Familial Mediterranean fever

Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder that affects groups of patients originating from around the Mediterranean Sea (hence its name). It is prominently present in the Armenian people (up to 1 in 7 affected), Sephardi Jews (and, to a much lesser extent, Ashkenazi Jews), people from Turkey, the Arab countries and Lebanon.

Clinical symptoms

Attacks

There are seven types of attacks. 90% of all patients have their first attack before they are 20 years old. All develop over 2-4 hours and last anytime between 6 hours and 4 days. Most attacks involve fever:
Abdominal attacks, featuring abdominal pain affecting the whole abdomen with all signs of acute abdomen (e.g. appendicitis). They occur in 95% of all patients and may lead to unnecessary laparotomy. Incomplete attacks, with local tenderness and normal blood tests, have been reported.
Joint attacks, occurring in large joints, mainly of the legs. Usually, only one joint is affected. 75% of all FMF patients experience joint attacks.
Chest attacks with pleuritis (inflammation of the pleural lining) and pericarditis (inflammation of the pericardium). Pleuritis occurs in 40%, but pericarditis is rare.
Scrotal attacks due to inflammation of the tunica vaginalis. This occurs in up to 5% and may be mistaken for acute scrotum (i.e. testicular torsion)
Myalgia (rare in isolation)
Erysipeloid (a skin reaction on the legs, rare in isolation)
Fever without any symptoms (25%)

Complications

AA-amyloidosis with renal failure is a complication and may develop without overt crises. AA (amyloid protein) is produced in very large quantities during attacks and at a low rate between them, and accumulates mainly in the kidney, as well as the heart, spleen, gastrointestinal tract and the thyroid.

There appears to be an increase in the risk for developing particular vasculitis-related diseases (e.g. Henoch-Schoenlein purpura), spondylarthropathy, prolonged arthritis of certain joints and protracted myalgia.

Diagnosis

The diagnosis is clinically made on the basis of the history of typical attacks, especially in patients from the ethnic groups in which FMF is more highly prevalent. An acute phase response is present during attacks, with high C-reactive protein levels, an elevated white blood cell count and other markers of inflammation. In patients with a long history of attacks, monitoring the renal function is of importance in predicting chronic renal failure.

A genetic test is also available now that the disease has been linked to mutations in the MEFV gene. Sequencing of exons 2, 3, 5, and 10 of this gene detects an estimated 97% of all known mutations.

Disease mechanism

Pathophysiology

Virtually all cases are due to a mutation in the MEFV gene, which codes for a protein called pyrin or marenostenin. This was discovered in 1997 by two different groups. Various mutations of this gene lead to FMF, although some mutations cause a more severe picture than others. Mutations occur in exons 2, 3, 5 and 10.

The function of pyrin has not been completely elucidated, but it appears to be a suppressor of the activation of caspase 1, the enzyme that stimulates production of interleukin 1ß, a cytokine central to the process of inflammation. It is not conclusively known what exactly sets off the attacks, and why overproduction of IL-1 would lead to particular symptoms in particular organs (e.g. joints or the peritoneal cavity).

Genetics

The MEFV gene is located on the chromosome 16 (16p13). The disease inherits in an autosomal recessive fashion. Therefore, two asymptomatic carrier parents have a 25% chance of a child with the disorder. FMF patients who marry a carrier or another FMF patient have a 50% and 100% chance, respectively, in having a child with FMF.

Treatment

Attacks are self-limiting, and require analgesia and non-steroidal anti-inflammatory drugs (such as diclofenac).

Since the 1970s, colchicine, a drug otherwise mainly used in gout, has been shown to decrease attack frequency in FMF patients. The exact way in which colchicine suppresses attacks is unclear. While this agent is not without side-effects (such as abdominal pain and muscle pains), it may markedly improve quality of life in patients. The dosage is typically 1-2 mg a day. Development of amyloidosis is delayed with colchicine treatment. Interferon is being studied as a therapeutic modality.

History

A New York allergist, Dr Sheppard Siegal, first described the attacks of peritonitis in 1945; he termed this “benign paroxysmal peritonitis", as the disease course was essentially benign. Dr Hobart Reimann, working in the American University in Beirut, described a more complete picture which he termed “periodic disease".

