she looked exactly like Jonas,’’ Emma says.

In fourth grade, Wyatt started using “Nicole’’ as a name, and many classmates were calling him “Nikki.’’ The next year, the family went to court and had the name legally changed to Nicole.

To Kelly, it seemed the next logical step. Family discussions merely centered around what the name would be. In the end, Nicole chose it. “I believed in Nicole,’’ her mother says. “She always knew who she was.’’

Wayne was nervous. Could he call his son Nicole? As usual, he relied on his wife’s instincts. “I have to tell you, Kelly’s the leader in our family,’’ he says. “Both she and Nicole are extremely strong-willed, and I went with the flow.’’

At first, though, he couldn’t bring himself to use the new name. An Air Force veteran and former Republican, he realizes now he was grieving the loss of a son. “But once you get past that, I realize I never had a son,’’ he says.

Legal battles

When fifth grade started, Wyatt was gone. Nicole showed up for school, sometimes wearing a dress and sporting shoulder-length hair. She began using the girls’ bathroom. Nikki’s friends didn’t have a problem with the transformation; there were playdates and sleepovers.

“They said, ‘It was about time!’ ’’ Nicole says. She was elected vice president of her class and excelled academically.

But one day a boy called her a “faggot,’’ objected to her using the girls’ bathroom, and reported the matter to his grandfather, who is his legal guardian. The grandfather complained to the Orono School Committee, with the Christian Civic League of Maine backing him. The superintendent of schools then decided Nicole should use a staff bathroom.

“It was like a switch had been turned on, saying it is now OK to question Nicole’s choice to be transgender and it was OK to pursue behavior that was not OK before,’’ Wayne says. “Every day she was reminded that she was different, and the other kids picked up on it.’’

According to a 2009 study by the Gay, Lesbian and Straight Education Network, 90 percent of transgender youth report being verbally harassed and more than half physically harassed. Two-thirds of them said they felt unsafe in school.

To protect her from bullying at school, Nicole was assigned an adult to watch her at all times between classes, following her to the cafeteria, to the bathroom. She found it intrusive and stressful. It made her feel like even more of an outsider.

“Separate but equal does not work,’’ she says.

It was a burden that Jonas shouldered as well. The same boy who in fifth grade objected to her using the girls bathroom made the mistake of saying to Jonas in sixth grade that “freaking gay people’’ shouldn’t be allowed in the school. Jonas jumped on him and a scuffle ensued.

“He’s taken on a lot,’’ Wayne says. “Middle school boys and sexuality, you know . . . boys can get picked on.’’

Nicole and her parents filed a complaint with the Maine Humans Right Commission over her right to use the girls bathroom. The commission found that she had been discriminated against and, along with the Maines family, filed a lawsuit against the Orono School District. The suit is pending in Penobscot County Superior Court, and the Maines family is represented by lawyers from the Gay & Lesbian Advocates & Defenders (GLAD) in Boston and by Jodi Nofsinger, who serves on the Maine ACLU board.

“What Nicole and Jonas both went through in school was unconscionable,’’ says Jennifer Levi, one of the GLAD lawyers on the case. “Their one huge stroke of luck was having Kelly and Wayne as parents.’’

A huge relief

Since that first visit to Spack when Nicole was 9, her parents discussed putting her into the GeMS Clinic when the right time came. They were glad there was time to adjust to the idea. “Baby steps,’’ Kelly calls their path toward treatment.

“I wasn’t always on board,’’ Wayne says. “Kelly and I were not on the same page. My question was, what is this doctor doing? It scared me. I was grieving. I was losing my son.’’

But the more he watched his child struggle, the better he felt about going to Spack. And once he got there, he says, it was a huge relief. “Not only does he know what he’s doing, he’s extremely comforting. He’s got to deal with a ton of dads who are just freaking out, and he made me feel good.’’

Spack’s experience runs deep; before the clinic was established, he had long worked with transgender youth, as well as with adults. “The most striking thing about these kids was the fact that they were just normal young people who had this incredibly unusual and problematic situation,’’ says Spack, 68.

He believes it is crucial to intervene with such children before adolescent changes begin in earnest.

“Most of us look pretty similar until we hit puberty,’’ he says. “I bet I could go to any fourth or fifth-grade class, cut the hair of the boys, put earrings on various kids, change their clothing, and we could send all those kids off to the opposite-gender bathrooms and nobody would say boo.’’

He adds: “We can do wonders if we can get them early.’’


Not everyone agrees that they should, of course, and Spack has heard the arguments: Man should not interfere with what God has wrought. Early adolescents are too young for such huge decisions, much less life-altering treatment.

Though GeMS treatment is now considered the standard of care by mainstream medical groups, some have their doubts. Dr. Kenneth Zucker, a psychologist and head of the gender-identity service at the Center for Addiction and Mental Health in Toronto, says he worries about putting youngsters on puberty blockers, drugs that suppress the release of testosterone in boys and estrogen in girls.

“One controversy is, how low does one go in starting blockers?’’ Zucker says. “Should you start at 11? At 10? What if someone starts their period at 9?’’ Nicole started on the blockers at age 11.

He also questions the role the parents have played; have they simply followed the child’s lead? “Say a 5-year-old says repeatedly that he wants to be a girl,’’ Zucker says. “The parents deduce this must mean the child is transgender, so they socially transition him to living in the other gender.’’

Spack and others, however, say the issue is a medical one and that early intervention makes sense. “We’re talking about a population that has the highest rate of suicide attempts in the world, and it’s strongly linked to nontreatment, especially if they are rejected within their family for being who they think they are,’’ says Spack, who adds that nearly a quarter of his patients admitted to “serious self-harm’’ before coming to him.

As for the criticisms about “playing God,’’ Spack quotes from the Old Testament: “Leviticus says, ‘If thy neighbor is bleeding by the side of the road, you shall not stand idly by the blood of thy neighbor.’ It’s a mandate. I think these kids have been bleeding.’’

