Public release date: 5-May-2003 Contact: Karl Leif Bates batesk@umich.edu 734-647-1842 eurekalert.org-University of Michigan

Bleeding disorder tied to defect in cellular transport mechanism

ANN ARBOR, Mich.---Defects in a cargo receptor that shuttles proteins from one place to another within the cell lie at the root of a rare bleeding disorder, according to a study published in the June issue of the journal Nature Genetics.

An international research team led by David Ginsburg of the University of Michigan's Life Sciences Institute and the Howard Hughes Medical Institute examined the genes of 19 patients from 12 families with a rare bleeding disorder called Combined Deficiency of Factor V and Factor VIII, or F5F8D for short. The group has concluded that the bleeding disorder isn't due to a problem within these two clotting factors themselves; it's a problem of transporting the factors inside the cell.

Rather than addressing this question with a biochemical approach to the transporter proteins, Ginsburg said they used genetic analysis of the diseased families to find the problem. "That's the power of genetics," he said. "We can learn some fundamental things about biology by looking at the genes of these families with a rare disease."

Factor V and Factor VIII are just two of the many proteins that participate in a complex cascade of chemical reactions that lead to blood clotting. Various forms of abnormal bleeding and clotting have been tied to problems in many of these blood factors, but this disorder simultaneously involves two factors.

Earlier work on the disorder had identified a genetic mutation that causes defects in a protein called LMAN1, which apparently prevented a cell from secreting Factor V and Factor VIII. But about 30 percent of the F5F8D patients had normal levels of LMAN1, so this mutation alone couldn't account for all of the disease. The F5F8D patients in this study were all normal for LMAN1.

What the researchers found is that a mutation in a second gene, called MCFD2, can result in the same disease state. (MCFD2 is short for multiple coagulation factor deficiency 2.) The team identified seven distinct mutations in the MCFD2 gene which appeared in nine of the 12 families studied.

The researchers propose that these two proteins, LMAN1 and MCFD2, bind together to form a transporter which is specifically tailored to carry the two blood clotting factors from the cell's endoplasmic reticulum to the Golgi body. A mutation in the gene that makes either of the two proteins will result in a malformed transporter, and thus the inability to secrete Factor V and Factor VIII.

This work on bleeding disorders may also provide a solution for the opposite problem, clotting disorders. A drug that targeted the MCFD2 protein could reduce both Factor V and Factor VIII, lowering the risk of unwanted blood coagulation. Ginsburg said such a drug might be an attractive alternative to the oral anticoagulants, such as coumadin, because it would not affect other clotting factors. Ginsburg's lab is currently pursuing MCFD2 as a therapeutic target, and the U-M technology transfer office has applied for a patent.

There are still three families in the study who have the bleeding disorder, but weren't found to have mutations in either the LMAN1 or MCFD2 genes. "It's possible that we just missed it in the genetic screen, but it's also possible that there is a third gene involved," Ginsburg said.

Ginsburg's co-author on this work and others involving Factor VIII and LMAN1 is Randal Kaufman, a U-M biological chemistry professor and Howard Hughes investigator. U-M research investigator Bin Zhang is the first author on the paper. Ginsburg is the Warner-Lambert/Parke-Davis Professor of Medicine, departments of internal Medicine and Human Genetics, a charter member of the Life Sciences Institute and a Howard Hughes Medical Institute investigator. Co-authors from Tel Aviv, London, Berlin and Caracas, Venezuela participated by sharing F5F8D patients.

This research was supported by the National Institutes of Health, the Howard Hughes Medical Institute, the National Hemophilia Foundation and the Heart and Stroke Foundation of Canada.

Links "Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex" is available online at Nature Genetics - www.nature.com Life Sciences Institute – lifesciences.umich.edu Howard Hughes Medical Institute - www.hhmi.org National Hemophilia Foundation - www.hemophilia.org

