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Even my grandchildren are all past that stage. Ryan wondered if he ever slept. Half a dozen ASW search aircraft, a bunch of frigates, and an Alfa -class attack boat, all running around in circles. Ryan took out his notes and summarized his education in submarine technology. Twenty thousand sound reasonable? Ryan knew how to answer this. The other times had worked out fairly well. Greer was a man who looked for results. What does it all mean? We depend on our ability to track their boomers with our attack boats.

This could change the game a bit. You know what they have to spend on their Alfas. You spend that much money for a superstrong hull, then put a noisy power plant in it. Anyway, if this silent drive system really works, they might be able to creep up onto the continental shelf. This was one of the nastier nuclear war scenarios in which a sea-based missile was fired within a few hundred miles of its target.

Washington is a bare hundred air miles from the Atlantic Ocean. If the Soviets were able to kill the president that quickly, the resulting disruption of the chain of command would give them ample time to take out the land-based missiles—there would be no one with authority to fire. This scenario is a grandstrategic version of a simple mugging, Ryan thought.

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How are you feeling? Get some sleep, son. It was a fifteen-minute drive to the Marriott. Cincinnati was playing San Francisco, the two best quarterbacks in the league pitted against one another. Football was something he missed living in England, and he managed to stay awake nearly three hours before fading out with the television on. Except for the fact that everyone was in uniform, a visitor might easily have mistaken the room for a NASA control center. There were six wide rows of consoles, each with its own TV screen and typewriter keyboard supplemented by lighted plastic buttons, dials, headphone jacks, and analog and digital controls.

It was in a fairly nondescript building, uninspired government layer cake, with windowless concrete walls, a large air-conditioning system on a flat roof, and an acronym-coded blue sign on a well-tended but now yellowed lawn. There were armed marines inconspicuously on guard inside the three entrances. In the basement were a pair of Cray-2 supercomputers tended by twenty acolytes, and behind the building was a trio of satellite ground stations, all up-and down-links.

The men at the consoles and the computers were linked electronically by satellite and landline to the SOSUS system. Throughout the oceans of the world, and especially astride the passages that Soviet submarines had to cross to reach the open sea, the United States and other NATO countries had deployed gangs of highly sensitive sonar receptors. The hundreds of SOSUS sensors received and forwarded an unimaginably vast amount of information, and to help the system operators classify and analyze it a whole new family of computers had to be designed, the supercomputers.

SOSUS served its purpose admirably well. Very little could cross a barrier without being detected. Even the ultraquiet American and British attack submarines were generally picked up.

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The sensors, lying on the bottom of the sea, were periodically updated; many now had their own signal processors to presort the data they forwarded, lightening the load on the central computers and enabling more rapid and accurate classification of targets. He was responsible for an area forty nautical miles across, and his sector overlapped the ones east and west so that, theoretically, three operators were constantly monitoring any segment of the barrier. If he got a contact, he would first notify his brother operators, then type a contact report into his computer terminal, which would in turn be displayed on the master control board in the control room at the back of the floor.

The senior duty officer had the frequently exercised authority to prosecute a contact with a wide range of assets, from surface ships to antisubmarine aircraft. Two world wars had taught American and British officers the necessity of keeping their sea lines of communication—SLOCs—open. Although this quiet, tomblike facility had never been shown to the public, and though it had none of the drama associated with military life, the men on duty here were among the most important in the service of their country.

In a war, without them, whole nations might starve. Franklin was leaning back in his swivel chair, puffing contemplatively on an old briar pipe. Around him the room was dead quiet. Even had it not been, his five-hundred-dollar headphones would have effectively sealed him off from the outside world.

A twenty-six year chief, Franklin had served his entire career on destroyers and frigates. To him, submarines and submariners were the enemy, regardless of what flag they might fly or what uniform they might wear. An eyebrow went up, and his nearly bald head cocked to one side. The pulls on the pipe grew irregular. His right hand reached forward to the control panel and switched off the signal processors so that he could get the sound without computerized interference. But it was no good. There was too much background noise. He switched the filters back on. Next he tried some changes in his azimuth controls.

The SOSUS sensors were designed to give bearing checks through the selective use of individual receptors, which he could manipulate electronically, first getting one bearing, then using a neighboring gang to triangulate for a fix. The contact was very faint, but not too far from the line, he judged. Franklin queried his computer terminal. The USS Dallas was up there. Another noise came through, a low-frequency rumble that only lasted a few seconds before fading out. Not all that quiet, though. He set his pipe down and began making adjustments on his control board. Commander Quentin was a former destroyer skipper on a limited duty after a winning battle with cancer.

Almost a winning battle, Franklin corrected himself. Chemotherapy had killed the cancer—at the cost of nearly all his hair, and turning his skin into a sort of transparent parchment. Too bad, he thought, Quentin was a pretty good man. The control room was elevated a few feet from the rest of the floor so that its occupants could see over the whole crew of duty operators and the main tactical display on the far wall.

It was separated from the floor by glass, which allowed them to speak to one another without disturbing the operators. Franklin found Quentin at his command station, where he could tap into any console on the floor. It was about time. Like many people he had a gut suspicion that cancer was contagious. I read a pair of Alfas , a Charlie , a Tango , and a few surface ships.

What gives, sir? Quentin rubbed his eyes. The man looked tired. The Typhoon that was supposed to have sailed the other day, maybe? The operators we have on that sector are a little young. That part of the team was still green, used to working on ships. SOSUS required more finesse. Real faint, but I think I got her crossing my sector, headed northwest for Toll Booth.

If we get an Orion down there, we might just get her locked in. Can we rattle their cage a little? Quentin chuckled. Nice work, though. You know her reputation. It was not the grandest office in the Kremlin, but it suited his needs. The large office windows overlooked the Kremlin walls; except for those he would have had a view of the Moscow River, now frozen solid. Padorin did not miss the view, though he had won his spurs commanding river gunboats forty years before, running supplies across the Volga into Stalingrad. Padorin was now the chief political officer of the Soviet Navy.

His job was men, not ships. On the way in he nodded curtly to his secretary, a man of forty. The yeoman leaped to his feet and followed his admiral into the inner office to help him off with his greatcoat. He had won that in combat as a freckled boy of twenty, shuttling back and forth on the Volga. Those were good days, he told himself, dodging bombs from the German Stukas and the more random artillery fire with which the Fascists had tried to interdict his squadron…Like most men he was unable to remember the stark terror of combat.

It was a Tuesday morning, and Padorin had a pile of mail waiting on his desk. His yeoman got him a pot of tea and a cup—the usual Russian glass cup set in a metal holder, sterling silver in this case. Padorin had worked long and hard for the perqs that came with this office. He settled in his chair and read first through the intelligence dispatches, information copies of data sent each morning and evening to the operational commands of the Soviet Navy.

A political officer had to keep current, to know what the imperialists were up to so that he could brief his men on the threat. He had access to all of the correspondence from the former, while that from the latter had been carefully vetted since the Soviet armed services share as little information as possible. The usual Monday afternoon meeting had covered most of what had to be done that week, and nearly everything Padorin was concerned with was now in the hands of his staff for disposition. He checked his desk calendar—good, no appointments until ten.

Near the bottom of the pile was an official-looking envelope from the Northern Fleet. The code number at the upper left corner showed that it came from the Red October. Padorin rechecked his ops dispatches. He shrugged. Missile submarines were supposed to be elusive, and it would not have surprised the old admiral at all if Ramius were twisting a few tails. The son of Aleksandr Ramius was a prima donna who had the troubling habit of seeming to build his own personality cult: he kept some of the men he trained and discarded others.

Padorin reflected that those rejected for line service had made excellent zampoliti , and appeared to have more line knowledge than was the norm. Even so, Ramius was a captain who needed watching. Sometimes Padorin suspected that he was too much a sailor and not enough a Communist. On the other hand, his father had been a model Party member and a hero of the Great Patriotic War.

Certainly he had been well thought of, Lithuanian or not. And the son? Years of letter-perfect performance, as many years of stalwart Party membership. He was known for his spirited participation at meetings and occasionally brilliant essays. The people in the naval branch of the GRU, the Soviet military intelligence agency, reported that the imperialists regarded him as a dangerous and skilled enemy. Good, Padorin thought, the bastards ought to fear our men. He turned his attention back to the envelope.

Red October , now there was a fitting name for a Soviet warship! Named not only for the revolution that had forever changed the history of the world but also for the Red October Tractor Plant. Many was the dawn when Padorin had looked west to Stalingrad to see if the factory still stood, a symbol of the Soviet fighting men struggling against the Hitlerite bandits. The envelope was marked Confidential, and his yeoman had not opened it as he had the other routine mail. The admiral took his letter opener from the desk drawer.

Stolen Child

It was a sentimental object, having been his service knife years before. Later a machinist had trimmed the blade down. Padorin stopped reading and started over. He forgot the cigarette smoldering in his ashtray as he reached the bottom of the first page. A joke. This was going too fucking far! He turned the page. Padorin stopped and looked out the window. The Kremlin wall at this point was a beehive of niches for the ashes of the Party faithful.