The next step

The clinic, which includes geneticists, social workers, psychiatrists, psychologists, and nurses, has so far treated 95 patients for disorders that range from babies born with ambiguous genitalia to cases where normal sexual development does not occur.

About a third of the patients have undergone puberty suppression.

Each patient must have been in therapy with someone familiar with transgender issues and who writes a letter recommending the treatment. The child’s family also must undergo extensive psychological testing before and during treatment. And the patient must be in the early stage of puberty, before bodily changes are noticeable.

Nicole and Jonas are the first set of identical twins the program has seen, and they have provided critical comparative data, Spack says.

The effects of the blockers - an injection given monthly to prevent the gonads from releasing the unwanted hormones - are reversible; patients can stop taking them and go through puberty as their biological sex. This is critical, Spack says, because a “very significant number of children who exhibit cross-gender behavior’’ before puberty “do not end up being transgender.’’

Since the 1970s, the blockers have been used for the rare condition of precocious puberty, when children as young as 3 can hit puberty. They are kept on the blockers until they are of appropriate age. “The drugs have a great track record; we already know that these kids do fine,’’ says Spack. “There are no ill consequences.’’

It is the next big step - taking sex hormones of the opposite gender - that creates permanent changes, such as breasts and broadened hips, that cannot be hormonally reversed.

“In puberty,’’’ Spack says, “when your body starts making a statement, you either have to accept it or reject it.’’

There is no definitive answer to the question of what causes gender identity disorder, though studies suggest a genetic contribution. “It’s still a very open question,’’ Zucker says. And how could it affect just one of two identical twins? “There can be genetic changes during fetal development that maybe hit one twin but not the other.’’

Changed atmosphere

After the family’s lawsuit against the Orono schools was publicized, the atmosphere in town changed. When they went to the movies, people pointed and whispered. There were fewer party invitations, fewer sleepovers.

In the sixth grade, the twins joined the school’s Outing Club. All year they attended meetings to prepare for the crowning event: a whitewater rafting trip. Wayne went to several meetings, too, so he could serve as a chaperone.

Wayne thought he had a good relationship with the club leader. But then the man informed him that Nicole would not be allowed to sleep in the tent with the girls - the same girls who had slept over her house several times. She and her father could have a separate tent.

A difficult family conversation followed. Jonas and Wayne went on the trip. Nicole stayed home.

After that episode, Kelly and Wayne decided a new start would be good for the family. The summer after the sixth grade, they moved to a larger, more diverse community in southern Maine, and the twins enrolled in public school. Wayne still works at UMaine and stays in Orono during the week, spending weekends with his family.

For two years, in seventh and eighth grade, Nicole went “stealth,’’ as she calls it: passing as a girl. She did not tell anyone that she was biologically male. Though she made friends at school, she never brought them to the house. After that hard last year in Orono, the family was afraid to come out.

This fall the twins entered high school, transferring to a smaller, private school known for open-mindedness. Before they arrived, the school changed its bathrooms to unisex. And before classes started, the family met with members of the school’s Gay Straight Alliance - “so she’d have older kids watching her back,’’ says Wayne. After the meeting, the group changed its name to include transgender; it is now the Gay Straight Transgender Alliance.

“It made me a lot more comfortable,’’ Nicole says. “I thought, this is OK. I can do this.’’

She recently started telling some of her new friends her story. One girl replied: “Does this mean you’re going to start wearing boys’ clothes to school?’’

“No,’’ replied Nicole. “I’m male to female.’’

The girl’s reaction? “She was like, ‘Ohhhhhhhhhhhhhhh.’ ’’

Concerns about safety

The male hormone suppressors have done their job, and the next step is to add female hormones so that Nicole will undergo puberty as a girl and develop as a woman, with breasts and curvy hips. She is due to see Spack in January, and a date may then be set for adding estrogen, which she will take every day for the rest of her life. Though she will have a higher risk of breast cancer than if she were a male, she will have a lower risk of prostate cancer, Spack says. The treatment will leave her infertile.

But before the estrogen is administered, the GeMS clinic will reevaluate Nicole to make sure that she still identifies as a female and wants to continue.

“In my experience, the patients just blossom physically and mentally when they get the hormones of the gender they affirm,’’ Spack says. “It’s quite amazing. I feel good about Nicole and who she is and where she’s going.’’

An endocrinologist in Maine now administers the blockers Nicole needs, but Spack still sees her in Boston every four to six months. The Maines family has grown close to him and others in the clinic. “I love going to see him,’’ says Wayne, who has thanked Spack for “saving my daughter’s life.’’ The Maines family declined to talk about the cost of the treatment but said insurance has covered much of it.

But as well as things are going, the Maines family still worries about Nicole’s safety. Last year Wayne and Nicole attended Transgender Day of Remembrance in Maine, which honors those who have been killed in hate crimes.

Wayne spoke to the crowd, telling them that as much as Nicole is loved at home, her family cannot always protect her.

“I remind her that she needs to always be aware of her surroundings, to stay close to friends and her brother if she feels uncomfortable, and to call me anytime she feels threatened,’’ he said.

Lobbying the Legislature

Last winter, Maine state representative Kenneth Fredette, a Republican from Penobscot County, sponsored a bill that would have repealed protections for transgender people in public restrooms, instead allowing schools and businesses to adopt their own policies. The bill was a response to the Maines’ 2009 lawsuit against the Orono School District.

Last spring Wayne and Nicole roamed the halls of the State House, button-holing legislators and testifying against the bill. “I’d be in more danger if I went into the boys bathroom,’’ Nicole told the lawmakers, who ultimately rejected the bill.

“She knows how to work a room,’’ her father says proudly. “She even convinced a cosponsor to vote the other way.’’

In October, the family was honored for its activism in helping defeat the transgender bathroom bill. The Maineses received the Roger Baldwin Award, named for a founder of the American Civil Liberties Union, from the Maine chapter of the ACLU.

Surrounded by Kelly and the kids, Wayne told the audience that he and his wife have had top-notch guides as they confronted the unknown.

