The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals.

Bidirectional signals mediated by membrane-anchored ephrins and Eph receptor tyrosine kinases have important functions in cell-cell recognition events, including those that occur during axon pathfinding and hindbrain segmentation. The reverse signal that is transduced into B-ephrin-expressing cells is thought to involve tyrosine phosphorylation of the signal's short, conserved carboxy-terminal cytoplasmic domain. The Src-homology-2 (SH2) domain proteins that associate with activated tyrosine-phosphorylated B-subclass ephrins have not been identified, nor has a defined cellular response to reverse signals been described. Here we show that the SH2/SH3 domain adaptor protein Grb4 binds to the cytoplasmic domain of B ephrins in a phosphotyrosine-dependent manner. In response to B-ephrin reverse signalling, cells increase FAK catalytic activity, redistribute paxillin, lose focal adhesions, round up, and disassemble F-actin-containing stress fibres. These cellular responses can be blocked in a dominant-negative fashion by expression of the isolated Grb4 SH2 domain. The Grb4 SH3 domains bind a unique set of other proteins that are implicated in cytoskeletal regulation, including the Cbl-associated protein (CAP/ponsin), the Abl-interacting protein-1 (Abi-1), dynamin, PAK1, hnRNPK and axin. These data provide a biochemical pathway whereby cytoskeletal regulators are recruited to Eph-ephrin bidirectional signalling complexes.

Forward signaling mediated by ephrin-B3 prevents contralateral corticospinal axons from recrossing the spinal cord midline.

To investigate Eph-ephrin bidirectional signaling, a series of mutations were generated in the ephrin-B3 locus. The absence of both forward and reverse signaling resulted in mice with mirror movements as typified by a hopping locomotion. The corticospinal tract was defective as axons failed to respect the midline boundary of the spinal cord and bilaterally innervated both contralateral and ipsilateral motor neuron populations. A second mutation that expresses a truncated ephrin-B3 protein lacking its cytoplasmic domain did not lead to hopping, indicating that reverse signaling is not required for corticospinal innervation. Ephrin-B3 is concentrated at the spinal cord midline, while one of its receptors, EphA4, is expressed in postnatal corticospinal neurons as their fibers pathfind down the contralateral spinal cord. Our data indicate ephrin-B3 functions as a midline-anchored repellent to stimulate forward signaling in EphA4-expressing axons.

Crystal structure of an Eph receptor-ephrin complex.

The Eph family of receptor tyrosine kinases and their membrane-anchored ephrin ligands are important in regulating cell-cell interactions as they initiate a unique bidirectional signal transduction cascade whereby information is communicated into both the Eph-expressing and the ephrin-expressing cells. Initially identified as regulators of axon pathfinding and neuronal cell migration, Ephs and ephrins are now known to have roles in many other cell-cell interactions, including those of vascular endothelial cells and specialized epithelia. Here we report the crystal structure of the complex formed between EphB2 and ephrin-B2, determined at 2.7 A resolution. Each Eph receptor binds an ephrin ligand through an expansive dimerization interface dominated by the insertion of an extended ephrin loop into a channel at the surface of the receptor. Two Eph-Ephrin dimers then join to form a tetramer, in which each ligand interacts with two receptors and each receptor interacts with two ligands. The Eph and ephrin molecules are precisely positioned and orientated in these complexes, promoting higher-order clustering and the initiation of bidirectional signalling.

National health expenditures, 1999.

The health care spending share of gross domestic product (GDP) remained steady between 1993 and 1999 as moderate-to-strong economic growth coincided with a rapid shift to managed care. This shift, along with decelerating growth in Medicare spending, appears to have generated a mostly one-time saving that lowered aggregate health expenditure growth.

EphB2 guides axons at the midline and is necessary for normal vestibular function.