He started to read it again. His hands began to shake. I am coming over now. Sonarman Second Class Ronald Jones, his division officer noted, was in his usual trance. The young college dropout was hunched over his instrument table, body limp, eyes closed, face locked into the same neutral expression he wore when listening to one of the many Bach tapes on his expensive personal cassette player.

Jones was the sort who categorized his tapes by their flaws, a ragged piano tempo, a botched flute, a wavering French horn. He listened to sea sounds with the same discriminating intensity. In all the navies of the world, submariners were regarded as a curious breed, and submariners themselves looked upon sonar operators as odd. Their eccentricities, however, were among the most tolerated in the military service.

He became so familiar with the humpback whales that summered in the area that he took to calling them by name. On retiring, he went to work for the Woods Hole Oceanographic Institute, where his talent was regarded not so much with amusement as awe. Three years earlier, Jones had been asked to leave the California Institute of Technology in the middle of his junior year.

Now he was serving his time in the navy to finance his return. It was his announced intention to get a doctorate in cybernetics and signal processing. In return for an early out, after receiving his degree he would go to work for the Naval Research Laboratory. Lieutenant Thompson believed it. On joining the Dallas six months earlier, he had read the files of all his men. He had a placid face and sad brown eyes that women found irresistible. On the beach Jones had enough action to wear down a squad of marines.

Jones was a skinny kid who listened to Bach. The USS Dallas , a class attack submarine, was forty miles from the coast of Iceland, approaching her patrol station, code-named Toll Booth. She was two days late getting there. In that exercise the Dallas , teamed with HMS Swiftsure , had used the foul weather to penetrate and ravage the simulated enemy formation. It was yet another four-oh performance for the Dallas and her skipper, Commander Bart Mancuso, one of the youngest submarine commanders in the U. For three weeks, the Dallas was to report on traffic in and out of Red Route One.

Over the past fourteen months, newer Soviet submarines had been using a strange, effective tactic for shedding their American and British shadowers. Southwest of Iceland the Russian boats would race down the Reykjanes Ridge, a finger of underwater highlands pointing to the deep Atlantic basin.

Spaced at intervals from five miles to half a mile, these mountains with their knife-edged ridges of brittle igneous rock rivaled the Alps in size. Their peaks were about a thousand feet beneath the stormy surface of the North Atlantic. Before the late sixties submarines could barely approach the peaks, much less probe their myriad valleys. Throughout the seventies Soviet naval survey vessels had been seen patrolling the ridge—in all seasons, in all weather, quartering and requartering the area in thousands of cruises. The Victor had skirted the Icelandic coast and gone deep as she approached the ridge.

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The Los Angeles had followed. All at once she went to full speed and moved southwest. The skipper of the Los Angeles made a determined effort to track the Victor and came away from it badly shaken. Although the class submarines were faster than the older Victors , the Russian submarine had simply not slowed down—for fifteen hours, it was later determined.

At first it had not been all that dangerous. Submarines had highly accurate inertial navigation systems able to fix their positions to within a few hundred yards from one second to another. But the Victor was skirting cliffs as though her skipper could see them, like a fighter dodging down a canyon to avoid surface-to-air missile fire. The Los Angeles could not keep track of the cliffs. At any speed over twenty knots both her passive and active sonar, including the echofathometer, became almost useless.

The Los Angeles thus found herself navigating completely blind. It was, the skipper later reported, like driving a car with the windows painted over, steering with a map and a stopwatch. Worst of all, his charts were made for surface ships. Objects below a few hundred feet had been known to be misplaced by miles—something that mattered to no one until recently. The interval between mountains had quickly become less than his cumulative navigational error—sooner or later his submarine would drive into a mountainside at over thirty knots.

The captain backed off. The Victor got away. Initially it was theorized that the Soviets had somehow staked out one particular route, that their submarines were able to follow it at high speed. Russian skippers were known to pull some crazy stunts, and perhaps they were trusting to a combination of inertial systems, magnetic and gyro compasses attuned to a specific track. This theory had never developed much of a following, and in a few weeks it was known for certain that the Soviet submarines speeding through the ridge were following a multiplicity of tracks.

The only thing American and British subs could do was stop periodically to get a sonar fix of their positions, then race to catch up. But the Soviet subs never slowed, and the s and Trafalgars kept falling behind. The Dallas was on Toll Booth station to monitor passing Russian subs, to watch the entrance to the passage the U. Navy was now calling Red Route One, and to listen for any external evidence of a new gadget that might enable the Soviets to run the ridge so boldly.

Until the Americans could copy it, there were three unsavory alternatives: they could continue losing contact with the Russians; they could station valuable attack subs at the known exits from the route; or they could set up a whole new SOSUS line. He ordinarily had a contact figured out in far less time. The sailor leaned back and lit a cigarette. Thompson himself was a masters candidate in electrical engineering, an expert in sonar system design.

His eyes screwed shut as he concentrated on the sound. It was a very faint low-frequency rumble—or swish. He listened for several minutes before setting the headphones down, then shook his head. He referred to a subsystem of the BQQ-5 multifunction submarine sonar. Its main component was an eighteen-foot-diameter dome located in the bow. The dome was used for both active and passive operations. A new part of the system was a gang of passive sensors which extended two hundred feet down both sides of the hull.

This was a mechanical analog to the sensory organs on the body of a shark. More like water going through a pipe, except for that funny rumble that comes and goes. Anyway, the bearing is about two-five-zero. Jones took a double-plugged wire from a hook. One plug went into a socket on his sonar panel, the other into the jack on a nearby oscilloscope. The two men spent several minutes working with the sonar controls to isolate the signal. They ended up with an irregular sine wave which they were only able to hold a few seconds at a time.

Know what I mean, Mr. His vintage Janis Joplin tapes were his own business. During her last overhaul, the Dallas had received a very special toy to go along with her BQQ-5 sonar system. Called the BC, it was the most powerful computer yet installed aboard a submarine. Though only about the size of a business desk, it cost over five million dollars and ran at eighty million operations per second.

It used newly developed sixty-four-bit chips and made use of the latest processing architecture. Its bubble memory could easily accommodate the computing needs of a whole squadron of submarines. In five years every attack sub in the fleet would have one. Its purpose, much like that of the far larger SOSUS system, was to process and analyze sonar signals; the BC stripped away ambient noise and other naturally produced sea sounds to classify and identify man-made noise. It could identify ships by name from their individual acoustical signatures, much as one could identify the finger or voice prints of a human.

As important as the computer was its programming software. The problem the program addressed was one of signal versus noise. It overcame the difficulty seismologists had discriminating between random noise that is constantly monitored on seismographs and genuinely unusual signals that foretell a seismic event. The first Defense Department use of the program was in the Air Force Technical Applications Command AFTAC , which found it entirely satisfactory for its mission of monitoring nuclear events throughout the world in accordance with arms control treaties.

The Navy Research Laboratory also redrafted it for its own purposes. Though inadequate for seismic predictions, it worked very well indeed in analyzing sonar signals. The program was known in the navy as the signal algorithmic processing system SAPS. For all the fantastic speed of the BC, the six hundred thousand steps of the program, punctuated by numerous GOTO loops, took time to run as the machine eliminated natural sounds with its random profile criteria and then locked into the anomalous signal.

It took twenty seconds, an eternity in computer time. The answer came up on the VDT. Jones pressed a key to generate a copy on the adjacent matrix printer. Thompson chuckled. For all the ballyhoo that had accompanied the new system, it was not all that popular in the fleet. Something about seismic activity around Iceland, like when that island poked up back in the sixties.

Jones lit another cigarette. He knew the student who had originally drafted this abortion they called SAPS. Besides, since it had been originally designed to look for seismic events, Jones suspected it of a tendency to interpret anomalies as seismic events. It was one thing to use computers as a tool, quite another to let them do your thinking for you. Besides, they were always discovering new sea sounds that nobody had ever heard before, much less classified.

Commander Mancuso came in just then, the usual mug of coffee in his hand. If there was one frightening thing about the captain, Thompson thought, it was his talent for showing up when something was going on. Did he have the whole boat wired? He was a small man, only five eight, who had fought a battle against his waistline all his life and was now losing because of the good food and lack of exercise on a submarine.

His dark eyes were surrounded by laugh lines that were always deeper when he was playing a trick on another ship. Was it day, Thompson wondered? The crew of the Dallas was like one big family, albeit one of the old frontier families, since everybody worked pretty damned hard. The captain was the father.

The executive officer, everyone would readily agree, was the mother. The officers were the older kids, and the enlisted men were the younger kids. The important thing was, if you had something to say, the captain would listen to you. To Jones, this counted for a lot. Mancuso nodded thoughtfully. No sense letting all this expensive gear go to waste.

Jones grinned. Mancuso had pointed out that it would not be a major feat, since the sonar gear in this room alone cost over twenty million dollars. Jones was the sonar watch supervisor. The other two watchstanders noted the new signal, and Jones switched his phones to the towed array jack while the two officers kept out of the way.

He took a scratch pad and noted the time before working on his individual controls. The BQR was the most sensitive sonar rig on the boat, but its sensitivity was not needed for this contact. Jones shook his head. Victor class for sure. Bearing zero-five-zero. Skipper, we got good water around us, and the signal is real faint.