05/05/2003 - Source: <a href=www.latintrade.com>LatinTrade-BNamericas US Power company AES Corporation (NYSE: AES) expects to receive US$125mn net income from its Latin American subsidiaries in 2003, the company said in supplementary information to its first quarter results. AES' Latin American subsidiaries contributed only about US$1mn in the first quarter, accounting for less than 1% of the company's US$180mn income from subsidiaries. But by year end AES expects to receive US$30mn from Chilean subsidiary AES Gener, US$30mn from Argentina's Alicura, US$30mn from Puerto Rico, US$20mn from Brazilian thermo plant Uruguaiana, and US$15mn from other income. "The rest is very minimal, we expect nothing else from Brazil, or Argentina," CEO Paul Hanrahan said during a conference call to discuss first quarter results. AES recently announced that it would use its 2002 profits from AES Gener to pay interest on its US$300mn debt to that company, which is due in early 2004. But AES still expects to receive US$30mn net income from its subsidiary by the end of the year. "We have confidence we can do it, but to get that operating cash flow out of the business we have to smooth out the maturities at a Gener level," Hanrahan said. Meanwhile, Venezuela's exchange controls will prevent AES from receiving any income from its power utility Electricidad de Caracas (EDC) this year, Hanrahan said. EDC closed its collection offices during the national strike, and sales were hit by the general reduction in demand, he said, adding that demand has started to recover since the end of the strike in the first quarter and EDC has resumed collecting payments. "The real question is when will exchange controls end, and when will the economy get back on track in terms of growth," Hanrahan said, adding that by 2005 he expects EDC to earn US$150mn-200mn net income annually for AES. In Brazil, AES continues to negotiate with national development bank BNDES to refinance its US$1.2bn debt. The debts were primarily taken on to pay the government for ordinary and preferred shares in Sao Paulo electric power distributor Eletropaulo, in which AES owns a 74% stake. "We are confident that a workable solution could work to the benefit of AES and the Brazilian government," Hanrahan said, but cautioned that, "we are negotiating but there is no assurance we will be successful." According to local newspapers, AES VP Joseph Brandt was scheduled to meet Friday with BNDES to discuss his company's US$1.2bn debts with the bank. Proposals presented until now by both parties have been "minimally acceptable," BNDES finance director Roberto Thimoteo said, quoted by O Estado de Sao Paulo. One of AES' local subsidiaries, AES Elpa, has exceeded a 90-day grace period on its defaulted debts, and BNDES has taken "preliminary" steps to foreclose on the shares that it holds in Eletropaulo, Hanrahan said. Earlier this week, BNDES asked the securities clearinghouse, CBLC to begin the sale process for preferred shares held by a second subsidiary, AES Transgas. The bank is not keen to become a shareholder in Eletropaulo, but will do so if it believes that is the best way to recover the debts, Thimoteo said. AES' Brazil holdings currently represent a negative affect on the company's equity of about US$1bn per year, so the sale of some of its Electropaulo shares would actually have a positive effect on equity, Hanrahan said, adding that BNDES could sell as much as 54% of AES' stake in Electropaulo. AES income from continuing operations fell 38% to US$73mn, or US$0.13 per share, for the first quarter 2003 compared to US$118mn, or US$0.22 per share, in the same period last year. Net income for the quarter was US$93mn up from a US$313mn net loss in the first quarter of 2002. The net loss for 1Q02 included a charge for the cumulative effect of an accounting change. Revenues for the first quarter of 2003 were US$2.2bn.

<a href=www.latintrade.com>LatinTrade May, 2003

Javier Corrales, associate professor of political science at Amherst College, begins his book with a troublesome fact: According to a survey by Latinobaró-metro in 2001, less than 5% of Latin Americans have a high level of confidence in political parties. In some countries, political parties are among the most discredited institutions, ranking well below the armed forces.

Even with those results, Corrales rails against the theory that political parties are coming to an end. He believes they continue to play a fundamental role in governing a country. He also maintains that political institutions do not reflect society’s sentiments but, rather, mold the preferences and attitudes of the population, serving as the architects of public opinion. At the same time, they are a channel of communication between citizens and the executive power, possibly the main conduit of communication.

The author looks at the period when free market reforms were implemented in Latin America and the role of political parties in that process. Several studies regarding that era focus on the conflict between the government and political opposition, or between the government and interest groups. But Corrales believes the most crucial relationship is between the executive branch and the ruling party. “If the president manages to get the ruling party to cooperate with the reform process, the state’s capacity to govern the economy will increase,” he writes. To prove his hypothesis, he dedicates a large portion of the book to two countries that launched free market reforms under similar conditions in 1989 yet yielded different results: Argentina and Venezuela.

That year, the newly elected governments of Carlos Andrés Pérez in Venezuela and Carlos Saúl Menem in Argentina initiated similar economic reforms. Both presidents belonged to populist political parties: Pérez to Acción Democratica (AD) and Menem to the Peronist Party (PJ). During his first term, Menem was able to rein in a huge fiscal deficit and eradicate the inflation that had plagued the government of his predecessor, Raúl Alfonsín. This miracle won him PJ approval for his privatization plans and deregulation even though the free market practices Menem implemented differed from the ideology of his own party. Menem knew it would be difficult to rule without the support of the Peronists. In 1990, he declared: “There will be no national unity if there is no unity within the party.”

In Venezuela, on the other hand, philosophical differences between Pérez and AD led to the country’s worst political crisis in 30 years, characterized by explosive popular protests, two coup attempts, changes in the cabinet, interruption of reforms, an increased crime rate and economic woes. Pérez was finally forced out by the Venezuelan legislature in 1993, replaced by another former president, Rafael Caldera, who sunk the economy further when he curtailed reforms then later tried to implement them again under Agenda Venezuela. Hugo Chávez, Caldera’s successor, has opted to attack the party system, depending instead on the military. The current crisis in Venezuela, according to Corrales, exemplifies the problems caused by the weakening role of parties in political life.