Climate of Mediterranean Sea

The Dry Summer Subtropical climate, is also known as the “Mediterranean” climate because the land that borders the Mediterranean Sea is a type locality for this climate. The wet winter/dry summer seasonality of precipitation is the defining characteristic of this climate. Summer drought places a great deal of stress on the local vegetation, but plant structures have evolved to adapt to it.

Air flow into the Mediterranean Sea is through gaps in the mountain ranges, except over the southern shores east of Tunisia. Strong winds funneled through the gaps lead to the high evaporation rates of summer and the seasonal water deficit of the sea. The mistral, a cold, dry, northwesterly wind, passes through the Alps-Pyrenees gap and the lower Rhone valley; the strong northeasterly bora passes through the Trieste gap; and the cold easterly levanter and the westerly vendaval pass through the Strait of Gibraltar.

Hot, dry, southeasterly winds–known locally as the sirocco, ghibli (gibleh), or khamsin–frequently blow into the Mediterranean basin from the Sahara and the Arabian Peninsula as low-pressure centres traverse the sea in late winter and early spring.

History of the Mediterranean

Some of the most ancient civilizations (see Aegean civilization) flourished around the Mediterranean. It was opened as a highway for commerce by merchants trading from Phoenicia. Carthage, Greece, Sicily, and Rome were rivals for dominance of its shores and trade; under the Roman Empire it became virtually a Roman lake and was called Mare Nostrum [our sea]. Later, the Byzantine Empire and the Arabs dominated the Mediterranean.

Between the 11th and 14th cent., Italian city trading states such as Genoa, Venice, and Barcelona dominated the region; they struggled with the Ottomans for naval supremacy, particularly in the E Mediterranean. Products of Asia passed to Europe over Mediterranean trade routes until the establishment of a route around the Cape of Good Hope (late 15th cent.).

With the opening of the Suez Canal (1869) the Mediterranean resumed its importance as a link on the route to the East. The development of the northern regions of Africa and of oil fields in the Middle East has increased its trade.

Its importance as a trade link and as a route for attacks on Europe resulted in European rivalry for control of its coasts and islands and led to campaigns in the region during both world wars. Since World War II the Mediterranean region has been of strategic importance to both the United States and, until its dissolution, the Soviet Union. In 1995 countries bordering the Mediterranean signed a pact agreeing to protect it by eliminating toxic waste disposal there over a 10-year period.

Ancient

Two of the first human civilizations began in the Mediterranean area. Civilization first developed in Mesopotamia begnning with Sumer in the 4th millennium BC. Soon after, the Nile River valley was unified under the Pharaohs in the 4th millennium BC, and civilization quickly spread through the fertile crescent to the east coast of the sea and throughout the Levant, which happens to make the Mediterranean countries of Syria, Lebanon, and Israel part of the Cradle of Humanity. These areas shared similar climates and geographies, but it was more difficult to spread technologies and crops, such as flax, lentil, peas, barley, and cotton to other portions of the Mediterranean basin.

In time, large empires developed in Asia Minor, such as the Hittites. The main expansion was delayed until ships sturdy enough the cross the sea were developed. Cyprus and the other islands developed, and the Minoan civilization flourished on the island of Crete. While the river valley civilizations always had larger populations, the trading societies on the coast of the sea soon became the most prosperous, and rose to power.

Classical

The two most notable of these were the Greek city states and the Phoenicians. The Greeks expanded throughout the Black Sea and south through the Red Sea. The Phoenicians spread through the western Mediterranean including North Africa and Spain. The Phoenician heartland in the Levant was still dominated by powers rooted east in Mesopotamia or Persia, and the Phoenicians often provided the naval forces of the Persian Empire.

To the north of Greece, in Macedon, Greek technological and organizational skill was forged with a long history of cavalry warfare. Under Alexander the Great, this force turned east, and in a series of three decisive battles, routed the Persian forces and took their empire. The Phoenician lands were taken, as was Egypt. For the first time, the major centres of the Mediterranean were in one hand. Alexander’s empire quickly disintegrated, and the Middle East, Egypt, and Greece were soon again independent. Alexander’s conquests spread Greek knowledge and ideas throughout the region.