Not close meant anything over ten miles. He went back to working his controls. The lieutenant was already keying the signal into the BC The bulkhead-mounted speaker would have commanded a four-figure price in any stereo shop for its clarity and dynamic perfection; like everything else on the class sub, it was the very best that money could buy. The next thing Mancuso heard was the printer.

A Victor class, bearing zero-five-zero, estimated target speed thirty knots. Mancuso leaned out into the passageway to address Lieutenant Pat Mannion, officer of the deck. More easterly, bearing zero-seven-three, doing turns for about twenty-eight knots. We know this guy, too.

Yeah, Charlie II , number eleven. What the hell was going on? Good work, guys. He went a few steps forward into the attack center. The normal steaming watch was set. Mannion had the conn, with a junior officer of the deck and seven enlisted men. A first-class firecontrolman was entering data from the target motion analyzer into the Mark fire control computer. Another officer was entering control to take charge of the tracking exercise. There was nothing unusual about this.

The whole watch went about its work alertly but with the relaxed demeanor that came with years of training and experience. While the other armed services routinely had their components run exercises against allies or themselves in emulation of Eastern Bloc tactics, the navy had its attack submarines play their games against the real thing—and constantly. Submariners typically operated on what was effectively an at-war footing.

Alfa 3 , bearing zero-five-five. Running flat out. Sounds like an earthquake, but faint, sir. Our old friend, the Politovskiy. Anything else you can tell me? The sound on this one warbled, then settled down, like she was making a turn. And we have some more noise to the northeast.

Too confused to make any sense of just now. Mancuso smiled as he set the phone down, looking over at Mannion. Mannion looked at the paper tracks that Goodman was drawing to back up the computerized targeting process. Problem is, he thinks we work for him.

It also meant that they could not develop the range data necessary for a fire control solution. Not that anyone wanted to shoot, but this was the point of the exercise. There were two reasons for this. First, it would establish a base line from which to compute probable target range. Second, the deeper water would make for better acoustical conditions, opening up to them the distant sonar convergence zone. The captain studied the chart as his navigator gave the necessary orders, evaluating the tactical situation.

Bart had accompanied his father on these hunts, shot his first deer at the age of twelve and every year thereafter until entering the Naval Academy. He had never bothered after that. Since becoming an officer on nuclear submarines he had learned a much more diverting game. Now he hunted people. Like all nuclear submarines, the Dallas was trailing a lengthy wire antenna attuned to the extremely low-frequency transmitter in the central United States.

The channel had a frustratingly narrow data band width. Unlike a TV channel, which transmitted thousands of bits of data per frame, thirty frames per second, the ELF radio passed on data slowly, about one character every thirty seconds.

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The duty radioman waited patiently while the information was recorded on tape. When the message was finished, he ran the tape at high speed and transcribed the message, handing it to the communications officer who was waiting with his code book. A book, published every six months and distributed to every nuclear submarine, was filled with randomly generated transpositions for each letter of the signal. Each scrambled three-letter group in this book corresponded to a preselected word or phrase in another book. Deciphering the message by hand took under three minutes, and when that was completed it was carried to the captain in the attack center.

The old man was evidently contemplating a reshuffling of his entire force, no minor affair. The next wake-up signal, AAA—encrypted, of course—would alert them to go to periscope-antenna depth to get more detailed instructions from SSIX, the submarine satellite information exchange, a geosynchronous communications satellite used exclusively by submarines. The tactical situation was becoming clearer, though its strategic implications were beyond his ability to judge.

The ten-mile move eastward had given them adequate range information for their initial three contacts and another Alfa which had turned up a few minutes later. The first of the contacts, Vic 6 , was now within torpedo range. A Mark 48 was locked in on her, and there was no way that her skipper could know the Dallas was here. Though not much faster than the Victors and Charlies , and ten knots slower than the smaller Alfas , the Dallas and her sisters could move almost silently at nearly twenty knots. This was a triumph of engineering and design, the product of decades of work.

But moving without being detected was useful only if the hunter could at the same time detect his quarry. Sonars lost effectiveness as their carrier platform increased speed.

Submarines running at high speed from one point to another were blind and unable to harm anyone. As a result, the operating pattern of an attack submarine was much like that of a combat infantryman. With a rifleman it was called dash-and-cover; with a sub, sprint-and-drift. After detecting a target, a sub would race to a more advantageous position, stop to reacquire her prey, then dash again until a firing position had been achieved.

Mancuso had all of these things. He had spent fifteen years learning his craft, watching a generation of commanders as a junior officer, listening carefully at the frequent round-table discussions which made submarining a very human profession, its lessons passed on by verbal tradition.

Time on shore had been spent training in a variety of computerized simulators, attending seminars, comparing notes and ideas with his peers. Submariners lived by a simple motto: There are two kinds of ships, submarines…and targets. What would Dallas be hunting? Mancuso wondered. Russian subs? Well, if that was the game and the Russians kept racing around like this, it ought to be easy enough. His boat and his crew were performing as well as any man could ask. In Jones he had one of the ten best sonar operators in the fleet.

Mancuso was ready, whatever the game might be. As on the opening day of hunting season, outside considerations were dwindling away. He was becoming a weapon. About that, enough time to see his boss, see Skip, get the presents for Sally, and check the house. The house looked to be in good shape. He had rented it to an instructor at the Naval Academy. The officer was a Bible-thumper from Kansas, and made an acceptable custodian.

Five and a half hours of sleep in the past—thirty? Something like that; he was too tired to look at his watch. Sleeplessness murders judgment. But it made little sense telling himself that, and telling the admiral would make less. Ryan dropped his topcoat on the sofa and walked over to pour a mug of navy brew. He decided against Coffee Mate or sugar. Better to endure it naked and get the caffeine full force. Ryan looked at his watch. Ryan scanned it. Must be nearly everything they have at sea.

Not much on the ones in port, though. By the way, that is every ship they have at sea in the Western Hemisphere. Every damned one. Any ideas? Looks like a medium-sized ASW exercise. Do they have a war game laid on? Ryan nodded. Have they ever run a major game in December? No idea what the signal said, eh? In fact it was a law unto itself. Their army? Voyska PVO? Ryan stretched. Have you talked to Admiral Davenport? It looks like a lot of boats are heading into the North Atlantic. Their units in the Norwegian Sea are racing southwest.

We need a few more hours. Two old Novembers. Ryan smiled to himself. An American or allied ship was a she; the Russians used the male pronoun for a ship; and the intelligence community usually referred to a Soviet ship as it. Probably wrong. Reciprocal bearing, transcription error, something like that. Must be a goof, because it was heading south earlier. No news on them. So all we have at the moment is the report on the stray Yankee. NORAD has gone to a slightly increased alert status, they tell me.

Some extra P-3s are working out of Iceland. Nothing much else at the moment. He shook a finger at Ryan. Probably some admiral, maybe old Sergey himself, decided to toss a drill at his boys. Greer knew all this. By the time he had graduated from there and finished training at submarine school, the war was almost over. He reached the Japanese coast on his first cruise the day after the war ended.

If the Russkies can fool all of us, maybe we ought to read up on our Marx. Sooo—we stay up and watch. Fortunately, sir, you make a decent cup of coffee. If we can finish up on the Afghanistan stuff, maybe I can fly back tomorr—tonight. Breakfast was sent up twenty minutes later. Both men were accustomed to big ones, and the food was surprisingly good.

Ordinarily CIA cafeteria food was government-undistinguished, and Ryan wondered if the night crew, with fewer people to serve, might take the time to do their job right. Or maybe they had sent out for it. The two men sat around until Davenport phoned at quarter to seven. All the boomers are heading towards port. We have good tracks on two Yankee s, three Delta s, and a Typhoon. Memphis reported when her Delta took off for home at twenty knots after being on station for five days, and then Gallery queried Queenfish.

Davenport had already thought of that. The blood in Norfolk was supposed to have been ankle deep after that fiasco. The USS Tullibee , a small one-of-a-kind attack sub, had long carried a reputation for bad luck. In this case it had spilled over onto a lot of others. Have they ever done this before? What about the ones in the Pacific? Ramius is too good a skipper to let that happen. Nothing to worry about yet. Ten minutes later a messenger arrived with a cart from central files.

Greer was the sort who liked to see the raw data himself. This suited Ryan. The information on the cart was from a variety of sources, but to Ryan the most significant were tactical radio intercepts from listening posts on the Pakistani border, and, he gathered, from inside Afghanistan itself. The nature and tempo of Soviet operations did not indicate a backing off, as seemed to be suggested by a pair of recent articles in Red Star and some intelligence sources inside the Soviet Union. They spent three hours reviewing the data. We know that from both military and political intelligence reports.

The tenor of the data is pretty clear. In a case like this the bureaucratic mind finds it most easy to do nothing. So, their field commanders are told to continue the mission, while the senior party bosses fumble around looking for a solution and covering their asses for getting into the mess in the first place. The admiral snorted. Greer wondered if that would change in time. He hoped not. After lunch a package arrived by messenger from the National Reconnaissance Office. It contained the photographs taken earlier in the day on two successive passes by a KH satellite.

