Showing papers by "Oregon Health & Science University published in 1995"
TL;DR: Orphanin FQ may act as a transmitter in the brain by modulating nociceptive and locomotor behavior by binding to its receptor in a saturable manner and with high affinity.
Abstract: A heptadecapeptide was identified and purified from porcine brain tissue as a ligand for an orphan heterotrimeric GTP- binding protein (G protein)- coupled receptor (LC132) that is similar in sequence to opioid receptors. This peptide, orphanin FQ, has a primary structure reminiscent of that of opioid peptides. Nanomolar concentrations of orphanin FQ inhibited forskolin-stimulated adenylyl cyclase activity in cells transfected with LC132. This inhibitory activity was not affected by the addition of opioid ligands, nor did the peptide activate opioid receptors. Orphanin FQ bound to its receptor in a saturable manner and with high affinity. When injected intracerebroventricularly into mice, orphanin FQ caused a decrease in locomotor activity but did not induce analgesia in the hot-plate test. However, the peptide produced hyperalgesia in the tail-flick assay. Thus, orphanin FQ may act as a transmitter in the brain by modulating nociceptive and locomotor behavior.
1,807 citations
TL;DR: Numeric grading schemes for disease severity, risk factors, and outcome criteria present in the original document have been updated to reflect increased knowledge of venous disease and advances in diagnostic techniques.
1,205 citations
TL;DR: It is proposed that the loss of one functional copy of the CBP gene underlies the developmental abnormalities in RTS and possibly the propensity for malignancy.
Abstract: THE Rubinstein-Taybi syndrome (RTS) is a well-defined syndrome with facial abnormalities, broad thumbs, broad big toes and mental retardation as the main clinical features1-3. Many patients with RTS have been shown to have breakpoints in, and microdeletions of, chromosome 16pl3.3 (refs 4-8). Here we report that all these breakpoints are restricted to a region that contains the gene for the human CREB binding protein (CBP), a nuclear protein participating as a co-activator in cyclic-A IMP-regulated gene expression9-12. We show that RTS results not only from gross chromosomal rearrangements of chromosome 16p, but also from point mutations in the CBP gene itself. Because the patients are heterozygous for the mutations, we propose that the loss of one functional copy of the CBP gene underlies the developmental abnormalities in RTS and possibly the propensity for malignancy.
1,149 citations
TL;DR: The cloning of a novel human aspartate/ glutamate transporter, EAAT4, which is expressed predominantly in the cerebellum is reported, which combines the re-uptake of neurotransmitter with a mechanism for increasing chloride permeability, both of which could regulate excitatory neurotransmission.
Abstract: Excitatory amino-acid transporters (EAATs) in the central nervous system maintain extracellular glutamate concentrations below excitotoxic levels and may limit the activation of glutamate receptors. Here we report the cloning of a novel human aspartate/glutamate transporter, EAAT4, which is expressed predominantly in the cerebellum. The transport activity encoded by EAAT4 has high apparent affinity for L-aspartate and L-glutamate, and has a pharmacological profile consistent with previously described cerebellar transport activities. In Xenopus oocytes expressing EAAT4, L-aspartate and L-glutamate elicited a current predominantly carried by chloride ions. This chloride conductance was not blocked by components that block endogenous oocyte chloride channels. Thus EAAT4 combines the re-uptake of neurotransmitter with a mechanism for increasing chloride permeability, both of which could regulate excitatory neurotransmission.
1,129 citations
TL;DR: The data suggest that neuroD may participate in the terminal differentiation step during vertebrate neuronal development and seems competent to bypass the normal inhibitory influences that usually prevent neurogenesis in ventral and lateral ectoderm.
Abstract: Basic helix-loop-helix (bHLH) proteins are instrumental in determining cell type during development. A bHLH protein, termed NeuroD, for neurogenic differentiation, has now been identified as a differentiation factor for neurogenesis because (i) it is expressed transiently in a subset of neurons in the central and peripheral nervous systems at the time of their terminal differentiation into mature neurons and (ii) ectopic expression of neuroD in Xenopus embryos causes premature differentiation of neuronal precursors. Furthermore, neuroD can convert presumptive epidermal cells into neurons and also act as a neuronal determination gene. However, unlike another previously identified proneural gene (XASH-3), neuroD seems competent to bypass the normal inhibitory influences that usually prevent neurogenesis in ventral and lateral ectoderm and is capable of converting most of the embryonic ectoderm into neurons. The data suggest that neuroD may participate in the terminal differentiation step during vertebrate neuronal development.