Mice lacking the EphB2 receptor tyrosine kinase display a cell-autonomous, strain-specific circling behavior that is associated with vestibular phenotypes. In mutant embryos, the contralateral inner ear efferent growth cones exhibit inappropriate pathway selection at the midline, while in mutant adults, the endolymph-filled lumen of the semicircular canals is severely reduced. EphB2 is expressed in the endolymph-producing dark cells in the inner ear epithelium, and these cells show ultrastructural defects in the mutants. A molecular link to fluid regulation is provided by demonstrating that PDZ domain-containing proteins that bind the C termini of EphB2 and B-ephrins can also recognize the cytoplasmic tails of anion exchangers and aquaporins. This suggests EphB2 may regulate ionic homeostasis and endolymph fluid production through macromolecular associations with membrane channels that transport chloride, bicarbonate, and water.

Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina.

Optic nerve formation requires precise retinal ganglion cell (RGC) axon pathfinding within the retina to the optic disc, the molecular basis of which is not well understood. At CNS targets, interactions between Eph receptor tyrosine kinases on RGC axons and ephrin ligands on target cells have been implicated in formation of topographic maps. However, studies in chick and mouse have shown that both Eph receptors and ephrins are also expressed within the retina itself, raising the possibility that this receptor-ligand family mediates aspects of retinal development. Here, we more fully document the presence of specific EphB receptors and B-ephrins in embryonic mouse retina and provide evidence that EphB receptors are involved in RGC axon pathfinding to the optic disc. We find that as RGC axons begin this pathfinding process, EphB receptors are uniformly expressed along the dorsal-ventral retinal axis. This is in contrast to the previously reported high ventral-low dorsal gradient of EphB receptors later in development when RGC axons map to CNS targets. We show that mice lacking both EphB2 and EphB3 receptor tyrosine kinases, but not each alone, exhibit increased frequency of RGC axon guidance errors to the optic disc. In these animals, major aspects of retinal development and cellular organization appear normal, as do the expression of other RGC guidance cues netrin, DCC, and L1. Unexpectedly, errors occur in dorsal but not ventral retina despite early uniform or later high ventral expression of EphB2 and EphB3. Furthermore, embryos lacking EphB3 and the kinase domain of EphB2 do not show increased errors, consistent with a guidance role for the EphB2 extracellular domain. Thus, while Eph kinase function is involved in RGC axon mapping in the brain, RGC axon pathfinding within the retina is partially mediated by EphB receptors acting in a kinase-independent manner.

National health expenditures, 1998.

In 1998, national health care expenditures reached $1.1 trillion, an increase of 5.6 percent from the previous year. This marked the fifth consecutive year of spending growth under 6 percent. Underlying the stability of the overall growth, major changes began taking place within the Nation's health care system. Public payers felt the initial effects of the Balanced Budget Act of 1997 (BBA), and private payers experienced increased health care costs and increased premium growth.

National health expenditures, 1997.

In 1997 health spending in the United States increased just 4.8 percent to $1.1 trillion. As a share of gross domestic product (GDP), national health expenditures (NHE) absorbed 13.5 percent of the country's output in 1997--a share that has remained relatively constant for 5 years. Despite the relative stability in recent years, signs of changing trends are emerging.

Business, households, and government: health care spending, 1995.

For the period 1990-95, we will present data on health care spending by business, households, and government. In addition, we will measure the relative impact of these expenditures on each sector's ability to pay. In 1994 and 1995, health care costs experienced the slowest growth in 3 decades. Combined with healthy revenue growth, slow cost growth helped ease or stabilize the financing burden faced by business, households and government.

National health expenditures, 1996.

The national health expenditures (NHE) series presented in this report for 1960-96 provides a view of the economic history of health care in the United States through spending for health care services and the sources financing that care. In 1996 NHE topped $1 trillion. At the same time, spending grew at the slowest rate, 4.4 percent, ever recorded in the current series. For the first time, this article presents estimates of Medicare managed care payments by type of service, as well as nursing home and home health spending in hospital-based facilities.

National health expenditures, 1994.

This article presents data on health care spending for the United States, covering expenditures for various types of medical services and products and their sources of funding from 1960 to 1994. Although these statistics for 1994 show the slowest growth in more than three decades, health spending continued to grow faster than the overall economy. The Federal Government continued to fund an increasing share of health care expenditures in 1994, offset by a falling share from out-of-pocket sources. Shares paid by State and local governments and by other private payers including private health insurance remained unchanged from 1993.

National health expenditures, 1995.