The first set of visible light shots taken an hour after the FLASH signal had gone out from Moscow showed the fleet at anchor or tied to the docks. On infrared a number of them were glowing brightly from internal heat, indicating that their boilers or gas-turbine engine plants were operating. The second set of photos had been taken on the next orbital pass at a very low angle.

Ryan scrutinized the blowups. Every fast oiler they have is following them out. But we still have their boomers heading back in. No amphibious ships in this photo, just combatants. Only the new ones, too, the ones with range and speed. This must have been laid on today. Ryan had been to the office of the director of central intelligence several times before to deliver briefings and occasional personal messages from Sir Basil Charleston to his highness, the DCI.

Arthur Moore was a former judge of the Texas State Supreme Court, and the room reflected his southwestern heritage. He and Admiral Greer were sitting on a sofa near the picture window. Greer waved Ryan over and passed him a folder. The folder was made of red plastic and had a snap closure. Neither notation was unusual. A computer in the basement of the Langley headquarters selected random names at the touch of a key; this prevented a foreign agent from inferring anything from the name of the operation.

Ryan opened the folder and looked first at the index sheet. This one was initialed by the DCI himself. Ryan turned the index sheet. The report was a xeroxed copy of something that had been typed on a manual machine, and it had too many strikeovers to have been done by a real secretary.

If Nancy Cummings and the other elite executive secretaries had not been allowed to see this…Ryan looked up. The highest ranking agent-in-place the CIA had ever had, he was the stuff that legends are made of. The information he smuggled out through his British contact, Greville Wynne, was supremely valuable, and Western countries had come to depend on it—too much.

Penkovskiy was discovered during the Cuban Missile Crisis in It was his data, ordered and delivered under great pressure and haste, that told President Kennedy that Soviet strategic systems were not ready for war. This information enabled the president to back Khrushchev into a corner from which there was no easy exit.

This advantage was given him by a courageous agent whom he would never meet. Already under suspicion, this finished him. He paid for his treason with his life. He warned Penkovskiy—too late. It was the final ironic joke of a brave man that his own death would advance the career of an agent whom he had recruited. He thus had access to political and military intelligence of the highest order. This made his information extraordinarily valuable—and, paradoxically, highly suspect.

But he had outlived many small-fry agents. On the first day of each month a new code name was chosen for his data, a name made known only to the highest echelon of CIA officers and analysts. There were also a number of security measures that protected the agent and were unique to him. He had outlived twelve station chiefs; one of these, a retired field officer, had a brother who was a Jesuit. Every morning the priest, an instructor in philosophy and theology at Fordham University in New York, said mass for the safety and the soul of a man whose name he would never know.

Four separate times he had been offered extraction from the Soviet Union. Each time he had refused. The document Ryan was reading had been in transit for twenty hours. It had taken five for the film to reach the American embassy in Moscow, where it was delivered at once to the station chief. He developed the film himself in his private darkroom. Next he transcribed the message from the film to flash paper on his own portable typewriter, translating from the Russian as he went. The film was then burned to ashes, the report folded into a metal container much like a cigarette case.

This held a small pyrotechnic charge that would go off if the case were improperly opened or suddenly shaken; two CARDINAL signals had been lost when their cases were accidentally dropped. By eight that morning the diplomatic bag was in the State Department. The DCI made three copies on his personal Xerox machine and burned the flash paper in his ashtray. These security measures had struck a few of the men who had succeeded to the office of the DCI as laughable. When Ryan finished the report he referred back to the second page and read it through again, shaking his head slowly.

The WILLOW document was the strongest reinforcement yet of his desire not to know how intelligence information reached him. He closed the folder and handed it back to Admiral Greer. Is that understood? The judge, everyone said, had been a hell of a field officer in his day. The loss had delayed a Chinese offensive for several months, saving thousands of American and allied lives. But it had been a bloody operation. All of the Chinese personnel and all of the Norwegian crewmen had vanished.

It was a bargain in the simple mathematics of war, but the morality of the mission was another matter. For this reason, or perhaps another, Moore had soon thereafter left government service to become a trial lawyer in his native Texas. He had been recalled to the CIA three years earlier because of his unique combination of absolute personal integrity and experience in black operations.

Judge Moore hid a Harvard law degree and a highly ordered mind behind the facade of a West Texas cowboy, something he had never been but simulated with ease. Ryan, what do you think of this? The problem was, his conclusion was too incredible. Ryan had trained himself to be objective. He ran through the four alternatives he had considered, careful to examine each in detail. This was no time to allow personal views to intrude on his thinking.

He spoke for ten minutes. I cannot evaluate that possibility. The biggest question is the availability of our own assets. Do we have the pieces in place? Greer answered. One carrier, Kennedy. I checked. Admiral White, I believe, commanding a small battle group. Our wives are friendly. I hunted with him last September, a grouse shoot in Scotland. He makes noises like a good operator, and I hear he has a good reputation.

But we have to tell our side first. Ryan, you will prepare the briefing papers and deliver the briefing yourself. Prove it. Bob, I want you to confirm this report. Moore looked at his watch. Ryan, you have ninety minutes. Get cracking. Arch Ophthalmol ; 12 : Smoking and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Risk factors for incident age-related macular degeneration: pooled findings from 3 continents. Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study. Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study.

Am J Epidemiol ; 7 : The LOC gene, smoking, body mass index, environmental associations with advanced age-related macular degeneration. Hum Hered ; 63 : CFH gene variant, YH, and smoking, body mass index, environmental associations with advanced age-related macular degeneration. Hum Hered ; 61 3 : Cigarette smoking strongly modifies the association of LOC and age-related macular degeneration.

Am J Hum Genet ; 78 5 : Klein R. Overview of progress in the epidemiology of age-related macular degeneration. Ophthalmic Epidemiol ; 14 4 : The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol ; 45 2 : Chiu CJ, Taylor A. Nutritional antioxidants and age-related cataract and maculopathy.

Exp Eye Res ; 84 2 : A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. Erratum in: ; 9 : Int J Vitam Nutr Res ; 71 1 : Sunlight exposure, antioxidants, and age-related macular degeneration. Age-related macular degeneration and antioxidant status in the POLA study. Dietary intake of antioxidants and risk of age-related macular degeneration. JAMA ; 24 : Macular pigment: a review of current knowledge.

Arch Ophthalmol ; 7 : Serum antioxidants and age-related macular degeneration in a population-based case-control study. Antioxidant status and neovascular age-related macular degeneration. Arch Ophthalmol ; 1 : Erratum in: Arch Ophthalmol ; 11 : Lutein and zeaxanthin in the diet and serum and their relation to age-related maculopathy in the third national health and nutrition examination survey. Am J Epidemiol ; 5 : Lutein and zeaxanthin status and risk of age-related macular degeneration. Invest Ophthalmol Vis Sci ; 44 6 : Plasma lutein and zeaxanthin and other carotenoids as modifiable risk factors for age-related maculopathy and cataract: the POLA Study.

Invest Ophthalmol Vis Sci ; 47 6 : Associations between antioxidant and zinc intake and the 5-year incidence of early age-related maculopathy in the Beaver Dam Eye Study. Am J Clin Nutr ; 87 6 : Dietary antioxidants and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Associations of plasma carotenoids with risk factors and biomarkers related to cardiovascular disease in middle-aged and older women. Am J Clin Nutr ; 88 3 : J Nutr ; 9 : Distribution, interconversion, and dose response of n-3 fatty acids in humans.

The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Prog Retin Eye Res ; 24 1 : Dietary fat and risk for advanced age-related macular degeneration. Arch Ophthalmol ; 5 : Cigarette smoking, fish consumption, omega-3 fatty acid intake, and associations with age-related macular degeneration: the US Twin Study of Age-Related Macular Degeneration.

Dietary fat and age-related maculopathy. Eur J Clin Nutr ; 61 11 : Oily fish consumption, dietary docosahexaenoic acid and eicosapentaenoic acid intakes, and associations with neovascular age-related macular degeneration. Am J Clin Nutr ; 88 2 : Prospective study of dietary fat and the risk of age-related macular degeneration. Am J Clin Nutr ; 73 2 : Dietary fatty acids and the 5-year incidence of age-related maculopathy. Risk factors for five-year incident age-related macular degeneration: the Reykjavik Eye Study. Am J Ophthalmol ; 3 : Progression of age-related macular degeneration: association with dietary fat, transunsaturated fat, nuts, and fish intake.

Erratum in: Arch Ophthalmol ; 3 : Am J Clin Nutr ; 90 6 : Dietary omega-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration: a systematic review and meta-analysis. Dietary lutein, zeaxanthin, and fats and the progression of age-related macular degeneration.

Can J Ophthalmol ; 42 5 : Elevated serum homocysteine, low serum vitamin B12, folate, and age-related macular degeneration: the Blue Mountains Eye Study. Plasma homocysteine, vitamin B12 and folate levels in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol ; 5 : Homocysteine, vitamin B12, and folic acid in age-related macular degeneration. Eur J Ophthalmol ; 15 6 : Association of neovascular age-related macular degeneration and hyperhomocysteinemia.