1,064 citations
TL;DR: In this paper, the authors used the 1987 Southern California Air Quality Study (SCAQS) data to gain an understanding of the dynamics of organic aerosol formation and to quantify secondary organic emissions.
1,015 citations
[...]
TL;DR: Treatment of osteoporosis in men consists both of nonpharmacological (lifestyle factors, calcium and vitamin D supplementation) and pharmacological approaches, with efficacy similar to that seen in women.
Abstract: With the aging of the population, there is a growing recognition that osteoporosis and fractures in men are a significant public health problem, and both hip and vertebral fractures are associated with increased morbidity and mortality in men. Osteoporosis in men is a heterogeneous clinical entity: whereas most men experience bone loss with aging, some men develop osteoporosis at a relatively young age, often for unexplained reasons (idiopathic osteoporosis). Declining sex steroid levels and other hormonal changes likely contribute to age-related bone loss, as do impairments in osteoblast number and/or activity. Secondary causes of osteoporosis also play a significant role in pathogenesis. Although there is ongoing controversy regarding whether osteoporosis in men should be diagnosed based on female- or male-specific reference ranges (because some evidence indicates that the risk of fracture is similar in women and men for a given level of bone mineral density), a diagnosis of osteoporosis in men is generally made based on male-specific reference ranges. Treatment consists both of nonpharmacological (lifestyle factors, calcium and vitamin D supplementation) and pharmacological (most commonly bisphosphonates or PTH) approaches, with efficacy similar to that seen in women. Increasing awareness of osteoporosis in men among physicians and the lay public is critical for the prevention of fractures in our aging male population.
880 citations
TL;DR: Depending on one's viewpoint, telemedicine may be seen as a valuable tool for providing badly needed specialty care services and faith in this technology is not universal, however.
Abstract: TELEMEDICINE can be broadly defined as the use of telecommunications technologies to provide medical information and services. Although this definition includes medical uses of the telephone, facsimile, and distance education,telemedicineis increasingly being used as shorthand for remote electronic clinical consultation. Interest in the field has increased dramatically in the 1990s. State and federal allocations for telemedicine and related technologies are likely to exceed $100 million in fiscal 1994-1995.1At least 13 federal agencies, including the US Department of Commerce, Health Care Financing Administration (HCFA), Office of Rural Health Policy, and US Department of Defense, have begun telemedicine research and demonstration programs. Many states are using their own resources to build state-of-the-art telemedicine systems, some with capital investments exceeding $50 million. Faith in this technology is not universal, however. Depending on one's viewpoint, telemedicine may be seen as a valuable tool for providing badly needed specialty care services
783 citations
TL;DR: Depressive disorder can be successfully prevented among adolescents with an elevated future risk of depressive disorder, and survival analyses indicated a significant 12-month advantage for the prevention program.
Abstract: Objective This investigation attempted to prevent unipolar depressive episodes in a sample of high school adolescents with an elevated risk of depressive disorder. Method Adolescents at risk for future depressive disorder by virtue of having elevated depressive symptomatology were selected with a two-stage case-finding procedure. The Center for Epidemiologic Studies-Depression Scale (CES-D) was administered to 1,652 students; adolescents with elevated CES-D scores were interviewed with the Schedule for Affective Disorders and Schizophrenia for School-Age Children. Subjects with current affective diagnoses were referred to nonexperimental services. The remaining 150 consenting subjects were considered at risk for future depression and randomized to either a 15-session cognitive group prevention intervention or an “usual care” control condition. Subjects were reassessed for DSM-III-R diagnostic status after the intervention and at 6− and 12-month follow-up points. Results Survival analyses indicated a significant 12-month advantage for the prevention program, with affective disorder total incidence rates of 14.5% for the active intervention, versus 25.7% for the control condition. No differences were detected for nonaffective disorders across the study period. Conclusion Depressive disorder can be successfully prevented among adolescents with an elevated future risk.
690 citations
TL;DR: In order to screen for brain region specific mRNAs which are transcriptionally regulated by acute cocaine and amphetamine, PCR differential display was employed and identified a previously uncharacterized mRNA whose relative levels in the striatum are induced four- to fivefold by acute psychomotor stimulant administration.