“As a conventional dad, hunter, and former Republican, it took me longer to understand that I never had two sons,’’ he told them. “My children taught me who Nicole is and who she needed to be.’’

Typical teens

In some respects, Jonas has had as tough a time as Nicole. For one thing, there’s the personality difference: Nicole is the dominant twin, talkative and tough, while Jonas is cautious and reserved.

“If this had been Jonas, I would have had to home school him,’’ his mother says.

The twins have always been close. During an interview, Nicole sits next to her brother on the couch and occasionally lays her head on his shoulder. At one point, when Jonas goes silent as the twins talk of their lives, she whispers words of encouragement into his ear.

But the next minute, like typical teenage siblings, they’re teasing and tussling. Jonas displays a faint scar on his arm where Nicole jabbed him with a pencil. Both have black belts in tae kwon do, which they started at age 5.

They often hang out in Jonas’s spacious basement room, where they watch TV and play video games.

“I love having a sister,’’ says Jonas, who acknowledges being protective of her. “We have a very strong relationship.’’

Nicole calls Jonas her closest friend.

“I would say my brother got lucky with me. Because we grew up with only boy neighbors, I developed a liking to shoot-’em-up and military video games,’’ she says. “I could have come out a lot girlier.’’

At 14, Jonas is handsome, Nicole pretty. Jonas is midway through puberty. His shoulders have broadened, his voice has deepened, and there’s a shadow on his upper lip. He’s 5 feet 6 and weighs 115 pounds, with a size 11 shoe.

Nicole is petite: 5 feet 1, 100 pounds. She’s got long, dark hair and she wears girls’ size 14-16. Her closet contains nice shirts and jeans, party dresses, glittery shoes, and a pair of footy pajamas.

“The thought of being a boy makes me cringe,’’ she says. “I just couldn’t do it.’’

Excited, worried about surgery

Nicole’s final step on her journey to womanhood would be gender reassignment surgery. Doctors generally won’t perform it until the age of consent, which is 18. No hospitals in New England perform such surgery, says Spack. The nearest that do are in Montreal and Philadelphia.

Nicole says she’s excited about the idea of surgery, though a bit worried about the results - “and maybe the pain, too.’’

While she’s interested in boys, she has expressed fear that “nobody is ever going to love me.’’

She has gone on weekend retreats sponsored by the Trans Youth Equality Foundation and to summer camp for transgender children, where she developed her first crush on a boy.

Over the years, the family has become close to several adult transsexuals, and Nicole has seen that some have found happy marriages. “She says she does feel better about it,’’ Kelly says, “but still wonders if she ever met a boy who falls for her, and then found out that she was trans, if he would still like her, or say awful things as he skedaddled out the door.’’

Nicole knows there is a long road ahead, but she feels she’s on the right path.

“Obviously my life is not going to be as easy as being gender-conforming, but there are perks like being able to get out there and do things that will benefit the [transgender] community,’’ she says. “I think everything’s going to turn out pretty well for me.’’

For now, at least, life feels more normal to the Maines family.

Wayne recently spoke at GLAD’s Spirit of Justice dinner in Boston and was introduced by Nicole. She kept her composure in her brief remarks and thanked GLAD for giving them a rare chance to “safely speak out.’’

Wayne choked up when thanking the group for its support. He recounted young Wyatt asking him, sadly, “Daddy, why can’t boys wear dresses?’’ Wayne hated to tell his son that society wouldn’t accept that.

But today, when Nicole asks her father what he thinks of a certain dress she’s wearing, his typical response, he told the audience, is: “That dress is too short. Go change your clothes.’’

In conversation later, Wayne tells another story of how things have changed, for good and forever. He and the twins were getting out of the car recently, and he grabbed their hands to walk with them.

Jonas, being a teenage boy, shook his father off, while Nicole was happy to walk hand-in-hand, swinging arms.

“She’ll do that the rest of her life,’’ Wayne says with a wide grin. “It was an epiphany for me.’’

Thursday, December 1, 2011

Phys Ed: Why Doesn’t Exercise Lead to Weight Loss?

For some time, researchers have been finding that people who exercise don’t necessarily lose weight. A study published online in September in The British Journal of Sports Medicine was the latest to report apparently disappointing slimming results. In the study, 58 obese people completed 12 weeks of supervised aerobic training without changing their diets. The group lost an average of a little more than seven pounds, and many lost barely half that.

How can that be? Exercise, it seems, should make you thin. Activity burns calories. No one doubts that.
Phys Ed

“Walking, even at a very easy pace, you’ll probably burn three or four calories a minute,” beyond what you would use quietly sitting in a chair, said Dan Carey, Ph.D., an assistant professor of exercise physiology at the University of St. Thomas in Minnesota, who studies exercise and metabolism.

But few people, an overwhelming body of research shows, achieve significant weight loss with exercise alone, not without changing their eating habits. A new study from scientists at the University of Colorado School of Medicine in Denver offers some reasons why. For the study, the researchers recruited several groups of people. Some were lean endurance athletes; some sedentary and lean; some sedentary and obese. Each of the subjects agreed to spend, over the course of the experiment, several 24-hour periods in a special laboratory room (a walk-in calorimeter) that measures the number of calories a person burns. Using various calculations, the researchers could also tell whether the calories expended were in the form of fat or carbohydrates, the body’s two main fuel sources. Burning more fat than carbohydrates is obviously desirable for weight loss, since the fat being burned comes primarily from body fat stores, and we all, even the leanest among us, have plenty of those.

The Denver researchers were especially interested in how the athletes’ bodies would apportion and use calories. It has been well documented that regular endurance training increases the ability of the body to use fat as a fuel during exercise. They wondered, though, if the athletes — or any of the other subjects — would burn extra fat calories after exercising, a phenomenon that some exercisers (and even more diet and fitness books) call “afterburn.”

