Noggin is a mesenchymally derived stimulator of hair-follicle induction.

The induction of developmental structures derived from the ectoderm, such as the neural tube or tooth, occurs through neutralization of the inhibitory activity of members of the bone-morphogenetic protein (BMP) family by BMP antagonists. Here we show that, during hair-follicle development, the neural inducer and BMP-neutralizing protein Noggin is expressed in the follicular mesenchyme, that noggin-knockout mice show significant retardation of hair-follicle induction, and that Noggin neutralizes the inhibitory action of BMP-4 and stimulates hair-follicle induction in embryonic skin organ culture. As a crucial mesenchymal signal that stimulates hair-follicle induction, Noggin operates through antagonistic interactions with BMP-4, which result in upregulation of the transcription factor Lef-1 and the cell-adhesion molecule NCAM, as well as through BMP4-independent downregulation of the 75 kD neurotrophin receptor in the developing hair follicle.

The Mechanical Response and Tolerance of the Anteriorly-Tilted Human Pelvis Under Vertical Loading.

Military vehicle underbody blast (UBB) is the cause of many serious injuries in theatre today; however, the effects of these chaotic events on the human body are not well understood. The purpose of this research was to replicate UBB loading conditions on the human pelvis and investigate the resulting response in a controlled laboratory setting. In addition to better understanding the response of the human pelvis to high rate vertical loading, this test series also aimed to identify high rate injury thresholds. Twenty-seven post mortem human surrogate (PMHS) component pelvis tests were completed using the University of Virginia's (UVa) simulated blast rig under a range of loading conditions and postures. Of those tests, 17 were in the anteriorly-tilted posture and used to construct the human injury probability curve. Average seat pan (rigid) accelerations for this subset of tests ranged from 300 to 2400 g over 2 to 3 ms of positive phase duration. Post-test computed tomography (CT) scans and necropsies were performed to determine injuries and revealed a frequent occurrence of anterior and posterior injuries, resulting in unstable pelvis ring fractures. The resulting Human Injury Probability Curve (HIPC) yielded mean forces of 5529, 8516, and 12431 N as measured by mass compensated seat platen loadcells applied through the rigid seat to the bilateral ischium are associated with a 10, 25, and 50% risk for unstable pelvic ring sacrum fractures in an anteriorly-tilted pelvis (28° from vertical), respectively.

Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton.

Noggin is a bone morphogenetic protein (BMP) antagonist expressed in Spemann's organizer. Murine Noggin is expressed in condensing cartilage and immature chondrocytes, as are many BMPs. In mice lacking Noggin, cartilage condensations initiated normally but developed hyperplasia, and initiation of joint development failed as measured by the expression of growth and differentiation factor-5. The maturation of cartilage and Hoxd expression were unaffected. Excess BMP activity in the absence of Noggin antagonism may enhance the recruitment of cells into cartilage, resulting in oversized growth plates; chondrocytes are also refractory to joint-inducing positional cues.

Sonic hedgehog signaling is essential for hair development.

BACKGROUND: The skin is responsible for forming a variety of epidermal structures that differ amongst vertebrates. In each case the specific structure (for example scale, feather or hair) arises from an epidermal placode as a result of epithelial-mesenchymal interactions with the underlying dermal mesenchyme. Expression of members of the Wnt, Hedgehog and bone morphogenetic protein families (Wnt10b, Sonic hedgehog (Shh) and Bmp2/Bmp4, respectively) in the epidermis correlates with the initiation of hair follicle formation. Further, their expression continues into either the epidermally derived hair matrix which forms the hair itself, or the dermal papilla which is responsible for induction of the hair matrix. To address the role of Shh in the hair follicle, we have examined Shh null mutant mice. RESULTS: We found that follicle development in the Shh mutant embryo arrested after the initial epidermal-dermal interactions that lead to the formation of a dermal papilla anlage and ingrowth of the epidermis. Wnt10b, Bmp2 and Bmp4 continued to be expressed at this time, however. When grafted to nude mice (which lack T cells), Shh mutant skin gave rise to large abnormal follicles containing a small dermal papilla. Although these follicles showed high rates of proliferation and some differentiation of hair matrix cells into hair-shaft-like material, no hair was formed. CONCLUSIONS: Shh signaling is not required for initiating hair follicle development. Shh signaling is essential, however, for controlling ingrowth and morphogenesis of the hair follicle.

Wnt family proteins are secreted and associated with the cell surface.

Members of the Wnt gene family are proposed to function in both normal development and differentiation as well as in mammary tumorigenesis. To understand the function of Wnt proteins in these two processes, we present here a biochemical characterization of seven Wnt family members. For these studies, AtT-20 cells, a neuroendocrine cell line previously shown to efficiently process and secrete Wnt-1, was transfected with expression vectors encoding Wnt family members. All of the newly characterized Wnt proteins are glycosylated, secreted proteins that are tightly associated with the cell surface or extracellular matrix. We have also identified native Wnt proteins in retinoic acid-treated P19 embryonal carcinoma cells, and they exhibit the same biochemical characteristics as the recombinant proteins. These data suggest that Wnt family members function in cell to cell signaling in a fashion similar to Wnt-1.