These eastern powers soon began to be overshadowed by those further west. In North Africa the former Phoenician colony of Carthage rose to dominate its surroundings with an empire that contained many of the former Phoenician holdings. However, it was a city on the Italian peninsula, Rome, that would eventually dominate the entire Mediterranean basin. Spreading first through Italy, Rome defeated Carthage in the Punic Wars, becoming the leading force in the region. The Romans soon spread east taking Greece, and the Greek heritage played an important role in the Roman Empire.

By this point the coastal trading cultures were thoroughly dominant over the inland river valleys that had once been the heart of the great powers. Egyptian power moved from the Nile cities to the coastal ones, especially Alexandria. Mesopotamia became a fringe border region between the Roman Empire and the Persians.

For several centuries the Mediterranean was a “Roman Lake,” surrounded on all sides by the empire. One portion of the empire was Judea, and in time, a religion founded in that region, Christianity, spread throughout the empire and eventually became its official faith. The empire began to crumble, however, and collapsed in the fifth century.

Temporarily the east was again dominant as the Byzantine Empire formed from the eastern half of the Roman one. The western part of the empire, Gaul, Iberia, and the Maghreb were invaded by nomadic horse peoples from the Eurasian steppe. These conquerors soon became settled, and adopted many of the local customs, forming many small and warring kingdoms.

Middle Ages

Another power was rising in the east, that of Islam, whilst Byzantine and Persia were both weakened by centuries of stalemate warfare. In a rapid conquest the Islam faith motivated armies swept through much of the Middle East; reducing Byzantine lands by half and completely engulfing the Persians.

In Anatolia the expansion was blocked by the still capable Byzantines. The Byzantine governors and indigenous kingdoms of North Africa could not mount such a resistance, and the Muslim conquerors swept through the region, and at the far west crossed the sea taking Spain before being halted in southern France by the Franks.

Much of North Africa became a peripheral area to the main Muslim centres in the Middle East, but Spain and Morocco soon broke from this distant control and founded one of the most advanced societies in the world at this time.

Europe was reviving, however, as more organized and centralized states began to form in the later Middle Ages. Motivated by religion and dreams of conquest, the kings of Europe launched a number of Crusades to try to roll back Muslim power and retake the holy land. The Crusades were unsuccessful in this goal, but they were far more effective in weakening the already tottering Byzantine Empire that began to lose increasing amounts of territory to the Ottoman Turks. They also rearranged the balance of power in the Muslim world as Egypt once again emerged as a major power in the eastern Mediterranean.

Europe continued to increase in power as the Renaissance began in Northern Italy. The Islamic states had never been major naval powers, and trade from the east to Europe was soon in the hands of Italian traders, especially the Venetians, who profited immensely from it.

Ottoman power continued to grow, and in 1453, the Byzantine Empire was extinguished with the fall of Constantinople. The Ottomans already controlled Greece and much of the Balkans, and soon also began to spread through North Africa.

North Africa had grown wealthy from the trade across the Sahara Desert, but the Portuguese, who along with other Christian powers, had been engaged in a long campaign to evict the Muslims from Iberia, had found a method to circumvent this trade by trading directly with West Africa. This was enabled by a new type of ships, the caravel, that made trade in the rough Atlantic waters profitable for the first time. The reduction in the Saharan trade weakened North Africa, and made them an easy target for the Ottomans.

Modern

The growing naval prowess of the European powers confronted further rapid Ottoman expansion in the region when the Battle of Lepanto checked the power to the Ottoman navy. However, as Braudel argued forcefully, this only slowed the Ottoman expansion instead of ending it. The prized island of Cyprus became Ottoman in 1571.

The last resistance in Tunisia ended in 1574 and almost a generation long siege in Crete pushed Venetians out of this strategic island in 1669. A balance of power was then established between Spain and Ottoman Empire until 18th century, each dominating their respective half of Mediterranean, reducing Italian navies as naval powers became increasingly more irrelevant.

The development of oceanic shipping began to affect the entire Mediterranean, however. While once, all trade from the east had passed through the region, the circumnavigation of Africa allowed gold, spices, and dyes to be imported directly to the Atlantic ports of western Europe. The Americas were also a source of extreme wealth to the western powers, of which, some of the Mediterranean states were largely cut off from.

The base of European power thus shifted northward and once wealthy Italy became a peripheral area dominated by foreigners. The Ottoman Empire also began a slow decline that saw its North African possessions gain de facto independence and its European holdings gradually reduced by the increasing power of Austria and Russia.