Abstract: involves alterations in specific patterns of gene expression. In order to screen for brain region specific mRNAs which are transcriptionally regulated by acute cocaine and amphetamine, PCR differential display was employed. This approach identified a previously uncharacterized mRNA whose relative levels in the striatum are induced four- to fivefold by acute psychomotor stimulant administration. Isolation and characterization of corresponding cDNA clones resulted in complete nucleotide sequence analysis, including prediction of the encoded protein product. Alternate polyA site utilization in the predicted 3′ noncoding region results in the appearance of an RNA doublet, approximately 700 and 900 bases in length, following Northern analysis. A presumed alternate splicing event further generates diversity within the transcripts, and results in the presence or absence of an in-frame 39 base insert within the putative protein coding region. As a result, the predicted translation products are either 129 or 116 amino acids in length. A common hydrophobic leader sequence at the amino terminus is present within each predicted polypeptide, suggesting that the protein product is targeted for entry into the secretory pathway. Basal expression of the RNA doublet is limited to neuroendocrine tissues, further implying that the protein product plays a functional role in both neuronal and endocrine tissues.
655 citations
TL;DR: Results suggest that both PKA and CaN are targeted to subcellular sites by association with a common anchor protein and thereby regulate the phosphorylation state of key neuronal substrates.
Abstract: Specificity of protein kinases and phosphatases may be achieved through compartmentalization with preferred substrates. In neurons, adenosine 3', 5'-monophosphate (cAMP)-dependent protein kinase (PKA) is localized at postsynaptic densities by association of its regulatory subunit with an A kinase anchor protein, AKAP79. Interaction cloning experiments demonstrated that AKAP79 also binds protein phosphatase 2B, or calcineurin (CaN). A ternary complex of PKA, AKAP, and CaN was isolated from bovine brain, and colocalization of the kinase and the phosphatase was established in neurites of cultured hippocampal neurons. The putative CaN-binding domain of AKAP79 is similar to that of the immunophilin FKBP-12, and AKAP79 inhibited CaN phosphatase activity. These results suggest that both PKA and CaN are targeted to subcellular sites by association with a common anchor protein and thereby regulate the phosphorylation state of key neuronal substrates.
TL;DR: Reopening after GABAA receptor desensitization may enhance inhibitory synaptic transmission by prolonging the response to a brief synaptic GABA transient and underlie the expression of long-lasting components of the IPSC.
TL;DR: The results indicate that the gene repression and cell immortalization functions associated with El A involve the inactivation of a family of related proteins that normally participate in second-messenger-regulated gene expression.
Abstract: The 265K nuclear protein CBP was initially identified as a co-activator for the protein kinase A (PKA)-phosphorylated form of the transcription factor CREB. The domains in CBP that are involved in CREB binding and transcriptional activation are highly related to the adenoviral E1A-associated cellular protein p300 (refs 2, 3), and to two hypothetical proteins from Caenorhabditis elegans, R10E11.1 and K03H1.10 (refs 4 and 5, respectively), whose functions are unknown. Here, we show that CBP and p300 have similar binding affinity for the PKA-phosphorylated form of CREB, and that p300 can substitute for CBP in potentiating CREB-activated gene expression. We find that E1A binds to CBP through a domain conserved with p300 and represses the CREB-dependent co-activator functions of both CBP and p300. Our results indicate that the gene repression and cell immortalization functions associated with E1A involve the inactivation of a family of related proteins that normally participate in second-messenger-regulated gene expression.
TL;DR: It is concluded that PMS2 is involved in DNA mismatch repair in a variety of tissues and links among mismatch repair, genetic recombination, and chromosome synapsis in meiosis are suggested.
TL;DR: The results suggest that these proteins mediate both transporter- and channel-like modes of permeation, providing a potential mechanism for dampening cell excitability, in addition to removal of transmitter.
TL;DR: In this article, the efficacy of macular grid photocoagulation in preserving or improving central visual acuity in eyes with macular edema due to central vein occlusion was evaluated.
TL;DR: These data demonstrate that enalapril attenuates progressive increases in LV dilatation and hypertrophy in patients with LV dysfunction and support the possibility that the favorable effects of en alapril reported in the SOLVD trials were related to inhibition of LV remodeling.
