Echocardiographic and pathologic identification of an aorto-left atrial fistula secondary to infective endocarditis in a canine patient.

A dog was presented for lameness, fever, and extreme lethargy. On physical exam, a new heart murmur, arrhythmia, and joint effusion were detected. These findings were not detected two months prior. A diagnostic work-up confirmed septic suppurative inflammation in multiple joints. Echocardiogram revealed aortic valvular endocarditis along with a communication, as a consequence of a fistula, that extended from just below the aortic sinotubular junction to the left atrial lumen. Due to a poor prognosis, humane euthanasia was elected. Necropsy and histopathology confirmed infective endocarditis of the aortic valve and an aorto-left atrial fistulous tract extending from the left coronary sinus of the aortic valve to the lumen of left atrium.

Genetic inactivation of acrAB or inhibition of efflux induces expression of ramA.

OBJECTIVES: The transcriptional activator RamA regulates production of the multidrug resistance efflux AcrAB-TolC system in several Enterobacteriaceae. This study investigated factors that lead to increased expression of ramA. METHODS: In order to monitor changes in ramA expression, the promoter region of ramA was fused to a gfp gene encoding an unstable green fluorescence protein (GFP) on the reporter plasmid, pMW82. The ramA reporter plasmid was transformed into Salmonella Typhimurium SL1344 and a ΔacrB mutant. The response of the reporter to subinhibitory concentrations of antibiotics, dyes, biocides, psychotropic agents and efflux inhibitors was measured during growth over a 5 h time period. RESULTS: Our data revealed that the expression of ramA was increased in a ΔacrB mutant and also in the presence of the efflux inhibitors phenylalanine-arginine-ß-naphthylamide, carbonyl cyanide m-chlorophenylhydrazone and 1-(1-naphthylmethyl)-piperazine. The phenothiazines chlorpromazine and thioridazine also increased ramA expression, triggering the greatest increase in GFP expression. However, inducers of Escherichia coli marA and soxS and 12 of 17 tested antibiotic substrates of AcrAB-TolC did not induce ramA expression. CONCLUSIONS: This study shows that expression of ramA is not induced by most substrates of the AcrAB-TolC efflux system, but is increased by mutational inactivation of acrB or when efflux is inhibited.

Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11.

The bones that comprise the axial skeleton have distinct morphological features characteristic of their positions along the anterior/posterior axis. We previously described a novel TGF-beta family member, myostatin (encoded by the gene Mstn, formerly Gdf8), that has an essential role in regulating skeletal muscle mass. We also identified a gene related to Mstn by low-stringency screening. While the work described here was being completed, the cloning of this gene, designated Gdf11 (also called Bmp11), was also reported by other groups. Here we show that Gdf11, a new transforming growth factor beta(TGFbeta) superfamily member, has an important role in establishing this skeletal pattern. During early mouse embryogenesis, Gdf11 is expressed in the primitive streak and tail bud regions, which are sites where new mesodermal cells are generated. Homozygous mutant mice carrying a targeted deletion of Gdf11 exhibit anteriorly directed homeotic transformations throughout the axial skeleton and posterior displacement of the hindlimbs. The effect of the mutation is dose dependent, as Gdf11+/- mice have a milder phenotype than Gdf11-/- mice. Mutant embryos show alterations in patterns of Hox gene expression, suggesting that Gdf11 acts upstream of the Hox genes. Our findings suggest that Gdf11 is a secreted signal that acts globally to specify positional identity along the anterior/posterior axis.

Regulation of left-right patterning in mice by growth/differentiation factor-1.

The transforming growth factor-beta (TGF-beta) superfamily encompasses a large group of structurally related polypeptides that are capable of regulating cell growth and differentiation in a wide range of embryonic and adult tissues. Growth/differentiation factor-1 (Gdf-1, encoded by Gdf1) is a TGF-beta family member of unknown function that was originally isolated from an early mouse embryo cDNA library and is expressed specifically in the nervous systemin late-stage embryos and adult mice. Here we show that at early stages of mouse development, Gdfl is expressed initially throughout the embryo proper and then most prominently in the primitive node, ventral neural tube, and intermediate and lateral plate mesoderm. To examine its biological function, we generated a mouse line carrying a targeted mutation in Gdf1. Gdf1-/- mice exhibited a spectrum of defects related to left-right axis formation, including visceral situs inversus, right pulmonary isomerism and a range of cardiac anomalies. In most Gdf1-/- embryos, the expression of Ebaf (formerly lefty-1) in the left side of the floor plate and Leftb (formerly lefty-2), nodal and Pitx2 in the left lateral plate mesoderm was absent, suggesting that Gdf1 acts upstream of these genes either directly or indirectly to activate their expression. Our findings suggest that Gdf1 acts early in the pathway of gene activation that leads to the establishment of left-right asymmetry.