Biomarkers of cardiovascular disease as risk factors for age-related macular degeneration. Ophthalmology ; 12 : Evaluation of plasma homocysteine and risk of age-related macular degeneration. Arch Intern Med ; 4 : Association between vitamin D and age-related macular degeneration in the Third National Health and Nutrition Examination Survey, through Age-related maculopathy and the impact of blue light hazard. Acta Ophthalmol Scand ;. The long-term effects of visible light on the eye. Sunlight and age-related macular degeneration. Sunlight and the year incidence of age-related maculopathy: the Beaver Dam Eye Study.

Risk factors for neovascular age-related macular degeneration. Risk factors for age-related maculopathy: the Visual Impairment Project. Sun exposure and age-related macular degeneration. An Australian case-control study. Ophthalmology ; 5 : Sunlight-related factors and the year incidence of age-related maculopathy. Ophthalmic Epidemiol ; 16 2 : Age-related macular degeneration after extracapsular cataract extraction with intraocular lens implantation.

Cataract surgery and the risk of aging macula disorder: the rotterdam study. Invest Ophthalmol Vis Sci ; 49 11 : Cataract surgery is associated with a higher rate of photodynamic therapy for age-related macular degeneration. Cataract surgery and the year incidence of age-related maculopathy: the Blue Mountains Eye Study. Ophthalmology ; 11 : Cataract surgery and the 5-year incidence of late-stage age-related maculopathy: pooled findings from the Beaver Dam and Blue Mountains eye studies.

The association of cataract and cataract surgery with the long-term incidence of age-related maculopathy: the Beaver Dam eye study. Early age-related maculopathy in eyes after cataract surgery. Eye ; 21 4 : Is pseudophakia a risk factor for neovascular age-related macular degeneration? Invest Ophthalmol Vis Sci ;48 4 : A blue-blocking intraocular lens should be used in cataract surgery. Journal Nutr Health Aging. Age-related changes that predispose to age-related macular degeneration AMD occur in the outer retina, more specifically the region that includes the photoreceptors, the retinal pigment epithelium RPE , Bruch.

Retinal anatomy is highly organized and vascular and avascular compartments are strictly segregated in the retina 1. The blood-retinal barriers, inner and outer, are fundamental for the integrity of structure and optimization of function in neuro-sensorial retina 2. The outer blood-retinal barrier is formed, among its various components, by the RPE tight junctions. The intercellular cohesiveness of the RPE is not easily disrupted. Tight junctions appear as a necklace of strands that encircle each cell, binding each cell to its neighbors in a monolayer that separate the outer layer of the neural retina from the choriocapillaris 3.

Choriocapillaris is a great vascular network of fenestrated capillaries with high blood flow, fundamental for the metabolism of outer retina. This outer blood-retinal barrier retards transepithelial diffusion through the paracellular spaces 3. The RPE is a polarized epithelium that consist of a continuous pavement-like monolayer of cuboidal shaped cells that in macular area are tall, narrow and highly uniform in size and shape 4.

Interdigitation of the apical processes of the RPE with the cone and rod outer segments provides only a tenuous adhesion of the RPE to the sensory retina 5. From internal to external these layers are: the basement membrane of the RPE, the inner collagenous zone, the elastic tissue layer, the outer collagenous zone and the basement membrane of the choriocapillaris. It is composed of elements from both, the retina and choroid, but is an integral part of choroid 8. Its inner surface is smooth, whereas its outer surface is composed of a series of collagenous protrusions that extend externally to form the pillars separating and supporting the choriocapillaris 5.

Due to its specific location and properties, this tissue is thought to be a vital limiting layer for metabolic transport between the RPE cells and the choriocapillaris 9. The choriocapillaris consists of a continuous layer of fenestrated endothelial cells surrounded by a basement membrane. In the macula the choriocapillaris is arranged in a lobular pattern of highly concentrated interconnecting capillaries supplied by a central arteriole and drained by circumferential venules 5, The fenestrations, nm in diameter, are abundant and seem to play an important role in permitting the passage of glucose and vitamin A to the RPE and retina.

The peculiar structure of the choroidal vascular tree in the macula provides this area with the highest rate of blood flow of any tissue in the body 5. With aging, the neurosensory retina was shown to develop thickening of the internal limiting membrane, diminution of neural elements with age-related loss of rods before cones, gliosis in the peripheral retina, and diminution of capillaries around the fovea, while the lumina of the choriocapillaris and the choroidal thickness become reduced by half There is a linear thickening due to deposits of collagen, lipids and debris.

Its diminished function results in apoptosis of these cells from incorrect cell adhesion The RPE is a monolayer of regularly arranged hexagonal cells that spans the retina from the margins of the optic disc anteriorly to the ora serrata. The number of RPE cells diminishes with age. Macular RPE cells become wither, flatter and increase in height with advancing age 4, In each RPE cell there is a progressive accumulation of lipofuscin during life and in people over 80 years of age, the debris can occupy more than one fifth of the total volume of an RPE cell 18, RPE cells have a brown color in young eyes but with age, they become increasingly more golden colored, owing to the accumulation of lipofuscin pigment granules Lipofuscin in the RPE is the source of fundus autofluorescence.

The major component of lipofuscin is N-retinylidene-N-retinylethanol-amine A2E , a retinoid product of the visual cycle The A2E produced interferes with the function of RPE cells, leading to its apoptosis and subsequent geographic atrophy Age-related changes also include a decrease in the number of melanin granules, loss of basal digitations and irregularity in shape. The RPE cells become separated from their basal membrane by membranous debris and abnormal secretory products and subsequently occurs deposition of collagen and fibronectin and latter formation of basal laminar deposits Basal laminar deposits are composed of basement membrane protein and long-spacing collagen located between the RPE plasma and basement membranes Basal laminar deposits are considered the precursors of AMD and can appear around the age of 40 years These two types of deposits can only be shown on pathological specimens and not by clinical evaluation The combination of the deposits with secondary changes in the RPE results in the formation of drusen.

Drusen change in size, shape, color, distribution and consistency with the passing years The presence of small, hard drusen alone is not sufficient to diagnose early AMD. These deposits are ubiquitous and the new development of small drusen in an adult eye without prior evidence of hard drusen is not age dependent Hard drusen are discrete nodules or deposits composed of hyaline-like material.

During fluorescein angiography hard drusen behave as pin-point window defects Soft drusen have a tendency to cluster and merge with one another demonstrating confluence During fluorescein angiography soft drusen hyperfluoresce early and either fade or stain in the late phase 5.

The RPE degeneration and nongeographic atrophy of the RPE are characterized by pigment mottling and stippled hypopigmentation with thinning of the neurosensory retina Histopathology shows mottled areas of RPE hypopigmentation or atrophy overlying diffuse basal linear and basal laminar deposits Incidence and prevalence rates of RPE depigmentation are age dependent Focal hyperpigmentation of the RPE, clinically evident as pigment clumping at the level of the outer retina or sub-retinal space, increases the risk of progression to the late phases of the disease 34,36, Aging is known to be associated with increased oxidative damage and the retina is a fertile environment for reactive oxygen species.

Apart from the presence of two retinal blood supplies that generate an highly oxygenated environment, the exposure to high levels of cumulative irradiation, high levels of photosensitizers, large amounts of polyunsaturated fatty acids, readily oxidizable lipid, protein and carbohydrate substrates, and the huge proteolytic burden in the RPE contribute to this particular predisposition to oxidative stress 41, This state of accumulation of toxic elements is said to ultimately tip the balance of the ocular immune privilege towards immune activation and inflammation.

In this sequence of events, patient's susceptibility to AMD would be determined by both the environment and his genetic profile Geographic atrophy is clinically characterized by roughly oval areas of hypopigmentation that allows for increased visualization of the underlying choroidal vessels and is the consequence of RPE cell loss. Loss of RPE cells leads to gradual degeneration of photoreceptors and thinning of the retina that may extend to the outer plexiform and inner nuclear layers 6, Compensatory RPE cell proliferation leads to hyperpigmentary changes frequently observed at the periphery of the hypopigmented areas 6.

The atrophy of RPE is usually more severe than the loss of choriocapillaris but the choriocapillaris seem to be highly constricted in areas of complete RPE cell loss In neovascular AMD early choroidal neovascularization occurs under the RPE 46 and eventually breaks through 47 , leading to accumulation of lipid-rich fluid under the RPE or neuroretina.

In haemorrhagic forms blood breaks through the RPE into the subretinal space and sometimes through the retina and into the vitreous The pattern of growth of CNV often simulates that of a sea fan with radial arterioles and venules supplying and draining a circumferential dilated capillary sinus 5. As neovascularization of the sub-RPE space occurs, initially the blood flow through the neovascular network is sluggish and there is little or no exudation.

This is a period of occult neovascularization and the overlying RPE and neuroretina may be minimally affected 5. With an increase of blood flow through the network the endothelium decompensates and exudation extends into the subpigment epithelial space creating in some cases RPE detachments. The exudation may also extend through the RPE and detach the overlying retina. Macrophages have been documented both morphologically and functionally in neovascular AMD 48, Activated macrophages and microglia may secret cytokines and chemokines that promote cellular damage and angiogenesis Often anastomosis between the retinal circulation and the underlying choroidal circulation develops within these old disciforme scars 32, However its specific role and relevance in development and progression to neovascular and atrophic forms of AMD are discussed in others chapters of this book.