Abstract: Background Studies of Left Ventricular Dysfunction (SOLVD) demonstrated that enalapril therapy significantly improved the clinical course of patients with left ventricular (LV) dysfunction. The goals of this substudy were to evaluate changes in LV structure and function in SOLVD patients and to test the hypothesis that enalapril inhibits remodeling in patients with LV dysfunction. Methods and Results Patients entering both the prevention and treatment arms of SOLVD from 5 of the 23 clinical centers were recruited for this substudy. The 301 patients who participated underwent Doppler-echocardiographic evaluation according to standard protocol before randomization to either enalapril or placebo and again after 4 and 12 months of therapy. Recorded data were analyzed in a blinded fashion at a central core laboratory. Analysis of baseline clinical characteristics showed that patients enrolled in the substudy were generally representative of the SOLVD population, although prevention arm patients were slightly o...
TL;DR: It is indicated that CaM-K II alone is sufficient to augment synaptic strength and that this enhancement shares the same underlying mechanism as the enhancement observed with LTP.
Abstract: Ca(2+)-sensitive kinases are thought to play a role in long-term potentiation (LTP). To test the involvement of Ca2+/calmodulin-dependent kinase II (CaM-K II), truncated, constitutively active form of this kinase was directly injected into CA1 hippocampal pyramidal cells. Inclusion of CaM-K II in the recording pipette resulted in a gradual increase in the size of excitatory postsynaptic currents (EPSCs). No change in evoked responses occurred when the pipette contained heat-inactivated kinase. The effects of CaM-K II mimicked several features of LTP in that it caused a decreased incidence of synaptic failures, an increase in the size of spontaneous EPSCs, and an increase in the amplitude of responses to iontophoretically applied alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate. To determine whether the CaM-K II-induced enhancement and LTP share a common mechanism, occlusion experiments were carried out. The enhancing action of CaM-K II was greatly diminished by prior induction of LTP. In addition, following the increase in synaptic strength by CaM-K II, tetanic stimulation failed to evoke LTP. These findings indicate that CaM-K II alone is sufficient to augment synaptic strength and that this enhancement shares the same underlying mechanism as the enhancement observed with LTP.
TL;DR: Current efforts are focusing on several areas, including the development of non- or minimally-shrinking dental composites containing spiro-orthocarbonates as additives to dimethacrylates or epoxy-base resins, and the production of alternative filler materials for ideal wear resistance and esthetics.
Abstract: The clinical performance of dental composites has been significantly improved over the past decade through modifications in formulation that include: using more stable polymerization promoters for greater color stability; incorporating high concentrations of finely ground fillers to produce adequate strength and excellent wear resistance while retaining translucency ; adding radiopacifying agents for improved diagnostics; and utilizing dentin adhesives. However, there are problems which limit the use of composites, especially in posterior teeth. The materials remain very technique-sensitive, due to the extensive contraction which accompanies polymerization and negatively influences marginal sealing. In addition, the materials are generally considered to have inadequate mechanical properties and wear resistance in contact areas to serve as total replacements for amalgams. Current efforts are focusing on several areas, including the development of non- or minimally-shrinking dental composites containing spi...
TL;DR: The recent origin of this dominant mutation and its current high frequency suggest that the Ashkenazi population descends from a limited group of founders, and emphasize the importance of genetic drift in determining disease allele frequencies in this population.
Abstract: We have examined data on six closely linked microsatellite loci on chromosome 9q34 from 59 Ashkenazi Jewish families with idiopathic torsion dystonia (ITD). Our data show that the vast majority (>90%) of early–onset ITD cases in the Ashkenazi population are due to a single founder mutation, which we estimate first appeared approximately 350 years ago. We also show that carriers preferentially originate from the northern part of the historic Jewish Pale of settlement (Lithuania and Byelorussia). The recent origin of this dominant mutation and its current high frequency (between 1/6,000 and 1/2,000) suggest that the Ashkenazi population descends from a limited group of founders, and emphasize the importance of genetic drift in determining disease allele frequencies in this population.
TL;DR: The results suggest that glutamate diffusion and binding to transporters, rather than uptake, are likely to dominate the synaptic concentration decay kinetics.
TL;DR: Physiological stimulation of NMDA receptors on rat hippocampal neurons resulted in desensitization that was prevented by intracellular 1,2-bis(o-aminophenoxy)ethane-N, N,N,N',N'-tetraacetic acid, adenosine-5'-O-(3-thiotriphosphate) (ATP-gamma-S), or inhibitors of phosphatase 2B (calcineurin).