“Many people believe that you rev up” your metabolism after an exercise session “so that you burn additional body fat throughout the day,” said Edward Melanson, Ph.D., an associate professor in the division of endocrinology at the School of Medicine and the lead author of the study. If afterburn were found to exist, it would suggest that even if you replaced the calories you used during an exercise session, you should lose weight, without gaining weight — the proverbial free lunch.

Each of Melanson’s subjects spent 24 quiet hours in the calorimeter, followed later by another 24 hours that included an hourlong bout of stationary bicycling. The cycling was deliberately performed at a relatively easy intensity (about 55 percent of each person’s predetermined aerobic capacity). It is well known physiologically that, while high-intensity exercise demands mostly carbohydrate calories (since carbohydrates can quickly reach the bloodstream and, from there, laboring muscles), low-intensity exercise prompts the body to burn at least some stored fat. All of the subjects ate three meals a day.

To their surprise, the researchers found that none of the groups, including the athletes, experienced “afterburn.” They did not use additional body fat on the day when they exercised. In fact, most of the subjects burned slightly less fat over the 24-hour study period when they exercised than when they did not.

“The message of our work is really simple,” although not agreeable to hear, Melanson said. “It all comes down to energy balance,” or, as you might have guessed, calories in and calories out. People “are only burning 200 or 300 calories” in a typical 30-minute exercise session, Melanson points out. “You replace that with one bottle of Gatorade.”

This does not mean that exercise has no impact on body weight, or that you can’t calibrate your workouts to maximize the amount of body fat that you burn, if that’s your goal.

“If you work out at an easy intensity, you will burn a higher percentage of fat calories” than if you work out a higher intensity, Carey says, so you should draw down some of the padding you’ve accumulated on the hips or elsewhere — if you don’t replace all of the calories afterward. To help those hoping to reduce their body fat, he published formulas in The Journal of Strength and Conditioning Research last month that detailed the heart rates at which a person could maximize fat burning. “Heart rates of between 105 and 134” beats per minute, Carey said, represent the fat-burning zone. “It’s probably best to work out near the top of that zone,” he says, “so that you burn more calories over all” than at the extremely leisurely lower end.

Perhaps just as important, bear in mind that exercise has benefits beyond weight reduction. In the study of obese people who took up exercise, most became notably healthier, increasing their aerobic capacity, decreasing their blood pressure and resting heart rates, and, the authors write, achieving “an acute exercise-induced increase in positive mood,” leading the authors to conclude that, “significant and meaningful health benefits can be achieved even in the presence of lower than expected exercise-induced weight loss.”

Finally and thankfully, exercise seems to aid, physiologically, in the battle to keep off body fat once it has been, through resolute calorie reduction, chiseled away. In other work by Melanson’s group, published in September, laboratory rats that had been overfed and then slimmed through calorie reduction were able to “defend” their lower weight more effectively if they ran on a treadmill and ate at will than if they had no access to a treadmill. The exercise seemed to reset certain metabolic pathways within the rats, Melanson says, that blunted their body’s drive to replace the lost fat. Similar mechanisms, he adds, probably operate within the bodies of humans, providing scientific justification for signing up for that Thanksgiving Day 5K.

Wednesday, November 30, 2011

Cash receipts can be harmful

I guess I’m supposed to get excited about all the holiday shopping going on and the deals you can get on days like Black Friday. But to me it just means it takes longer to get the same things done. The lines, the crowds... and the discounts don’t thrill me. I’d rather be somewhere else.

But if you do go shopping, there’s something you should know about your health.

I’m talking about the little slip of paper you tuck into your pocket or purse every time you buy anything. From gas to all those Christmas presents you’re getting for all your friends and family this week.

That receipt is most likely covered with bisphenol A (BPA) – the cancer-causing, estrogen-mimicking chemical.

Paper receipts are coated with BPA to get the ink from the receipt printer to develop on the paper. Problem is, BPA doesn't stay on the receipt, making it easy to be absorbed by anyone handling the paper.

What’s worse is that a new study found that BPA transfers readily from receipts to skin and can penetrate the skin to such a depth that it cannot be washed off.1

BPA is dangerous, even in small amounts. Studies show that it may cause cancers, diabetes, heart disease, obesity, and more.
Nearly every modern register uses this kind of paper. And every one of those receipts, according to new research, contains from 250 to 1,000 times more BPA than a plastic water bottle or soda can lining. Several states, and Canada and Europe, have banned using BPA in some of those kinds of products.
Two other new studies looked at how much of the BPA from each receipt gets from your skin into your bloodstream.
One looked at 15 different types of paper products. including thermal receipts, flyers, magazines, tickets, mailing envelopes, newspapers, food contact papers, food cartons, airplane boarding passes, luggage tags, printing papers, business cards, napkins, paper towels, and toilet paper, collected from several cities around the world.
Thermal papers accounted for 98% of the BPA you are exposed to.
The second study says that you absorb as much as 60% of the BPA you get on your skin.2
Fortunately, there are some good ways to avoid taking in BPA while you’re doing your seasonal shopping.
First, the easiest way to avoid getting BPA on your hands is to decline getting a receipt. If you don't need a receipt, leave it and ask the cashier not to print it if possible. For many small purchases and unless you're purchasing something you may want to take back, you probably don’t need one anyway.
Second, shop at stores that don’t have thermal printers that use BPA.
The Environmental Working Group’s research shows that some of the stores that use BPA-containing receipts in at least some outlets include McDonald's, CVS, KFC, Whole Foods, Wal-Mart, Safeway and the U.S. Postal Service.
Receipts from some major chains including Target, Starbucks and Bank of America ATMs issued receipts that were BPA-free or contained only trace amounts.3
Third, handle your receipts as little as possible, and make sure you wash your hands the right way when you get home. Washing your hands is one of the quickest, safest, easiest and most overlooked things you can do to protect your health on many levels. Unfortunately, few of us do it properly. Keep these three things in mind:

You don’t need a special soap. Expensive antibacterial soap is a waste of money and can contain toxic chemicals. Same goes for hand sanitizers.