By the nineteenth century the Northern European states were vastly more powerful, and began to colonize North Africa. France spread its power south by taking Algeria in 1830. Britain gained control of Egypt in 1882. The Ottoman Empire finally collapsed in the First World War and its holdings were carved up among France and Britain, but the Turkish regions quickly regained their independence becoming the independent state of Turkey.

Mediterranean Basin

The Mediterranean Basin refers to the lands around and surrounded by the Mediterranean Sea. In biogeography, the Mediterranean Basin refers to the lands around the Mediterranean Sea that have a Mediterranean climate, with mild, rainy winters and hot, dry summers, which supports characteristic Mediterranean forests, woodlands, and shrub vegetation.

Geography

The Mediterranean basin covers portions of three continents, Europe, Asia, and Africa. Europe lies to the north, and three large peninsulas, the Iberian Peninsula, Italy, and the Balkan Peninsula, extend into the Mediterranean-climate zone. A system of folded mountains, including the Pyrenees dividing Spain from France, the Alps dividing Italy from Central Europe, the Dinaric Alps along the eastern Adriatic, and the Balkan and Rhodope mountains of the Balkan Peninsula divide the Mediterranean from the temperate climate regions of Western and Central Europe.

The Mediterranean Basin extends into western Asia, covering the western and southern portions of the peninsula of Anatolia, excluding the temperate-climate mountains of central Anatolia. It includes the Mediterranean-climate Levant at the eastern end of the Mediterranean, bounded on the east and south by the Syrian and Negev deserts.

The northern portion of the Maghreb region of northwestern Africa has a Mediterranean climate, separated from the Sahara Desert, which extends across North Africa, by the Atlas Mountains. In the eastern Mediterranean the Sahara extends to the southern shore of the Mediterranean, with the exception of the northern fringe of the peninsula of Cyrenaica in Libya, which has a dry Mediterranean climate.

Origins

The Mediterranean Basin was shaped by the ancient collision of the northward-moving African-Arabian continent with the stable Eurasian continent. As Africa-Arabia moved north, it closed the former Tethys Sea, which formerly separated Eurasia from the ancient supercontinent of Gondwana, of which Africa was part. At the same time, about 170 mya in the Jurassic, a small Neotethys ocean basin formed shortly before the Tethys Sea was closed at the eastern end. The collision pushed up a vast system of mountains, extending from the Pyrenees in Spain to the Zagros Mountains in Iran.

This episode of mountain building, known as the Alpine orogeny, occurred mostly during the Oligocene (34 to 23 million years ago (mya)) and Miocene (23 to 5.3 mya) epochs. The Neotethys became larger during these collisions and associated folding and subduction. About 6 mya during the late Miocene, the Mediterranean was closed at its western end as well, which caused the entire sea to evaporate; this episode is known as the Messinian Salinity Crisis, which ended when the Atlantic reflooded the basin at the end of the Miocene.

The end of the Miocene also marked a change in the Mediterranean Basin’s climate. Fossil evidence shows that the Mediterranean Basin had a relatively humid subtropical climate with summer rainfall during the Miocene, which supported laurel forests. The shift to a Mediterranean climate occurred within the last 3.2 - 2.8 million years, during the Pliocene epoch, as summer rainfall decreased.

The subtropical laurel forests retreated, although they persisted on the islands of Macaronesia off the Atlantic coast of Iberia and North Africa, and the present Mediterranean vegetation evolved, dominated by coniferous trees and sclerophyllous trees and shrubs, with small, hard, waxy leaves that prevent moisture loss in the dry summers. Much of these forests and shrublands have been altered beyond recognition by thousands of years of human habitation. There are now very few relatively intact natural areas in what was once a heavily wooded region.

