State-coordinated services for traumatic brain injury survivors: toward a model delivery system

Since 1985, the state of Minnesota, through a variety of advocacy, legislative, and interagency efforts, has made incremental gains in public policy and service development for persons with traumatic brain injury (TBI). This article reviews the roles and functions of select state programs and departments in coordinating TBI services. Key initiatives, as well as the current model of public policy and services, are outlined. Current and future service development and initiatives are discussed. Finally, specific implementation recommendations are proposed.     

Why a "benign" mutation kills enzyme activity. Structure-based analysis of the A176V mutant of Saccharomyces cerevisiae L-asparaginase I

A conservative and apparently harmless A176V mutation in intracellular S. cerevisiae L-asparaginase (ScerAI) completely abolishes the enzyme activity. Sequence and structural comparisons with type II bacterial L-asparaginases show that the mutated residue is in a very conservative region and plays a vital role in the cohesion of functional tetramers of these enzymes through participation in side-chain...main-chain (Ser) Oy...O (Ala) hydrogen bonds across the tetramer interface. The fact that bacterial L-asparaginases of type I show less conservation in this region suggests that they may have different quaternary structure while adopting the subunit fold and intimate dimer architecture of type II enzymes. A comparison of all available sequences of microbial L-asparaginases confirms that separate intra- and extra-cellular enzymes evolved in prokaryotes and eukaryotes independently. However, an analysis of the available complete genome sequences reveals a surprising fact that Haemophilus influenzae possesses only a type II asparaginase while the archaebacterium Methanococcus jannaschii has a type I gene, but not a type II.     

Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. International AIDS Society-USA

OBJECTIVE: To provide recommendations for the treatment of acquired immunodeficiency syndrome-related cytomegalovirus (CMV) end-organ diseases, including retinitis, colitis, pneumonitis, and neurologic diseases. PARTICIPANTS: A 17-member panel of physicians with expertise in clinical and virological research and inpatient care in the field of CMV diseases. EVIDENCE: Available clinical and virological study results. Recommendations are rated according to the quality and strength of available evidence. Recommendations were limited to the treatment of CMV diseases; prophylaxis recommendations are not included. PROCESS: The panel was convened in February 1997 and met regularly through November 1997. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS: Although the epidemiological features of CMV diseases are changing in the setting of potent, combination antiretroviral therapy, continued attention must be paid to CMV diseases in patients infected with the human immunodeficiency virus to prevent irreversible endorgan dysfunction. The initial and maintenance treatment of CMV retinitis must be individualized based on the characteristics of the lesions, including location and extent, specific patient factors, and characteristics of available therapies among others. Management of relapse or refractory retinitis must be likewise individualized. Ophthalmologic screening for patients at high risk for retinitis or who have a prior diagnosis of extraretinal disease is recommended. Recommendations for gastrointestinal, pulmonary, and neurologic manifestations are included.     

Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer

Fas ligand (FasL) is produced by activated T cells and natural killer cells and it induces apoptosis (programmed cell death) in target cells through the death receptor Fas/Apol/CD95. One important role of FasL and Fas is to mediate immune-cytotoxic killing of cells that are potentially harmful to the organism, such as virus-infected or tumour cells. Here we report the discovery of a soluble decoy receptor, termed decoy receptor 3 (DcR3), that binds to FasL and inhibits FasL-induced apoptosis. The DcR3 gene was amplified in about half of 35 primary lung and colon tumours studied, and DcR3 messenger RNA was expressed in malignant tissue. Thus, certain tumours may escape FasL-dependent immune-cytotoxic attack by expressing a decoy receptor that blocks FasL.     

Cytokine induction of platelet activation

A three-dimensional, two-part model of the foot, for use in a simulation of human gait, is presented. Previous simulations of gait have not included the foot segment (e.g. Siegler et al., 1982, J. Biomechanics 15, 415-425) or have fastened it to the ground (e.g. Onyshko and Winter, 1980, J. Biomechanics 13, 361-368). A foot model based on viscoelastic elements (e.g. Meglan, 1991, Ph.D. thesis, Ohio State Univ.), allows more freedom of movement and thus models the physical system more closely. The current model was developed by running simulations of the foot in isolation from just before heel contact to just after toe-off. The driving inputs to the simulation were the resultant ankle joint forces and moments taken from a gait analysis. Nine linear, vertically oriented spring/damper systems, positioned along the midline of the foot were used to model the combined viscoelastic behaviour of the foot, shoe and floor. Associated with each vertical spring/damper system were two orthogonally placed, linear, horizontal dampers used to provide the shear components of the ground reaction force. Torques at the metatarsal-phalangeal joint were supplied by a linear, torsional spring and damper. Control about the vertical axis and the long axis of the foot was achieved by the use of linear, torsional dampers. The predicted kinetic and kinematic values are very similar to those taken from the gait analysis. The model represents an improvement over previous work because the transition from swing to stance was smooth and continuous without the foot being constrained to any specific trajectory.     

Inhibition of vascular smooth muscle cell proliferation by ribozymes that cleave c-myb mRNA

Proliferation of injured smooth muscle cells contributes to the reocclusion or restenosis of coronary arteries that often occurs following angioplasty procedures. We have identified and optimized nuclease-resistant ribozymes that efficiently cleave c-myb RNA. Three ribozymes targeting different sites in the c-myb mRNA were synthesized chemically and delivered to rat aortic smooth muscle cells with cationic lipids; all three inhibited serum-stimulated cell proliferation significantly. RNA molecules with two base substitutions in the catalytic core that render the ribozyme catalytically inactive had little effect on smooth muscle cell proliferation. Ribozymes with scrambled binding arm sequences also failed to affect cell cycle progression of vascular smooth muscle cells. Furthermore, inhibition of rat smooth muscle cell proliferation correlated with a reduction in intact c-myb mRNA. Efficacy of the chemically-modified ribozyme was compared directly to phosphorothioate antisense oligodeoxynucleotides targeting the same site in the c-myb RNA; the ribozyme had superior efficacy and showed greater specificity than the antisense molecules. Exogenously delivered ribozymes also inhibited porcine and human smooth muscle cell proliferation effectively. Ribozymes targeting c-myb or other regulators of smooth muscle cell proliferation may represent novel therapeutics for the treatment of restenosis after coronary angioplasty.     

The hydrophilic domain of Tic110, an inner envelope membrane component of the chloroplastic protein translocation apparatus, faces the stromal compartment

It has previously been found that Tic110, an integral protein of the chloroplast inner envelope membrane, is a component of the chloroplastic protein import apparatus. However, conflicting reports exist concerning the topology of this protein within the inner envelope membrane. In this report, we provide evidence that indicates that the large (>90-kDa) hydrophilic domain of Tic110 is localized within the chloroplast stroma. Trypsin, a protease that cannot penetrate the permeability barrier of the inner envelope membrane, degrades neither Tic110 nor other proteins exposed to the stromal compartment but is able to digest proteins exposed to the intermembrane space between the two envelope membranes. Previous reports indicating that trypsin is able to degrade Tic110 were influenced by incomplete quenching of protease activity. When trypsin is not sufficiently quenched, it is able to digest Tic110, but only after chloroplasts have been ruptured. It is therefore necessary to employ adequate quenching protocols, such as the one reported here, whenever trypsin is utilized as an analytical tool. Based on a stromal localization for the majority of Tic110, we propose that this protein may be involved in the recruitment of stromal factors, possibly molecular chaperones, to the translocation apparatus during protein import.