Ordinary, plain, unscented soap is the best. It kills just as many microbes and bacteria as antibacterial soap. A U.S. FDA advisory committee found that use of antibacterial soaps provides no benefits over plain soap and water.4

Your choice of hot or cold water makes no difference. For comfort, I like warm water.

The length of time washing your hands is important. Twenty seconds is the optimum length – that’s about the time it takes to sing the “Happy Birthday” song – twice.

Make sure you rinse the soap off your hands with running water and dry them well – preferably on a disposable paper towel.

To Your Good Health,
Al Sears, MD

Tuesday, September 20, 2011

Adjuvants May Hold Key To Unlocking Cancer Immunotherapy Revolution

Adjuvants May Hold Key To Unlocking Cancer Immunotherapy Revolution

The FDA approval of sipuleucel-T (Provenge), a patient-specific immunotherapy for androgen independent prostate cancer developed by Dendreon Corporation (DNDN), and ipilimumab (Yervoy), the first immune check point molecule for melanoma by Bristol-Myers Squibb (BMY), has renewed interest in the concept of immunotherapy as an approach to cancer treatment. Often overlooked, however, adjuvants can be an essential part of an effective vaccine and could help advance the field even further.

Adjuvants are substances that can:

Accelerate the generation of robust, longer lasting immune responses
Generate antibodies with increased avidity and neutralization capacity
Enhance immune responses in individuals with weakened immune systems
Reduce the amount of antigen and number of doses needed, reducing the cost of vaccination programs
Activate the cellular arm of the adaptive response, specifically T helper type 1 and cytotoxic T cell responses

For next generation cancer vaccines that require T cell immunity or a broader range of antibody response, adjuvants are playing an essential and central role. For example, GlaxoSmithKline’s (GSK) melanoma antigen epitope-3 (MAGE-A3) antigen-specific cancer immunotherapeutic (ASCI) uses the company’s AS15 adjuvant system [1], which incorporates three different adjuvants (QS-21, MPL, and CpG) and is currently in pivotal Phase III trials for both non-small cell lung cancer (NSCLC) and melanoma with data expected in 2012.


During the last 80 years many adjuvants have been used in experimental settings, but due to various shortcomings of most of them only three have made it into regular clinical usage [2] – largely for infectious diseases. Of the three adjuvants, only two have been used in vaccines licensed by the U.S. Food and Drug Administration.

Alum (1930s)

For infectious disease vaccines, the most commonly used adjuvants are aluminum salt based (aluminum phosphate and aluminum hydroxide, alum), which are safe and effective for antibody induction. Alum is a component of many licensed human vaccines, including diphtheria-pertussis-tetanus (DPT), diphtheria-tetanus (DT), DT combined with Hepatitis B virus (HBV), Haemophilus influenza B or inactivated polio virus (IPV), hepatitis A (HAV), Streptococcus pneumonia, meningococcal, and human papilloma virus (HPV).

MF59 (1997)

MF59 is a potent vaccine adjuvant that has been licensed for more than 13 years for use in an influenza vaccine focused on elderly subjects (Fluad) by Novartis (NVS) [3]. It consists of an oil-in-water nano-emulsion composed of shark oil (squalene). It is licensed in Europe for use in influenza vaccines, but not in the U.S.

MPL (2009)

MPL (monophosphoryl lipid A) is a derivative of bacterial endotoxin and a potent immunostimulant. MPL was the second FDA licensed adjuvant molecule and is used in Cervarix by GlaxoSmithKline (GSK), which is a prophylactic vaccine against HPV types 16 and 18. GlaxoSmithKline obtained MPL through the $300 million acquisition of Corixa Corporation in 2005. MPL is also the first and only toll-like receptor (TLR) ligand approved in a human vaccine. TLRs are a class of proteins that play a key role in the innate immune system [4].

Few adjuvants approved

Adjuvants do not receive FDA approval as stand-alone products, but rather as part of a registered vaccine adjuvant–antigen combination [5]. The fact that safety regulations are often much more stringent with vaccines, as they are prophylactic and the main targets are often pediatric patients, partly explains why there are so few adjuvants approved to date [6].

Several recent developments have favorably altered the landscape for adjuvant development. First, GSK’s Cervarix vaccine received approval in 2009 and contained the first adjuvant (MPL) licensed by the FDA since the approval of Alum back in the 1930s. The second development has been FDA approval of sipuleucel-T (Provenge) by Dendreon and ipilimumab (Yervoy) by Bristol-Myers Squibb, which has renewed interest in the concept of immunotherapy as an approach to cancer treatment. In the cancer setting, adjuvants are being tested as part of a therapeutic vaccine as opposed to being use as a prophylactic vaccine, which may result in a shorter duration of exposure and reduced safety concerns. Third, if an influenza pandemic were to occur, such as the 2009-10 H1N1 pandemic, the potential vaccine supply would fall several billion doses short of the amount needed to provide protection to the global population [7]. The antigen-sparing effect of adjuvants could allow for expansion of vaccine supply to meet the necessary global demands during a pandemic, as evidenced by supporting grants from the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services.

Investigational adjuvants

Several companies are developing promising new candidates that may finally adjunct or displace aluminum substances as a popular adjuvant:

Agenus (AGEN)

Agenus Inc. (AGEN) is developing QS-21, a saponin extracted from the bark of the Quillaja saponaria tree, also known as the soap bark tree or Soapbark, an evergreen tree native to warm temperate central Chile. (Author's note: Agenus is a client of MD Becker Partners.) Quillaia raw material has been used for decades as an ingredient to create the foaming in beverages such as root beer, low-alcohol beers and foaming carbonated beverages. It has also been widely used as an adjuvant in veterinary vaccines.