Mice lacking ornithine-delta-aminotransferase have paradoxical neonatal hypoornithinaemia and retinal degeneration.

Deficiency of ornithine-delta-aminotransferase (OAT) in humans causes hyperornithinaemia and gyrate atrophy (GA), a blinding chorioretinal degeneration. Surprisingly, OAT-deficient mice produced by gene targeting exhibit neonatal hypoornithinaemia and lethality, rescuable by short-term arginine supplementation. Post-weaning, these mice develop hyperornithinaemia similar to human GA patients. Subsequent studies in one human GA infant also showed transient hypoornithinaemia. Thus, the OAT reaction plays opposite roles in neonatal and adult mammals. Over several months, OAT-deficient mice develop a retinal degeneration with involvement of photoreceptors and pigment epithelium. OAT-deficient mice appear to be an excellent model of human GA.

Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A.

Haemophilia A is a classic X-linked disease which affects 1 in 5-10,000 males in all populations and is caused by defects in coagulation factor VIII. Roughly 60% of patients have severe disease with factor VIII activity < 1% of normal; they have frequent spontaneous bleeding into joints, soft tissues, muscles and internal organs. These patients usually require regular injections of plasma-derived or recombinant human factor VIII. Because this is expensive and can potentially lead to life-threatening complications, other forms of therapy, including gene therapy, have been proposed. Natural canine models of factor VIII and factor IX deficiency have been available for many years, and gene therapy attempts on these dogs have met with partial success. However, a small animal model of the disease is desirable for studies of factor VIII function and gene therapy. Using gene targeting, we have made a mouse with severe factor VIII deficiency.

Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice [corrected].

Overexpression of the gene encoding the beta-amyloid precursor protein (APP) may have a key role in the pathogenesis of both Alzheimer's disease (AD) and Down Syndrome (DS). We have therefore introduced a 650 kilobase (kb) yeast artificial chromosome (YAC) that contains the entire, unrearranged 400 kb human APP gene into mouse embryonic stem (ES) cells by lipid-mediated transfection. ES lines were generated that contain a stably integrated, unrearranged human APP gene. Moreover, we demonstrate germ line transmission of the APP YAC in transgenic mice and expression of human APP mRNA and protein at levels comparable to endogenous APP. This transgenic strategy may prove invaluable for the development of mouse models for AD and DS.

Induction of murine acquired immunodeficiency syndrome (MAIDS) in allophenic mice generated from strains susceptible and resistant to disease.

To examine whether a retroviral disease can be controlled in animals in which cells from a resistant strain coexist in a state of immunological tolerance with cells from a susceptible strain, allophenic mice were constructed and infected with LP-BM5 murine leukemia viruses which induce a fatal disorder, termed murine acquired immunodeficiency syndrome (MAIDS), characterized by lymphoproliferation and immunodeficiency in susceptible inbred strains of mice. We found that in two different strain combinations, resistance to MAIDS was contingent on the presence in individual animals of >50% of lymphocytes of resistant strain origin and correlated with reduction or elimination of retrovirus. In contrast, animals harboring substantial, but less than predominant, numbers of genetically resistant lymphocytes developed disease and died within the same time frame as susceptible control mice with uncontained proliferation of retrovirus.

National academy. New report triggers changes in the NRC.

A panel of eminent science and engineering administrators has delivered some stern advice to the National Research Council, the operating arm of the National Academy of Sciences, in a report on how the council does its business. The review concludes that the council takes too long to produce many of its reports, is not responsive enough to its sponsors, lacks clear lines of authority, and its staff is too often frustrated and stressed. To fix these problems, the panel urges the academy "to reduce unnecessary layers of approval," delegate more authority, appoint a chief management officer, and create "a service-oriented culture."

NASA life sciences. An improvement in vital signs.

Last week a hefty Russian module with living and working quarters for astronauts docked with the pieces of the international space station already in orbit, a critical step in creating a full-time orbiting laboratory. Meanwhile, NASA bureaucrats put the finishing touches on a realignment of the agency's struggling biology effort that should bolster fundamental research and allow scientists to make better use of the facility, scheduled to be completed in 2005. The two events raise the hopes of U.S. academic space life scientists that their discipline is at last on the ascent at NASA.