Age-related macular degeneration AMD is a complex disease with demographic and environmental risk factors age, diet, and smoking but also genetic risk factors. In fact, instead of having a single contributory gene, there are multiple genes of variable effects that seem to be involved turning the issue of genetics of AMD a complex one: AMD involves environmental factors and varying susceptibilities to these external factors based upon diferent genetic backgrounds 1.

The genetic component of the disease has been suspected from family, twin and sibling studies. According to several family studies, patients with a family history of AMD have an increased risk for developing AMD 2,3. The concordance for the presence of the disease is greater among homozigous twins than among heterozygous twins. In , Luo et al. Recurrence risk in relatives indicate increased relative risks in siblings 2. Many linkage and association studies have showed that chromosomes 1q 1q and 10q 10q26 had genes involved in this pathology It was the completion of the Human Genoma Project, 5 years ago, resulting in the knowledge of the sequencing of the human genome that allowed improved DNA sequencing and mapping technologies and consequently, identification of Single Nucleotide Polymorphism SNPs.

There are several types of genetic sequences variations polymorphisms in the human genome: repeated polymorphisms, insertions and deletions. These variants are also important because they serve as genetic markers and in this way they can help in determining those which confer increased or decreased risk of several diseases including AMD.

Dissection of the genetic background of AMD has undergone tremendous progress in the last 2 years. We know, now, some polymorphisms which modulate AMD risk. CFH is a negative regulator of alternative pathway of the complement system which means that in normal conditions, it inhibits the alternative pathway complement system.

It is encoded by a gene localized in 1q and its dysfunction may lead to excessive inflammation and tissue damage Complement activity is very important for the imune responses against pathogens and dying cells but, over-activation can result in complement-mediated damage to nearby healthy tissue cells. It is now accepted that CFH gene is an important susceptibility gene, harbouring variants and haplotypes short DNA sequences containing alleles associated with increased and reduced risk of AMD.

In the variant polymorphism CFH YH of the CFH gene, there is a substitution on the nucleotide in exon 9 where thymine T is changed for cytosine C rs which is the allele risk. This change leads to the substitution of the aminoacid in the position in the protein, from tyrosine Y to histidine H. The risk attributable for a disease is the rate of disease among individuals with a given characteristic minus the rate of the disease among indivuals without that characteristic. When compared with those with no risk allele TT, one copy of the TyrHis polimorphysm heterozygous for the risk allele TC , increases the risk of AMD by a factor of 2.

Complement factor B BF is involved in the activation of the complement alternative pathway and complement component 2 C2 is involved in the activation of the classical pathway of the complement and both have adjacent genes located base pair apart on chromosome 6p They hypothesized that the significance of the haplotypes is due largely to the BF variants, which are in strong linkage disequilibrium with C2.

BF is a complement activating factor and studies have demonstrated that at least one of the two variants associated with AMD R32Q BF leads to an impairment in the complement activation function of BF. C3 is the central element of the complement cascade and a candidate gene to be involved in AMD, since its cleavage product, C3a, not only was found in drusen but also was proved to induce vascular endothelial growth factor expression and promote choroidal neovascularization in both in vitro and in vivo In Majewski et al.

Later this finding has been replicated by other genome-wide linkage studies 26 and supported by a genome—scan meta-analysis 5. In Jakobsdottir et al. All initial genetic studies, about ten years ago, lacked statistical power because small samples were used , used cumbersome genotyping technologies and poorly defined cohort. In recent years, there are some publications of preliminary and unconfirmed genetic associations of the genes in this locus to AMD The risk confering polymorphism consists in a change in the 69 position aminoacid alanine A to serine S.

The frequency of the risk allele is higher in patients with advanced AMD than in those with early or intermediate AMD 27, Later two studies, based on semiquantitavive expression data of allele associated differences in HTRA1 mRNA or protein levels, suggested a diferent variant rs in the same LD block, in the promoter of HTRA1 gene as the functional variant 34, HTRA1 gene is located on chromosome 10q According to Tam et al. This means that smokers homozygous for the risk allele had a substantially higher risk of developing wet AMD than non smokers with the risk allele.

However Deangelis et al 41 , in reported no interaction between this SNP and smoking. All subsequent studies have failed to replicate the functional data 32, This basically means that, as there is strong linkage disequilibrium LD across ARMS2-HTRA1 region, genetic association studies alone are insufficient to distinguish between the two candidates.

It is also necessary not only the characterization of the extent of the variants associated to the disease but also the analysis of their possible functional relevance in the disease process Doing this, Fritsche et al. The deletion removes the polyadenilation signal sequence at position exclusively used for the addition of a poly A tract 19 bp downstream. The insertion introduces a 64 bp AU-rich element, known for its properties to control mRNA decay in many transcripts that encode a wide variety of proteins 43, They demonstrated that it is a major risk factor for AMD: individuals carrying a single copy of the risk allele deletion-insertion in ARMS2 gene have a 2.

Their work, also revealed that in homozygous for the deletion-insertion variant, expression of ARMS2 is absent. They localized the ARMS2 protein within the photoreceptor layer namely, to the mitochondria—enriched ellipsoid region of the inner segments and in accordance; they proposed a functional role of ARMS2 in mitochondrial homeostasis. According to Fritsche et al. However, as Fritsche et al. The ApoE gene, located on chromosome 19q One of the first works in this area was that of Michael Klein et al.

A similar interaction was observed in the groups taking zinc versus those not taking zinc: intake had a more protective effect in patients with non-risk alleles compared to patients with risk alleles. These results suggest that the zinc plus antioxidative treatment seems to have less impact on those with the high-risk CFH variant. For the CFH genotypes results show that only They found no statistical association with the LOC genotype but a statistical association with CFH genotype: risk allele genotypes have better results than non-risk allele genotypes.

Understanding the genetic basis of AMD has important implications for the ophthalmologists as it allows the identification of the biochemical pathway for a large proportion of AMD patients, raises the possibility to perform pre-symptomatic diagnostic testing of risk genotypes and to stratify the response to therapy based on genetic risks and supports the development of new therapies being the inhibition of complement a potential one among others that are already being tested.

JAMA ; 16 : Smith W, Mitchell P. Family history and age-related maculopathy: the Blue Mountains Eye Study. Aust N Z J Ophthalmol. Familial aggregation of age-related macular degeneration in the Utah population. Vision Res ; 48 3 : Meta-analysis of genome scans of age-related macular degeneration. Hum Mol Genet ; 14 15 : Clinical features in a large family and linkage to chromosome 1q.

Age-related macular degeneration--a genome scan in extended families. Am J Hum Genet ; 73 3 : The role of inflammation in the pathogenesis of age-related macular degeneration. Surv Ophthalmol ; 51 2 : Genetic factors of age-related macular degeneration. Prog Retin Eye Res ; 23 2 : Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid. Complement factor H polymorphism and age-related macular degeneration. Science ; : Complement factor H variant increases the risk of age-related macular degeneration.

Complement factor H polymorphism in age-related macular degeneration. Association of complement factor H polymorphisms with exudative age-related macular degeneration. Mol Vis ; Complement factor H polymorphisms in Japanese population with age-related macular degeneration. Strong association of the YH variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration. Am J Hum Genet ; 77 1 : Systematic review and meta-analysis of the association between complement factor H YH polymorphisms and age-related macular degeneration.

Hum Mol Genet ;15 18 : Extended haplotypes in the complement factor H CFH and CFH-related CFHR family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Ann Med ; 38 8 : Variation in factor B BF and complement component 2 C2 genes is associated with age-related macular degeneration. Nat Genet ; 38 4 : Prog Retin Eye Res ; 20 6 : Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. Exp Eye Res ; 73 6 : Drusen complement components C3a and C5a promote choroidal neovascularization.

Complement component C3 and risk of age-related macular degeneration. Ophthalmology ; 3 Age-related maculopathy: a genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions. Am J Hum Genet ; 75 2 : Susceptibility genes for age-related maculopathy on chromosome 10q Am J Hum Genet ; 77 3 : Allikmets R, Dean M. Bringing age-related macular degeneration into focus. Nat Genet ; 40 7 : Hum Mol Genet ; 15 21 : Hypothetical LOC is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk.

Hum Mol Genet ; 14 21 : The LOC polymorphism and age-related macular degeneration: replication in three case-control samples. Invest Ophthalmol Vis Sci ; 48 3 : The LOC polymorphism, inflammatory markers, smoking, and age-related macular degeneration. A population-based case-control study. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. HTRA1 promoter polymorphism in wet age-related macular degeneration. HtrA1 serine protease inhibits signaling mediated by Tgfbeta family proteins.

Development ; 5 : HtrA1-dependent proteolysis of TGF-beta controls both neuronal maturation and developmental survival. Cell Death Differ ; 15 9 : HTRA1 variant confers similar risks to geographic atrophy and neovascular age-related macular degeneration. Cell Cycle ; 6 9 : Association of the HTRA1 gene variant with age-related macular degeneration in the Japanese population.