The author applies his theory to eight other Latin American countries, including Cuba. When Fidel Castro lost subsidies from Moscow at the beginning of the 1990s, he had to adopt market reforms, open the country to foreign investment, allow certain independent businesses and legalize the dollar. Many believed such reforms would make the system crumble as it broke the structure of privileges. But the Cuban leader maintained strong state participation in new capitalist corporations, restricted private activity and even controlled the hiring of staff in foreign companies, which allowed him to place the most loyal government supporters in the best jobs, thus consolidating his support. 

Presidents Without Parties revives the theory that political parties are indispensable in order to rule. As he concentrates on the relationship between ruling parties and the executive power, however, Corrales fails to place enough emphasis on current economic phenomenon present in the crisis in Venezuela and the disaster in Argentina. Nevertheless, in a period when traditional political parties are distrusted and there is a boom in popular or marginal institutions, this book addresses an important issue in the debate about the future of Latin America.

Author: Andrés Hernández Alende

05/05/2003 - Source: <a href=www.latintrade.com>LatinTrade-Latin American Newsletters

While President Lula da Silva has been thrashing out his tax and pension reforms, battling state governors, party radicals and union discontent (all covered in this issue), he has not shied away from presenting a grand 'development vision'.

Sharply critical of his predecessor Fernando Henrique Cardoso for concentrating on economic regeneration at the expense of any broader goals, Lula has pursued a vision that ironically bears some resemblance to that of the dictatorship: a more independent foreign policy breaking with traditional adherence to US-backed positions.

In Lula's vision, Brazil asserts its leadership in Latin America and embraces globalisation in so far as it benefits the country. Lula's strategy for moving Brazil away from merely reacting to the US hemispheric cue ball is to thrust the Mercosul trading bloc to the top of his foreign policy agenda and deepen integration with South American neighbours. He set himself the task of meeting every political leader in the region, something he will achieve soon when the leaders of French Guiana, Guyana and Suriname visit.

Earlier this month, he signed a 'strategic alliance' with Peruvian President Alejandro Toledo, which is a blueprint for a free trade agreement with the Andean Community, the regions' other big trading bloc. He met Venezuela's Hugo Chávez, who has expressed a keen interest in joining Mercosul, on 25 April and meets Bolivia's Gonzalo Sánchez de Lozada and his cabinet on 29 April.

Stengthening Mercosul is a strategic priority for Brazil: a ballast against US unilateralism. Lula has been working to shore up support within the bloc ahead of Free Trade Area of the Americas' talks with the US. He sent personal letters to his counterparts in Argentina, Paraguay and Uruguay calling for a joint position on services, government purchases and investment.

The problem for Lula is that Mercosul is the centrepiece of his vision and it looks precarious: the bloc's future depends upon the outcome of Argentina's presidential election and if a new leader eschews Mercosul for closer ties with the US (see page 8). Uruguayan President Jorge Batlle, fresh from visiting Washington, is pushing for 'no more delays' in trade talks between Mercosul and the US. He visits Lula on 10 May.

Brazil is frustrated with Mercosul's trade spats, the most recent example being Argentina's decision to levy a duty on Brazilian sugar. This belies any common stance on agriculture before the FTAA. Brazil could be forced to start talking bilateral trade with the US after all.

05/05/2003 - Source: <a href=www.latintrade.com>LatinTrade-BNamericas

Venezuela's largest steelmaker, Sidor, has introduced an energy saving plan in the face of possible power rationing on account of the currently low water levels in the Guri reservoir, the hydroelectric source for the Guayana region where the company is located. "We do not have a contingency plan as such to deal with rationing, what we do have is an energy savings policy," a company spokesperson told BNamericas. The steelmaker established last year an across-the-board program seeking savings in its operational and administrative areas. One of the first measures to be introduced was the use of scheduled maintenance shutdowns to detect and gauge opportunities to save electrical energy. This measure was extended to include availing of the unscheduled stoppages provoked by lack of materials during the general strike in Venezuela at the end of last year and early this year.

Industrial services management at Sidor estimate the energy savings plan will reduce consumption by 743 million KWH a year. By far the heaviest consumer of power at Sidor is the electric arc furnace steelmaking area, accounting for 75% of the total; followed by direct reduction, hot and cold rolling, ancillary services, maintenance and finally the administrative areas. Meanwhile other big consumers of hydroelectric power in the region who are dependent on the Guri reservoir are also taking measures to deal with the situation. Local aluminum maker CVG-Alcasa needs large quantities of power to operate efficiently. "As there could be problems with power supplies from the Raul Leoni hydroelectric power station which is fed by the Guri reservoir, and almost all our lines use electric power, we do have contingency plans and we are looking at measures to take," an Alcasa spokesperson said. The reservoir is located 90km up river from the confluence of the Caroni and Orinoco rivers in Bolivar state. Ciudad Guayana-based Sidor currently produces some 3.2Mt/y steel. The Amazonia consortium - made up of Latin American steel companies Sivensa (Venezuela), Siderar (Argentina), Usiminas (Brazil), Tamsa and Hylsamex (both Mexico) - controls 70% of the company and Venezuela's state heavy industry holding company CVG has the other 30%.