Differential expression of human Wnt genes 2, 3, 4, and 7B in human breast cell lines and normal and disease states of human breast tissue.

Wnt gene expression was investigated by ribonuclease protection analysis in human breast cancer, nontumorous breast tissue, and a variety of human breast cell lines. We report the expression of Wnt3, Wnt4, and Wnt7b in human breast cell lines and Wnt2, Wnt3, Wnt4, and Wnt7b in human breast tissues. Wnt3a and Wnt7a were absent in the cell lines and tissues tested. The level of expression of Wnt2 and Wnt4 was 10- to 20-fold higher in fibroadenomas than it was in normal or malignant breast tissue, and in 10% of tumors Wnt7b expression was 30-fold higher than in normal or benign breast tissues. In contrast to the mouse, in which Wnt1 and Wnt3 are involved in tumorigenesis, our results suggest that Wnt2, Wnt4, and Wnt7b may be associated with abnormal proliferation in human breast tissue.

Wnt expression patterns in chick embryo nervous system.

Several lines of evidence suggest that Wnt genes play a critical role in regulating development of the vertebrate embryo. To address the role that this family may play in the development of the chicken central nervous system (CNS), we have used a PCR based strategy to clone partial sequences for Wnt genes. At least six different Wnt genes are expressed in the developing CNS of the chick embryo. The domains of expression overlap either partially or completely, and are expressed in spatial domains that prefigure morphological subunits of the embryonic neural tube. Wnt-1 and Wnt-4 are first expressed in the open neural plate in the region of the presumptive mesencephalon. Wnt-3a expression is first observed in the rhombencephalic regions of the open neural plate. After neural tube closure, when the embryonic subdivisions of the neural tube became apparent, Wnt-1, Wnt-3a and Wnt-4 are all broadly expressed in partially overlapping domains in the mesencephalon and caudal diencephalon, as well as in the rhombencephalon and spinal cord. The mesencephalic expression patterns are subsequently modified such that Wnt-1 and Wnt-4 are expressed in a characteristic ring just rostral to the isthmus, at the mesencephalic/metencephalic junction; and Wnt-1 and Wnt-3a expression become restricted to the dorsal midline. Wnt-1, Wnt-3a, Wnt-4, Wnt-5a and Wnt-8b are expressed in one or two caudal subdivisions of the developing diencephalon, the synencephalon and posterior parencephalon, but do not extend ventral to the zona limitans interparencephalica. In contrast, Wnt-7b is expressed in the anterior parencephalon. Both Wnt-7b and Wnt-8b are expressed in telencephalic portions of the secondary prosencephalon. The timing and spatial distribution of Wnt-gene expression in the chick embryo further support the general hypothesis that Wnt genes play key roles in patterning the developing vertebrate nervous system.

The health care system in the year 2000: three scenarios.

Because no one can predict the direction that national health policy might take over the next decade, the author outlines three of the more likely scenarios for the year 2000. He first describes seven major forces that have a stake in national health policy: the federal government, the state governments, business, organized labor, the public at large, the health industry, and the opinion-makers. he next indicates three ways these forces might come together (the scenarios), and last, gives a fuller description of the scenarios and the issues each would raise. He demonstrates in depth how the motivations of most of these forces are in conflict with one another and states that no national health policy is likely to emerge until there is a broad compromise that brings most of those conflicts to some sort of viable consensus. He urges those involved in health care to prepare for a range of possible policies such as, but not limited to, those outlined in this overview, and concludes by maintaining that no matter what health policy emerges, health professionals will use their common sense and good faith to make it work, as they always have.

The hospital of the year 2000: three scenarios.

Based on a presentation at the 27th Annual Duke Forum on Health and Hospital Affairs conducted in 1991 in Durham, N.C., this article is a discussion of the forces with a stake in national health policy, a discussion of three ways those forces might come together, and a description of those three scenarios and the issues each would raise.

How the AHA meets the challenge of change.

The American Hospital Association and its member institutions have always adapted, and must continue to adapt, to change. Socioeconomic developments that must be reckoned with include the energy crisis, an economic recession, and the growth of consumer consciousness. Political developments include the growing similarity of the two major political parties, increased fiscal conservatism, and an antigovernment mood.

Discontent over health costs colors congressional choices.

Drastic action on specific health issues this year may be less important than the growing discontent in Congress over health care costs. Even if economic trends moderate, hospitals will be confronted with the task of changing incentives in the system that fuel the rate of increase in costs.

Trustees: indispensable to hospitals' political thrust.

Because of trustees' unique role in the hospital and the community, they are a vital part of health care's political thrust. The American Hospital Association and the allied state and metropolitan hospital associations have responded to trustees' increased commitment to political action by stepping up their own commitment to trustee political involvement.