QS-21 has extensive clinical experience with thousands of patients receiving vaccines containing QS-21 adjuvant. Agenus has licensed QS-21 to various Big Pharma partners and today there are 15 vaccine candidates using QS-21 in clinical development for infectious diseases, oncology, and central nervous system disorders, including the following Phase III programs by GlaxoSmithKline that could address large markets:

MAGE-A3 ASCI vaccine candidate, which is being studied in the largest-ever trial in the adjuvant treatment of NSCLC and also in Phase III trials for melanoma, with data expected in 2012.
Mosquirix (RTS,S), the world’s most advanced malaria vaccine candidate, with Phase III data expected by the end of 2011

Agenus is entitled to receive milestone payments and royalties from corporate partners that have licensed QS-21.

Antigen Express, Inc., a wholly-owned subsidiary of Generex Biotechnology Corporation (GNBT)

Antigen Express is advancing its proprietary Ii-Key hybrid technology. (Author's note: Antigen Express is a client of MD Becker Partners.) Ii-Key modification entails attaching a four-amino acid peptide (LRMK) to virtually any antigen and results in increased stimulation of CD4+ helper T cells and a more robust specific response to the antigen. Using this technology platform, Antigen Express is building a deep pipeline of therapeutics aimed at a variety of major diseases, including cancer, infectious diseases and autoimmune-based syndromes.

The company’s lead product candidate using Ii-Key modification is AE37, a peptide vaccine derived from a fragment of the HER-2/neu protein, which is expressed in a variety of tumors including 75-80% of breast cancers as well as a high percentage of prostate, ovarian and other cancers [8].

A controlled, randomized, and single-blinded Phase II clinical study of AE37 in HER-2 expressing breast cancer patients is currently underway to establish clinical efficacy. The study endpoint is a reduction in cancer relapse after two years compared to the current standard of care treatment. There are currently over 200 patients enrolled in the study with either node positive or high-risk node-negative breast cancer.

Celldex Therapeutics (CLDX) and 3M Company (MMM)

3M Drug Delivery Systems has a portfolio of patent protected TLR agonists that have shown promise as vaccine adjuvants. The lead candidate, resiquimod (TLR7/8 agonist) has shown promising results in a number of animal models and has an extensive toxicology and clinical data package to support further development as a vaccine adjuvant.

Celldex Therapeutics entered into a non-exclusive clinical research collaboration with 3M Drug Delivery Systems to access resiquimod for clinical study with the company’s Antigen Presenting Cell (APC) Targeting Technology in exchange for an undisclosed licensing fee, milestones and royalties. Celldex is developing CDX-1401, a fusion protein consisting of a fully human monoclonal antibody with specificity for the dendritic cell receptor DEC-205 linked to the NY-ESO-1 tumor antigen, which is currently in a Phase I/II trial in combination with immune stimulating agents (resiquimod and/or poly-ICLC) for advanced cancers of the bladder, breast, ovary, non-small cell lung cancer, myeloma, sarcoma or melanoma.

Colby Pharmaceutical Company (private) and Juvaris BioTherapeutics

In September 2011, Juvaris BioTherapeutics, Inc. entered into an exclusive license agreement with Colby Pharmaceutical Company for the worldwide development and commercialization of Juvaris’ Cationic Lipid-DNA Complex (CLDC) technology and related JVRS-100 product candidate. Gene array studies with JVRS-100 show up-regulation of multiple immune response pathways compared to competing technologies. When combined with a vaccine antigen, JVRS-100 stimulates the adaptive immune response including specific antibodies and T-cell responses.

Idera Pharmaceuticals (IDRA)

Idera is developing numerous compounds that act as agonists for TLRs 3, 7, 8, or 9, which the company believes have the potential to be used as adjuvants in vaccines. In preclinical animal models, Idera’s TLR agonists have shown adjuvant activity when combined with various types of antigens.

In December 2007, Idera entered into an exclusive, worldwide licensing and collaboration agreement with Merck KGaA for the research, development and commercialization of Idera’s TLR9 agonists, including IMO-2055, for the treatment of cancer, excluding vaccines. Merck KGaA refers to IMO-2055 as EMD 1201081.

Merck KGaA expects to complete an ongoing Phase 2 clinical trial of IMO-2055 in combination with cetuximab (Erbitux) in second-line cetuximab-naïve patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). However, based on increased incidence of neutropenia and electrolyte imbalances reported in its Phase 1 trial of IMO-2055 in combination with cisplatin/5-FU and cetuximab in patients with first-line SCCHN and subsequent re-evaluation of its clinical development program, in July 2011 Merck KGaA informed Idera that it will not conduct further clinical development of IMO-2055.

Immune Design Corporation (private)

Founded by the co-founder of Corixa Corporation, Immune Design Corporation is developing its proprietary adjuvant known as glucopyranosyl lipid A (GLA). GLA is a novel, clinical-stage, human TLR-4 agonist, representing the next generation of MPL. According to the company, GLA is unique because it is a pure synthetic small molecule, straightforward to manufacture with excellent stability, rationally designed to optimally activate human TLR-4 receptors, induces Th1 CD4 helper cells and elicits broad humoral immunity and active in multiple formulations and compatible with most antigens. GLA was also shown to be safe and well-tolerated in humans subjects in a Phase I clinical study in combination with the influenza virus vaccine Fluzone by Sanofi Pasteur, the vaccines division of sanofi-aventis Group (SNY). Immune Design Corporation is developing its own proprietary pipeline of vaccine candidates formulated with the GLA adjuvant for evaluation in further human clinical trials.

Vical Inc. (VICL)

Vical is developing Vaxfectin, a novel proprietary cationic lipid-based formulation that has been shown to effectively enhance plasmid DNA-based (as well as protein- and peptide-based) vaccines. It is a commixture of a cationic lipid (GAP-DMORIE) and a neutral phospholipid (DPyPE) which, when combined in an aqueous vehicle, self-assemble to form liposomes. In mechanism of action studies, Vaxfectin has been shown to increase a number of cytokines and chemokines, while toll-like receptor signaling was contributory.