J Hum Genet ; 52 7 : Alleles in the HtrA serine peptidase 1 gene alter the risk of neovascular age-related macular degeneration. AU-rich elements and associated factors: are there unifying principles? Nucleic Acids Res ; 33 22 : The highways and byways of mRNA decay. Nat Rev Mol Cell Biol ; 8 2 : Khabar KS. The AU-rich transcriptome: more than interferons and cytokines, and its role in disease. J Interferon Cytokine Res ; 25 1 : Molecular pathology of age-related macular degeneration.

Prog Retin Eye Res ; 28 1 : Ophthalmic Genet ; 23 4 : Hum Mutat ; 27 4 : Ideggyogy Sz ; 60 : The epsilon4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration. Association of apolipoprotein E alleles with susceptibility to age-related macular degeneration in a large cohort from a single center. Invest Ophthalmol Vis Sci ; 45 5 : Invest Ophthalmol Vis Sci ; 47 9 : Joint effects of smoking history and APOE genotypes in age-related macular degeneration. Lack of an association of apolipoprotein E gene polymorphisms with familial age-related macular degeneration.

Apolipoprotein E gene and early age-related maculopathy: the Atherosclerosis Risk in Communities Study. Brantley MA, Jr. Association of complement factor H and LOC genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab. Eye Lond ; 22 6 : Association of complement factor H and LOC genotypes with response of exudative age-related macular degeneration to photodynamic therapy.


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Eye Lond ; 23 3 : Blood vessels develop and grow by three different basic mechanisms: vasculogenesis in which vessels form by concatenation of vascular precursor cells into solid cords that then lumenize; angiogenesis that is the growth of new blood vessels from pre-existing ones; and intussusception in which new blood vessels form by the proliferation of endothelial cells that form a pre-existing vessel into the vessel lumen, originating two blood vessels that split into two opposite sides 1. Angiogenesis, the growth of new vessels from pre-existing ones by sprouting of endothelial cells into a previously avascular tissue, is an essential process both in embryonic development and in adulthood 1,2.

It is a complex multistep process involving extracellular matrix degradation and proliferation, survival, migration and anastomosis of endothelial cells 2. The release of extracellular matrix proteases leads to the degradation of the basal membrane of blood vessels. Endothelial cells change shape, proliferate, invade stroma and form tubular structures that coalesce. This requires the coordinated action of a variety of anti and pro-angiogenic factors and cell-adhesion molecules in endothelial cells. Angiogenesis is of paramount importance as it promotes tissue repair; however, in certain conditions it may cause tissue damage.

If not tightly regulated, the angiogenic process is frequently imbalanced, and associated with several pathological situations 1,3. However, there is a consensus that Vascular Endothelial Growth Factor VEGF is the most important angiogenic factor and represents the crucial rate-limiting step during angiogenesis 3,10, The mediators of the angiogenic process can be modulated by some molecules and microenvironmental conditions.

VEGF is upregulated by cyclo. Inflammatory cells within a hypoxic environment release huge amounts of factors that exert effects on endothelial cells and degrade the extracellular matrix 2. It is the balance of stimulators and inhibitors that tightly controls the normally quiescent capillary vasculature. When this balance is upset angiogenesis develops Cell-cell and cell-matrix interactions may also play an important role in angiogenesis. Special focus has been recently given the Rac1 GTPase Recently, microRNA regulation of gene expression has been implicated in the control of pathologic ocular angiogenesis The ANG—TIE pathway is required for lymphatic and blood vessel development and is important for the development of mature blood vessels that originate from the VEGF induced endothelial sprouting.

This pathway controls vascular permeability, inflammation and pathological angiogenic responses in adult tissues Maturing of blood vessels include pericyte and coating of endothelial cell walls. PDGF is mainly believed to be an important mitogen for connective tissue. PDGF promotes migration and proliferation of endothelial cells as well as an increased recruitment of pericytes.

These findings suggest that PDGF is not only important in formation of new blood vessels but it is also very important for their maturation and stabilization Evidence suggests that processes of inflammation and angiogenesis are connected. Newly formed blood vessels enable the recruitment of inflammatory cells, which release a variety of proangiogenic cytokines and growth factors that will perpetuate angiogenesis During embryogenesis retinal vascularization begins in the most superficial or inner retinal layers at the optic nerve head, and radiates outwards from this central point.

It reaches the retinal periphery just before birth The migration of large numbers of vascular precursor cells VPCs from the optic disc is the first event in human retinal vascularization, and it is apparent before 12 gestational weeks They proliferate and differentiate to form a primordial vascular bed centered on the optic disc. Thus, vasculogenesis is responsible for the formation of the primordial vessels of the inner superficial plexus in the central human retina Formation of retinal vessels via vasculogenesis seems to be independent of metabolic demand and hypoxia-induced VEGF expression Angiogenesis is responsible for the formation of the remaining retinal vessels, including increasing vascular density in the central retina, vessel formation in the inner plexus of the peripheral retina, and formation of the outer plexus and the radial peri-papillary capillaries Formation of the outer plexus begins around the incipient fovea between 25 and 26 weeks of gestation, coincident with signals that indicate a functional visual pathway and photoreceptor activity The blood-retinal barriers, inner and outer, are fundamental for the integrity of structure and optimization of function of the neuro-sensorial retina Pathological retinal and choroidal angiogenesis generates chaotically orientated and physiologically deficient vessels that do not conform to neuronal histology, which can lead to vision-threatening oedema, exudation and haemorrhage 1.

Angiogenesis is a key aspect in many ocular pathologies that are leading causes of blindness in the world, such as neovascular age-related macular degeneration AMD , diabetic retinopathy, retinopathy of prematurity, central retinal vein occlusion and other diseases associated with ischemia and neovascularization Although angiogenesis is a highly complex and coordinated process requiring multiple receptors and ligands in endothelial cells, VEGF is a hypoxia-inducible cytokine that appears to be a pivotal element required for the process in a variety of normal and pathological circumstances 3, VEGF is a surrogate angiogenic marker, since it acts not only as a mitogen, but also as a survival factor for endothelial cells 2.

Furthermore, it is also involved in the stimulation of the invasive and migration capacity of endothelial cells and in the enhancement of vascular permeability Bone-marrow derived cells have also been described in choroidal neovascular lesion. Their importance in the pathologic process is still under debate The diagnosis of AMD is based on fundoscopic signs observed on the macula, irrespective of visual acuity The stages of AMD are categorized as early, in which visual symptoms are inconspicuous, moderate and late, usually associated with severe loss of vision However, in the same patient we can find the dry form in one eye and the wet in the other eye, or both forms in the same eye.

Moreover with time we can see the conversion of wet in dry or dry becoming wet The aging-dependent alterations in the outer retina have been already discussed in another chapter. AMD-related visual loss is a complex process starting by the deposition of debris in the outer retina All the aging changes in outer retina compromise the nutrition of photoreceptors and RPE and create a favourable environment for the development of choroidal neovascularization CNV. However other factors — genetic and environmental 40, 41 — are also important, but its role in the development of CNV is discussed in other chapters of this book.

Yannuzzi proposed a type 3 neovascularization, for retinal angiomatous proliferation RAP , indicating proliferating vessels within or below the retina itself There is hypothetically neovascularization extending anteriorly from the choroid in conjunction with retinal neovascularization progressing posteriorly, with both circulations eventually anastomosing. During the dynamic process of development of CNV there is a balance of angiogenesis promoters and inhibitors. After initiation, CNV grows to a certain size and progresses through the tissue planes by the action of Matrix Metalloproteinases MMP produced by endothelial cells and macrophages At some point the balance shifts toward antiangiogenic, antiproteolytic and antimigratory activity resulting in the involutional stage of CNV.

In this involutional stage the CNV may become collagenized and form a disciform scar. Subretinal fibrosis is the hallmark of this stage of the disease and is the result of the activity of inflammatory and endothelial cells and fibroblasts Age-related macular degeneration AMD is the leading cause of blindness in older population in industrialized nations 1,2. Focal RPE hyperpigmentation and atrophy can also be seen. This review summarizes the various biomarkers of AMD and analyses whether or not they may, one day, be exploited to determine risks of disease onset, measure progression of disease or even assess the effects of treatment of AMD.

Genetic predisposition for AMD has been demonstrated by familial aggregation studies and twin studies 5,6. The most commonly implicated genetic risk loci are located in chromosome 1q, which are related to several complement system regulators, such as complement factor H CFH and CFH-related proteins CFHR CFH, in particular, is a key regulator of the complement system of innate immunity: it maintains the homeostasis of the complement system and protects bystander host cells and tissues from damage by complement activation At least 6 genetic variants related to AMD development in Caucasians have been identified 7, , while only three of these have been described in Chinese and Japanese populations 15, The most documented risk-conferring single-nucleotide polymorphism results is a tyrosine-to-histidine substitution in 1q26 at position of the CFH protein.