This article presents data on health care spending for the United States, covering expenditures for various types of medical services and products and their sources of funding from 1960 to 1995. In 1995, $988.5 billion was spent to purchase health care in the United States, up 5.5 percent from 1994. Growth in spending between 1993 and 1995 was the slowest in more than three decades, primarily because of slow growth in private health insurance and out-of-pocket spending. As a result, the share of health spending funded by private sources fell, reflecting the influence of increased enrollment in managed care plans.

Business, households, and government: health spending, 1994.

During the 1990s, growth in health care costs slowed considerably, helping to lessen the spending strain on business, government, and households. Although cost growth has slowed, the Federal Government continues to pay an ever-increasing share of the total health care bill. This article reviews important health care spending trends, and for the first time, provides separate estimates of the employer and employee share of the premium costs for employer-sponsored private health insurance. This article also highlights some of the emerging trends in the employer-sponsored insurance market, including managed care, cost-sharing, and employment shifts.

State health expenditure accounts: building blocks for state health spending analysis.

The dynamics of financing health care among various levels of government and the private sector are rapidly changing; structural relationships among health care providers are also being altered. These changes are placing increased importance on State-level expenditure estimates that will be instrumental in measuring the differential impact of Federal policies and State-specific initiatives on individual States. This article presents personal health care expenditures (PHCE) for 1980-93. Statistics show wide variation in level and rate of growth of regional spending per person. These statistics also quantify differences in both the percent of health care costs in each State borne by Medicare and Medicaid and in the proportion of each State's economy devoted to the provision of health care.

National health spending trends, 1960-1993.

In 1993 the nation spent $884.2 billion on health care, a 7.8 percent increase from 1992. Although this spending growth was among the lowest rates of growth recorded since 1960, it is too soon to tell whether slower growth in health spending is a new trend or merely a temporary perturbation in the long-term trend. The portion of the economy devoted to health care increased from 13.6 percent in 1992 to 13.9 percent in 1993--a 0.3 percentage point increase that equaled the average rate of increase recorded since 1960. The federal government's share of the total health care bill rose between 1991 and 1993, the first significant change in the share of the nation's health care bill funded by the federal government since the early 1970s.

National health expenditures, 1993.

This article presents data on health care spending for the United States, covering expenditures for various types of medical services and products and their sources of funding from 1960 to 1993. Although these statistics show a slowing in the growth of health care expenditures over the past few years, spending continues to increase faster than the overall economy. The share of the Nation's health care bill funded by the Federal Government through the Medicaid and Medicare programs steadily increased from 1991 to 1993. This significant change in the share of health expenditures funded by the public sector has caused Federal health expenditures as a share of all Federal spending to increase dramatically.

Health spending by state: new estimates for policy making.

A new data set from the Health Care Financing Administration gives estimates of state spending for hospital care, physician services, and retail purchases of prescription drugs, which together account for 70 percent of health expenditures nationwide. Analysis of these data, which are the first uniform state data to be produced for nearly ten years, shows considerable variation among states and among regions in health care spending. The New England and Mideast regions show the consistently highest spending levels for all three categories; the Southwest and Rocky Mountain regions spent the smallest amount (as much as 17 percent below the U.S. average).

Business, households, and governments: health spending, 1991.

Governments have been thrust to the forefront of health care reform efforts as growth in government health care costs was faster than growth in all other sponsor sectors in 1991. In the business sector, real health care costs per worker have risen 65 times faster than real wages and salaries per worker during the past 26 years. Households continue to devote 5 percent of income after taxes to health care, the same percentage for the last 8 years. This article presents data supporting these findings, and an analysis of health care spending by each sponsor sector.

National health expenditures, 1991.

Spending for health care rose to $751.8 billion in 1991, an increase of 11.4 percent from the 1990 level. National health expenditures as a share of gross domestic product increased to 13.2 percent, up from 12.2 percent in 1990. The health care sector exhibited strong growth, despite slow growth in the overall economy. This combination resulted in the largest increase in the share of the Nation's output consumed by health care in the past three decades. In this article, the authors present estimates of health spending in the United States for 1991. The authors also examine reasons for the unusually large growth in Medicaid expenditures and highlight recent trends in the hospital sector.