Genomics. University company to exploit heart data.

This month, Boston University, which directs the Framingham Heart Study, a massive government effort begun in 1948 to monitor the cardiovascular health of more than 10,000 residents of this suburb of Boston, announced plans to form a bioinformatics company that will mine the data. The university will own 20% of Framingham Genomic Medicine Inc., which hopes to raise $21 million to begin modernizing the immense database and packaging it in a format that will be valuable to the pharmaceutical industry. The plan raises a host of difficult ethical issues, including patient privacy, academic conflicts of interest, and reciprocal value to the Framingham residents whose medical data will form the basis for the new enterprise.

ASIAN-AMERICAN SCIENTISTS: Silent No Longer: 'Model Minority' Mobilizes.

Angered and emboldened by the Wen Ho Lee case, many Asian-American researchers at national laboratories are decrying their status as "high-tech coolies"--and demanding change. It's a sudden and surprising turn of events for a community that traditionally has avoided political organization, legal recourse, and conflict with authority. And given the growing numerical muscle of Asian Americans in both public and private labs, the budding movement--if sustained--will be felt far beyond the secure fences of the Department of Energy's weapons labs.

ASIAN-AMERICAN SCIENTISTS: Lee Case Births a Reluctant Activist.

Until the past year, Alex Chao, a senior physicist at the Stanford Linear Accelerator Center, tended to keep his views to himself. But the Wen Ho Lee case turned Chao into a reluctant activist who has contributed money for Lee's defense, helped organize rallies in the San Francisco Bay area, and talked to his neighbors about the injustice he believes Lee and other Asian Americans have suffered.

ASIAN-AMERICAN SCIENTISTS: New Breed of Protester Asks: Why Not Us?

For nearly a year prior to this past June, grad student Roger Hu had been following with increasing anxiety the case of Wen Ho Lee, the Los Alamos National Laboratory physicist who had been arrested and jailed in New Mexico under suspicion of mishandling classified data. Now Hu struggles to keep up with his Massachusetts Institute of Technology classes in computer science and electrical engineering in his new life as an activist.

ASIAN-AMERICAN SCIENTISTS: Harbinger of a Litigious Future?

When the chair of the pharmacology department at the University of California, Davis, pledged in writing to find a permanent position for microbiologist Ronald Chuang, Chuang and his wife Linda--a researcher who works in his lab--were delighted. A dozen years later, Ronald Chuang still has no permanent position, and he and his wife filed suit in 1997 over what they allege is a long and egregious series of discriminatory acts by the university.

SOLAR SYSTEM EXPLORATION: A More Cautious NASA Sets Plans for Mars.

Twice burned by mission failures last year, NASA managers last week unveiled a new 15-year blueprint for Mars exploration. The revamped strategy allows for doing more science, but at a slower pace, while delaying a sample return until well into the next decade.

SOLAR SYSTEM EXPLORATION: Push to Revive Pluto Mission May Mean Competition for JPL.

An unusual coalition of scientists, activists, and politicians is pressuring NASA to rethink a September decision to put a 2004 mission to Pluto on hold because of budget constraints. The growing clamor is shaking up the planetary science community, which is also preparing for a mission at mid-decade to Europa, a moon of Jupiter. The biggest impact may be felt at the Jet Propulsion Laboratory in Pasadena, California, which could face serious competition for the first time in decades on contracts to build planetary missions.

SOLAR SYSTEM EXPLORATION: NASA Blasted for Rising Costs, Cancellations.

When NASA cancelled a project last month that would have sent a tiny rover crawling over an asteroid, the community of planetary scientists issued a public tongue lashing of the agency. Its letter warned of larger problems in the U.S. program caused by spiraling costs and recommended a sweeping reexamination of the outer solar system effort.

U.S. SPACE SCIENCE: Earmarks, Rising Costs Threaten NASA Missions.

The House and Senate are working out a final 2001 budget plan that should leave NASA with a small increase over this year. But the increase will be more than swallowed up by projects costing hundreds of millions of dollars that politicians have added to satisfy their constituents. At the same time, rising mission costs in the wake of two recent Mars failures are forcing agency officials to steal money from lower priority efforts such as a trip to Pluto. The two trends, warn NASA and science community officials, could prove devastating to NASA's space science efforts.