It causes a significant loss of binding of factor H to heparin, C-reactive protein and to peroxidised lipids on dead cells combined with reduced anti-inflammatory functions by factor H, leading to increased local complement activation A possible explanation for the protective effect of these deletions might be that CFHR1 and CFHR3 compete with CFH for binding to C3b, thus a deficiency of these proteins increases the efficacy of factor H and its regulatory effect on complement activation The prevalence of this deletion differs between ethnic groups, occurring in Besides components of the complement system 20 , several immunological molecules and inflammatory mediators have been identified at the site of AMD lesions In fact, chronic inflammation appears to be a causative factor for the development of AMD by causing endothelial dysfunction and facilitating interactions between modified lipoproteins, monocyte-derived macrophages, T-cells and normal cellular elements of the retinal vasculature In fact, using electron microscopy or immunohistochemistry methods, macrophages can be found in the area of geographic atrophy phagocytising pigment debris 23 and around CNV in wet AMD In order to grasp the role of inflammation on the development and progression of AMD, several markers of systemic inflammation have been extensively studied.

Classically seen as an inflammatory marker, CRP is now regarded as an independent risk for both cardiovascular and peripheral arterial disease It directly upregulates endothelial cell adhesion molecules and promotes the release of chemoatractant chemokines, which have a negative effect on the retinal microvasculature 22, A meta-analysis of data from more than Additionally, CRP may also have a direct role in AMD development through its ability to induce complement activation IL-6 is a marker for systemic inflammation, such as acute pancreatitis and chronic arthritis.

It has been implicated in angiogenesis, along with VEGF, in several in vitro and cancer studies Seddon and colleagues found a correlation between the level of IL-6 and chances of AMD progression Interestingly, high aqueous IL-6 levels might to predict resistance to intravitreal bevacizumab in patients with wet AMD Fibrinogen is also an established biomarker of acute and chronic inflammation In fact, fibrinogen plasma levels appear to be particularly increased in patients with exudative AMD Despite the increasingly sophisticated imaging techniques available, fundoscopy and colour fundus photographs CFP remain invaluable tools for the assessment of the severity and risk of progression of patients with AMD.

Drusen size, area and location are important predictors of AMD progression 40,41 : large soft drusens with ill-defined borders and extensive drusen area are the most important risk factors for the progression to advanced AMD identifiable on CFP 42, Yet, earlier macular changes can provide valuable information about the risk of AMD progression.

This has been extensively demonstrated in population-based observational studies and provides the basis for several AMD severity classifications. A simplified risk scale was developed based on these findings Table 1. It considers the presence of at least 1 large drusen diameter greater than or equal to that of a large vein at the disc margin and the presence of any pigment abnormality as 1 point each, and sums their presence across both eyes when both are free of advanced AMD.

The 5-year risk of advanced AMD using this scale increases as more risk factors are present: 0 factors, 0. This simplified scale is particularly useful in clinical practice because it allows fast risk stratification and is useful when discussing with patients their risk of progression to vision-threatening AMD. In recent years, several studies have studied the significance of reticular pseudodrusen RPD.

They were first described in as a yellowish interlacing network most commonly located on the superotemporal macula RPD are difficult to identify in clinical fundoscopic examination and are poorly visualized with regular CFP, so they are best seen with multimodal imaging In two population-based studies, the overall prevalence of RPD was 0.

Unfortunately, RPD presence remains an underreported and underresearched retinal phenotype, but the advent of new imaging modalities will certainly improve our knowledge about this phenotype Fundus autofluorescence FAF is a non-invasive method that supplies additional information to that obtained using CFP and fluorescence angiography In GA, the atrophic areas appear as hypoautofluorescent patches surrounded by non-atrophic retina of variable autofluorescence The FAF features of these borders of GA lesions appear to be particularly important to predict the progression of pre-existing GA, as variation in GA growth rates are dependent on the specific phenotype of FAF at baseline Due to the quantitative and highly reproducible data that it provides, optical coherence tomography OCT has quickly become an invaluable tool to evaluate AMD progression and treatment response.

AMD is a complex disease caused by a combination of genetic predisposition and environmental factors and the interplay between these remains a mystery. A better understanding of the involved pathophysiologic process or the identification of biomarkers for the conversion would enhance our ability to diagnose and treat the wet AMD, to develop better therapies and, eventually, to prevent vision loss associated with the disease.

Fluorescein angiography FA was introduced in ophthalmology by Novotny and Alvis in the sixties of the last century. They took serial fundus photographs after intravenous injection of sodium fluorescein to study the retinal and choroidal circulation 1. Initially, they used this technique in diabetic and hypertensive patients and after, the technique was used in age-related macular degeneration AMD. Nowadays, optical coherence tomography OCT is being more used than FA for monitoring the response to treatment, although FA is still very useful in some cases.

Sodium fluorescein is a small molecule, with a molecular weight of It is stimulated by light in the range of nm and then it enters into a higher energy state. The molecule emits longer wavelength fluorescence, between and nm, as it decays to a lower energy state. An excitation filter allows the passage of blue light, which stimulates the fluorescein in the eye, which emits yellow-green light. In addition, a barrier filter is used to block some reflected blue light, allowing only the yellow-green light to pass through.

This resultant fluorescence is recorded by a camera as an image 2. Sodium fluorescein diffuses through the fenestrated vessels of the choriocapillaris, but does not cross the internal and the external blood-retinal barriers. Thus, any condition that compromises these barriers, obstructs blood flow, or changes the normal pigmentation of the retinal pigment epithelium RPE can cause abnormalities on FA.

It is relatively inert, making intravenous injection safe and severe adverse reactions rare. Nevertheless, the patient should be properly informed of the potential risks of FA injection 3. They can be classified at those leading to decreased fluorescence hypofluorescence or increased fluorescence hyperfluorescence. Hypofluorescence either represents blocked fluorescence or a vascular filling defect Table 1. Table 1 - Causes of hypofluorescence. Hyperfluorescence can be the result of loss of the normal barrier to background choroidal fluorescence known as transmitted fluorescence.

A second reason for hyperfluorescence can arise from extravascular accumulation of the dye or from leakage from abnormal vessels Table 2 4. Table 2 - Causes of hypofluorescence. By convention, leakage of fluorescein into a space is referred to as pooling, while leakage into a tissue is called staining 5. FA is not usually indicated in these cases unless we suspect the presence of choroidal neovascularization CNV. Several types of drusen can be identified. Their angiographic appearance depends on the thinning of the overlying RPE, the histochemical composition and the age of the patient.

They are hyperfluorescent with phospholipid accumulation and in younger patients 7. Figure 2 - Coexistence of hard and soft drusen in the same eye of a patient with AMD. The confluence of soft drusen can produce a drusenoid pigment epithelial detachment PED , which shows hyperfluorescence and dye pooling without leakage beyond its margin with typical areas of focal hyperpigmentation Figure 3.

Figure 3 - Drusenoid pigment epithelial detachmen t. Focal hyperpigmentation is a risk factor for the development of choroidal neovascularization CNV and angiographically appears as a blocked fluorescence Figure 4. Figure 4 - RPE abnormalities with focal hyperpigmentation. Histopathologically it is characterized by focal RPE hypertrophy and pigment migration into the subretinal space. It also displays focal hyperautofluorescence suggesting that these cells contain lipofuscin 8.

Atrophy can occur in sharply defined areas of severe atrophy, known as geographic atrophy GA , or in less well-defined, more granular regions of less severe atrophy, known as non-GA. Both forms share the feature of RPE loss, more extensive and with associated atrophy of the overlying retina and underlying choriocapillaris in GA.

The angiographic appearance depends on the remaining pigment within the RPE and choriocapillaris vessels. Non-GA shows mottled early hyperfluorescence, which fades late consistent with window defect Figure 5. Figure 5 - Non-geographic atrophy. GA typically shows late well-defined hyperfluorescence from staining of the exposed deep choroid and sclera 9. Figure 6 - Geographic atrophy. Figure 7 - Severe atrophic AMD with sclerotic appearance of larger choroidal vessels. Classic CNV is characterized by well-demarcated hyperfluorescence in early phases on FA and late leakage that obscures the boundaries of the lesion Figure.

Figure 8 - Classic CNV. Figure 9 - Extrafoveal classic CNV. Figure 10 - Juxtafoveal classic CNV. Figure 11 - Subfoveal classic CNV. Another typical feature is the presence of a hyperpigmented rim, hypofluorescent on FA, surrounding the CNV Figure Figure 12 - Classic CNV with feeder vessel. Figure 13 - Classic CNV with loculated fluid. In loculated fluid, dye pooling is well-demarcated in a confined space of a localized sensory retinal detachment or within intraretinal cystic spaces.

It was a common finding in patients with new subfoveal CNV in the Macular Photocoagulation Study MPS and may confuse the treating physician as to the boundary of the lesion Figure 14 - Medium size classic CNV. Figure 15 - Large classic CNV. Importantly, larger classic CNV are associated to a poorer visual prognosis since they represent long-term duration of the pathological disorder. Classic CNV is an emergency and it requires early treatment to halt the progression of the disease.

Figure 16 - Old classic CNV with fibrosis. In the last decade of the last century, the advent of photodynamic therapy PDT with verteporfin promoted a classification of the lesions depending on the percentage of classic CNV.