Vical is developing several products that utilize Vaxfectin as an adjuvant. These include CyMVectin, the company’s prophylactic vaccine against cytomegalovirus (CMV) infection, and its pandemic influenza vaccines.


Beyond their established role in infectious diseases, adjuvants will also likely become important in cancer immunotherapy where they will be critical for targeting weakly immunogenic tumor antigens in order to overcome various tolerance mechanisms and facilitate induction of cytotoxic T lymphocytes. Several promising new adjuvants are currently being developed that offer superior properties and a set of desired characteristics, with clinical data expected in the near future.

The topic of adjuvants in cancer immunotherapy will covered in an upcoming panel session at the second annual Cancer Immunotherapy: A Long-Awaited Reality conference being held in New York City on October 6, 2011.


[1] Recent clinical experience with vaccines using MPL- and QS-21-containing adjuvant systems. Garçon N, Van Mechelen M. Expert Rev Vaccines. 2011 Apr;10(4):471-86. Review.

[2] The ABC of clinical and experimental adjuvants–a brief overview. Brunner R, Jensen-Jarolim E, Pali-Schöll I. Immunol Lett. 2010 Jan 18;128(1):29-35. Epub 2009 Nov 4.

[3] MF59 adjuvant: the best insurance against influenza strain diversity. O’Hagan DT, Rappuoli R, De Gregorio E, Tsai T, Del Giudice G. Expert Rev Vaccines. 2011 Apr;10(4):447-62.

[4] Impaired TLR3/IFN-beta signaling in monocyte-derived dendritic cells from patients with acute-on-chronic hepatitis B liver failure: relevance to the severity of liver damage. Li N, Li Q, Qian Z, Zhang Y, Chen M, Shi G. Biochem Biophys Res Commun. 2009 Dec 18;390(3):630-5. Epub 2009 Oct 13.

[5] Adjuvants for malaria vaccines. Coler RN, Carter D, Friede M, Reed SG. Parasite Immunol. 2009 Sep;31(9):520-8. Review.

[6] Delivery Technologies for Biopharmaceuticals: Peptides, Proteins, Nucleic Acids and Vaccines edited by Lene Jorgensen and Hanne Mørck Nielsen

[7] Global pandemic influenza action plan to increase vaccine supply by the World Health Organization at

[8] AE37: a novel T-cell-eliciting vaccine for breast cancer. Sears AK, Perez SA, Clifton GT, Benavides LC, Gates JD, Clive KS, Holmes JP, Shumway NM, Van Echo DC, Carmichael MG, Ponniah S, Baxevanis CN, Mittendorf EA, Papamichail M, Peoples GE.

Saturday, August 20, 2011

U.S. Scrambling to Ease Shortage of Vital Medicine


WASHINGTON — Federal officials and lawmakers, along with the drug industry and doctors’ groups, are rushing to find remedies for critical shortages of drugs to treat a number of life-threatening illnesses, including bacterial infection and several forms of cancer.

The proposed solutions, which include a national stockpile of cancer medicines and a nonprofit company that will import drugs and eventually make them, are still in the early or planning stages. But the sense of alarm is widespread.

“These shortages are just killing us,” said Dr. Michael Link, president of the American Society of Clinical Oncology, the nation’s largest alliance of cancer doctors. “These drugs save lives, and it’s unconscionable that medicines that cost a couple of bucks a vial are unavailable.”

So far this year, at least 180 drugs that are crucial for treating childhood leukemia, breast and colon cancer, infections and other diseases have been declared in short supply — a record number.

Prices for some have risen as much as twentyfold, and clinical trials for some experimental cures have been delayed because the studies must also offer older medicines that cannot be reliably provided.

On Wednesday, Dianne Nomikos, 65, went to M. D. Anderson Cancer Center in Houston for a 9 a.m. appointment to receive Doxil, a vital medicine for her ovarian cancer. She was told to go home and wait until new supplies arrived.

“My life is in jeopardy,” she said through tears in a telephone interview. “Without the drug, who knows what’s going to happen to me?”

The Obama administration is considering creating a government stockpile of crucial cancer medicines. The Centers for Disease Control and Prevention already stockpile antibiotics, antidotes and other drugs needed in the event of a terrorist attack or earthquake.

Under one plan, the government would store the dry ingredients for cancer drugs and, in the face of a shortage, distribute them to hospitals, where pharmacists could mix them into injectable compounds.

Dr. Richard Schilsky, a professor of medicine at the University of Chicago, said the number of cancers diagnosed in a year was easy to predict. “So we ought to be able to make a pretty good estimate of the grams required to treat every patient in the country in any given year,” he said.

Legislation proposed in both the House and the Senate would give the Food and Drug Administration the power to demand that drug makers give early warnings of possible supply disruptions. Senator Amy Klobuchar, Democrat of Minnesota, said the idea behind the bipartisan bill came after she found that the agency had prevented 38 shortages last year after getting early alerts of problems at drug makers.

“I can’t say the drug companies are excited” about the proposed legislation, she said in an interview. “But we need to give the F.D.A. more time.”

A group of leading oncologists has started a not-for-profit drug company that it hopes will soon be able to import supplies of some of the missing medicines. The company will eventually manufacture the drugs itself, according to Dr. George Tidmarsh, a pediatric oncologist and biotechnology entrepreneur who will lead it.

“We have a meeting with the F.D.A. next week,” Dr. Tidmarsh said. “This unfolding tragedy must stop, and right now.”

More than half the recent shortages have resulted because government or company inspectors found problems like microbial contamination that can be lethal on injection. Others have occurred because of capacity problems at drug plants or lack of interest because of low profits, according to the F.D.A.

Doxil, the cancer drug Ms. Nomikos needs, is made by Johnson & Johnson. Monica Neufang, a company spokeswoman, said, “Our third-party manufacturer has had some manufacturing issues related to capacity.”

Heather Bresch, president of the generic drug giant Mylan, says the shortages grow out of a sweeping consolidation of the generic drug industry into a few behemoths that compete only on price and have foreign plants that are rarely inspected.