Flora and Fauna

The Mediterranean Basin is the largest of the world’s five Mediterranean forests, woodlands, and shrub regions. It is home to a number of plant communities, which vary with rainfall, elevation, latitude, and soils.
Scrublands occur in the driest areas, especially areas near the seacoast where wind and salt spray are frequent. Low, soft-leaved scrublands around the Mediterranean are known as garrigue in France, phrygana in Greece, tomillares in Spain, and batha in Israel.
Shrublands are dense thickets of evergreen sclerophyll shrubs and small trees, and are the commonest plant community around the Mediterranean. Mediterranean shrublands are known as matorral in Spain, macchia in Italy, and maquis in France and elsewhere around the Mediterranean. In some places shrublands are the mature vegetation type, and in other places the result of degradation of former forest or woodland by logging or overgrazing, or disturbance by major fires.
Savannas and grasslands occur around the Mediterranean, usually dominated by annual grasses.
Woodlands are usually dominated by oak and pine, mixed with other sclerophyll and coniferous trees.
Forests are distinct from woodlands in having a closed canopy, and occur in the areas of highest rainfall and in riparian zones along rivers and streams where they receive summer water. Mediterranean forests are generally composed of evergreen trees, predominantly oak and pine. At higher elevations Mediterranean forests transition to mixed broadleaf and tall conifer forests similar to temperate zone forests.

The Mediterranean Basin is home to considerable biodiversity, including 22,500 endemic vascular plant species. Conservation International designates the region as a biodiversity hotspot, because of its rich biodiversity and its threatened status. The Mediterranean Basin has an area of 2,085,292 km², of which only 98,009 km² remains undisturbed.

Endangered mammals of the Mediterranean Basin include the Mediterranean Monk Seal, the Barbary Macaque, and the Iberian Lynx.

Ecoregions
Aegean and Western Turkey sclerophyllous and mixed forests (Greece, Macedonia, Turkey)
Anatolian conifer and deciduous mixed forests (Turkey)
Canary Islands dry woodlands and forests (Spain)
Corsican montane broadleaf and mixed forests (France)
Crete Mediterranean forests (Greece)
Cyprus Mediterranean forests (Cyprus)
Eastern Mediterranean conifer-sclerophyllous-broadleaf forests (Israel, Jordan, Syria, Turkey)
Iberian conifer forests (Portugal, Spain)
Iberian sclerophyllous and semi-deciduous forests (Portugal, Spain)
Illyrian deciduous forests (Albania, Bosnia and Herzegovina, Croatia, Greece, Italy, Slovenia)
Italian sclerophyllous and semi-deciduous forests (France, Italy)
Mediterranean acacia-argania dry woodlands and succulent thickets (Morocco, Canary Islands (Spain))
Mediterranean dry woodlands and steppe (Algeria, Egypt, Libya, Morocco, Tunisia)
Mediterranean woodlands and forests (Algeria, Morocco, Tunisia)
Northeastern Spain and Southern France Mediterranean forests (France, Spain)
Northwest Iberian montane forests (Portugal, Spain)
Pindus Mountains mixed forests (Albania, Greece, Macedonia)
South Appenine mixed montane forests (Italy)
Southeastern Iberian shrubs and woodlands (Spain)
Southern Anatolian montane conifer and deciduous forests (Israel, Jordan, Syria, Turkey)
Southwest Iberian Mediterranean sclerophyllous and mixed forests (France, Italy, Morocco, Portugal, Spain)
Tyrrhenian-Adriatic sclerophyllous and mixed forests (France, Italy)

History

Neanderthals inhabited western Asia and the non-glaciated portions of Europe starting about 230,000 years ago. Modern humans moved into western Asia from Africa less than 100,000 years ago. Modern humans, known as Cro-Magnons, moved into Europe approximately 50-40,000 years ago.

The most recent glacial period, the Wisconsin glaciation, reached its maximum extent approximately 21,000 years ago, and ended approximately 12,000 years ago. A warm period, known as the Holocene climatic optimum, followed the ice age.

Food crops, including wheat, chickpeas, and olives, along with sheep and goats, were domesticated in the eastern Mediterranean in the 9th millennium BCE, which allowed for the establishment of agricultural settlements. Near Eastern crops spread to southeastern Europe in the 7th millennium BCE. Poppy and oats were domesticated in Europe from the 6th to the 3rd millennium BCE. Agricultural settlements spread around the Mediterranean Basin. Megaliths were constructed in Europe from 4500 - 1500 BCE.

A strengthening of the summer monsoon 9000-7000 years ago increased rainfall across the Sahara, which became a grassland, with lakes, rivers, and wetlands. After a period of climatic instability, the Sahara settled into a desert state by the 4th millennium BCE.