“The race to the bottom has led to an increase of products coming from plants in China and India that may have uncertain supply and may have never been inspected,” Ms. Bresch said. “If the F.D.A. was required to inspect foreign drug plants at the same rate it does domestic ones, we might not have so many of these shortages.”

Ms. Bresch has helped to broker an agreement that would require the industry to pay $299 million a year for increased inspections of foreign drug plants, a deal that must be approved by Congress and one she says will prevent some shortages.

Top government officials have held a blizzard of meetings in recent weeks to tackle the shortage issue, and more are expected over the next month — including a public advisory meeting at the F.D.A. and hearings in Congress.

“Drug shortages represent a pressing public health issue, and we are actively working to understand the causes, the full scope of the problem in the U.S. and internationally, and possible solutions,” said Dr. Howard K. Koh, an assistant secretary for health.

A crucial problem is disconnection between the free market and required government regulation. Prices for many older medicines are low until the drugs are in short supply; then prices soar. But these higher prices do little to encourage more supply, because it can be difficult and expensive to overcome the technical and regulatory hurdles. And if supplies return to normal, prices plunge.

Executives at Premier, a hospital buying cooperative, said that in April and May its members received hundreds of offers from obscure drug wholesalers to sell drugs in short supply at vastly inflated prices. Of the 636 offers that included a price, 45 percent were at least 10 times the normal rate and 27 percent were at least 20 times normal.

Such sales offers are legal as long as suppliers prove that they bought the drugs appropriately. Some wholesalers buy certain drugs in large quantities because they are betting there will be a shortage. The excessive buying can help make their predictions come true. “We never like to see a situation where people can profit off of a national crisis and engage in price gouging,” Mike Alkire, Premier’s chief operating officer, said in an interview.

Joyce Burke, 47, of Mooresville, N.C., has breast cancer and is worried that she might not be able to get Taxol, which is in short supply. A drug that might have been substituted for Taxol has a side effect that leads some patients to lose their fingernails.

“I was not looking forward to losing my fingernails,” she said.

On Thursday, she received her first dose of Taxol, and her doctor said he had secured enough of the drug to give her a second dose in a little more than a week. She will need four doses to complete the treatment.

“And I asked, ‘What happens if you can’t find the rest?’ ” Ms. Burke said. “It’s not nearly as effective if you switch drugs midway through.”

Thursday, January 6, 2011

Is eating too many smoked and cured foods bad for me?

Dr Thomas Stuttaford
A 55-year-old reader from Chiswick has written to ask if eating cured foods, especially smoked cured foods, is dangerous. He fears that they may represent an appreciable medical hazard. He especially enjoys eating traditionally wood-smoked bacon, ham, chicken breast and kippers. He always prefers wood smoked products to unsmoked cured meats, but wonders if this is a wise decision.
Our reader shares a similar palate to my own. However, unlike him I am able to enjoy smoked goose breast or Yarmouth bloaters without worrying about the possibility that the cancer-forming (carcinogenic) chemicals found in cured meats or fish represent a significant danger to the ordinary diner.

For rather than being concerned about the curing process, which is well controlled by manufacturers, I am grateful that the salt and sodium nitrite used in the process deal a death blow to any Clostridium botulinum present. This is the bacterium that can cause botulism, a form of food poisoning that can have devastating, even occasionally fatal, results. The curing process also stops the meat going bad.

Most cured meats contain nitrosamines. These are formed when amines — breakdown constituents of proteins — are mixed with the sodium nitrite that, with salt (sodium chloride), is used to cure and preserve meat. The combination of small quantities of salt and sodium nitrite is such an effective mixture in preventing food poisoning and preserving the meat that no comparable alternative has been found.

Although there is evidence that nitrosamines are carcinogenic, it is doubtful if, in the small amounts the average person takes, it increases appreciably the risk of developing cancer after exposure to cured ham, bacon, other meats and fish. Choosing smoked meats and fish as an occasional hors d’oeuvre, or even having them as a main course from time to time, is unlikely to be significant. Research suggests that most people derive far more nitrates from vegetables, including such old faithfuls as spinach and cabbages, than from cured meats. It is estimated that only 1 per cent of someone’s nitrite concentration in the gut has been derived from cured meats and 90 per cent from vegetables. Nitrates are reduced to nitrites by organisms in the intestinal tract. Even so, it wouldn’t be considered a good idea to dine exclusively on cured and smoked foods.

Anxious lovers of smoked foods may also worry about the effect of benzopyrenes — potentially potent carcinogens — produced by smoking food. In smoked foods the levels of these may exceed 50 micrograms per kilogram. The relevant factor in considering possible problems caused either by the curing with salt and sodium nitrite or by the benzopyrenes from smoking is the amount of exposure to them. People who have a mixed diet can occasionally relish smoked foods without fearing that a few mouthfuls of smoked eel need to be followed by an immediate call to their local solicitor to update their will.

Those people who are obsessed with possible carcinogens in their food may also worry about the standard rasher or two of bacon in what hotels call the traditional English breakfast. They should perhaps choose to send back any burnt toast. Burnt toast, too, has a theoretical carcinogenic potential. Likewise, so has any unsaturated fat cooked at a high temperature. Research on cooking bacon has shown that the microwave is safer than the frying pan. The level of the nitrosopyrrolidines, a toxic substance produced by heating nitrosamines, is virtually undetectable when the bacon is cooked at a low temperature very slowly.

The crispier the bacon the higher the content of nitrosopyrrolidines. A medium well-done rasher cooked at 210F (99C) has ten times the quantity of nitrosopyrrolidines asmin slowly heated bacon. Cooked at 400F quickly, it has 17 times the amount and in crisped (virtually burnt) bacon there are 19 times as much nitrosopyrrolidines.

The good news is that the evidence that crispy bacon has ever harmed anyone is lacking. In fact there are more carcinogens in very hot fat. Another piece of reassuring news is that vitamin C in breakfast fruit juices may help to counteract nitrosamines.