Geology of Mediterranean Sea

The geology of the Mediterranean is complex, involving the break-up and then collision of the African and Eurasian plates, and the Messinian Salinity Crisis in the late Miocene when the Mediterranean dried up.

The Mediterranean Sea has an average depth of 1,500 m and the deepest recorded point is 5267 meters (about 3.27 miles) in the Calypso Deep in the Ionian Sea. The coastline extends for 46,000 km. A shallow submarine ridge (the Strait of Sicily) between the island of Sicily and the coast of Tunisia divides the sea in two main subregions (which in turn are divided into subdivisions), the Western Mediterranean and the Eastern Mediterranean. The Western Mediterranean covers an area of about 0.85 million km² and the Eastern Mediterranean about 1.65 million km².

In the last few centuries, mankind has done much to alter Mediterranean geology. Structures have been built all along the coastlines, exacerbating and rerouting erosional patterns. Many pollution-producing boats travel the sea that unbalance the natural chemical ratios of the region. Beaches have been mismanaged, and the overuse of the sea’s natural and marine resources continues to be a problem. This misuse speeds along and/or confounds natural processes. The actual geography has also been altered by the building of dams and canals.

The Mediterranean was once thought to be the remnant of the Tethys Ocean. It is now known to be a structurally younger ocean basin known as Neotethys. Neotethys formed during the Late Triassic and Early Jurassic rifting of the African and Eurasian plates.

Ecology of Mediterranean Sea

As a result of the drying of the sea during the Messinian Salinity Crisis, the marine biota of the Mediterranean are derived primarily from the Atlantic Ocean. The North Atlantic is considerably colder and more nutrient-rich than the Mediterranean, and the marine life of the Mediterranean has had to adapt to its differing conditions in the five million years since the basin was reflooded.

The opening of the Suez Canal in 1869 created the first salt-water passage between the Mediterranean and Red seas. The Red Sea is higher than the Eastern Mediterranean, so the canal serves as a salt-water river that pours Red Sea water into the Mediterranean.

The Bitter Lakes, which are hypersaline natural lakes that form part of the canal, blocked the migration of Red Sea species into the Mediterranean for many decades, but as the salinity of the lakes gradually equalized with that of the Red Sea, the barrier to migration was removed, and plants and animals from the Red Sea have begun to colonize the eastern Mediterranean.

The Red Sea is generally saltier and more nutrient-poor than the Atlantic, so the Red Sea species have advantages over Atlantic species in the salty and nutrient-poor Eastern Mediterranean. The construction of the Aswan High Dam across the Nile River in the 1960s reduced the inflow of freshwater and nutrient-rich silt from the Nile into the eastern Mediterranean, which has made conditions there even more like the Red Sea. This species exchange is known as the Lessepsian Migration, after Ferdinand de Lesseps, the engineer who oversaw the canal’s construction.

Geography of Mediterranean Sea

The Mediterranean Sea is connected to the Atlantic Ocean by the Strait of Gibraltar on the west and to the Sea of Marmara and Black Sea, by the Dardanelles and the Bosporus respectively, on the east. The Sea of Marmara is often considered a part of the Mediterranean Sea, whereas the Black Sea is generally not. The man-made Suez Canal in the south-east connects the Mediterranean Sea with the Red Sea.

Tides are very limited in the Mediterranean as a result of the narrow connection with the ocean.
The Mediterranean climate is generally one of wet winters and hot, dry summers. Special crops of the region are olives, grapes, oranges, tangerines, and cork. The region has a long history of civilization.

Large islands in the Mediterranean include:

Cyprus, Crete, Euboea, Rhodes, Lesbos, Chios, Kefalonia and Corfu in the eastern Mediterranean
Sardinia, Corsica, Sicily, and Malta in the central Mediterranean
Ibiza, Majorca and Minorca (the Balearic Islands) in the western Mediterranean

Bordering countries

Modern states(22 states)bordering the Mediterranean Sea are:
Europe (from west to east): Spain, France, Monaco, Italy, the island state of Malta, Slovenia, Croatia, Bosnia and Herzegovina, Serbia and Montenegro, Albania, Greece, Turkey, and the island state of Cyprus.

Asia (from north to south): Turkey, Syria, Lebanon, Israel and the Gaza Strip.
Africa (from east to west): Egypt, Libya, Tunisia, Algeria and Morocco