Abstract: Desensitization is a phenomenon that is common to many ligand-gated ion channels but has been demonstrated only rarely with physiological stimulation. Numerous studies describe desensitization of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor by exogenous agonists, but whether synaptic stimulation causes desensitization has been unknown. Synaptic stimulation of NMDA receptors on rat hippocampal neurons resulted in desensitization that was prevented by intracellular 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), adenosine-5'-O-(3-thiotriphosphate) (ATP-gamma-S), or inhibitors of phosphatase 2B (calcineurin), but not by inhibitors of phosphatases 1 and 2A or of tyrosine phosphatases. Synaptic NMDA receptors may fluctuate between phosphorylated and dephosphorylated forms, depending on the rate of synaptic stimulation and the magnitude of the associated influx of calcium through NMDA receptors.
TL;DR: A variety of iron oxide preparations with long blood half-life have been synthesized for MR imaging and potential applications of these agents include MR angiography, RES imaging, target specific imaging and neuronal transport imaging.
TL;DR: Laroscopic appendectomy appears to have distinct advantages over open appendectomy, and the laparoscopic procedures produced less pain and allowed more rapid return to full activities, and LAS required shorter hospital stays.
Abstract: Background While the advantages of laparoscopic cholecyslectomy are clear, the benefits of laparoscopic appendectomy (LA) are more subtle. We conducted a randomized clinical trial to evaluate whether LA is deserving of more widespread clinical application than it has yet received. Materials and methods Two hundred fiftythree patients with a preoperative diagnosis of acute appendicitis were randomized into three groups. LA with an endoscopic linear stapler (LAS) (U.S. Surgical Corp., Norwalk, Connecticut) was performed on 78 patients, LA with catgut ligatures (LAL) on 89, and open appendectomy (OA) on 86. LA was performed with a three-trocar technique. OA was accomplished through a right lower-quadrant transverse incision. Data with normal distributions were analyzed by analysis of variance. Nonparametric data were analyzed with either the Kruskal-Wallis H test or Fisher's exact test. Results The mean operative times for the procedures were 66 ± 24 minutes (LAS), 68 ± 25 minutes (LAL), and 58 ± 27 minutes (OA). The relative brevity of OA compared to LAS and LAL was statistically significant ( P P P = NS). Wound infections were more common following OA (n = 11) than LAL (n = 4) or LAS (n = 0) ( P P P P Conclusions Laparoscopic appendectomy appears to have distinct advantages over open appendectomy. The laparoscopic procedures produced less pain and allowed more rapid return to full activities, and LAS required shorter hospital stays. The only disadvantages to the laparoscopic approach were slightly increased operative time for both procedures, and increased emesis following LAL.
TL;DR: It is demonstrated that three recently described cAMP response elements (CREs), rather than a previously reported noncanonical AP-1 site, are critical for dopamine induction of the prodynorphin gene in striatal neurons.
TL;DR: The aim of this research is to provide a clear picture of the unique needs of children in the developing world and to help policymakers and clinicians better understand these needs.
Abstract: Department of Pediatrics (R.G.R., S.L., L.L.), Oregon Health Sciences University, Portland, Oregon 97201; the Department of Pediatrics, University of Gothenburg (K,A. W.), Gothenburg, Sweden; the Department of Pediatrics, University of Chile (F.C.), Santiago, Chile; Department of Pediatrics, University of California (Olive View Medical Center) (S.D.F.), Sylmar, California 91342; Department of Pediatrics, UCLA (B.L.), Los Angles, California 90024; Tokyo Metropolitan Kiyose Children’s Hospital (Y.H.), Tokyo, Japan; the Department of Pediatrics, Stanford University (R.L.H.), Stanford, California 94305; the Department of Medicine, Cedars Sinai Medical Center (S.M.), Los Angeles, California 90048; the Department of Pediatrics, Institute of Child Health (M.A.P.), London, United Kingdom; the Department of Pediatrics, Universitat Tubingen (M.B.R.), Tubingen, Germany; the Department of Pediatrics, Baystate Medical Center (E.O.R.), Springfield, Massachusetts 01199; the Department of Pediatrics, University of Virginia Health Sciences Center (A.D.R.), Charlottesville, Virginia 22908; the Department of Pediatrics, University of North Carolina (L.E. U.), Chapel Hill, North Carolina 27599; and Royal Childrenjs Hospital (G.A. W.), Melbourne, Australia
TL;DR: In this paper, the superpotent cyclic analog of the MSH-(4-10)-NH2 was found to be a potent and selective antagonist for melanocortin receptors.
Abstract: The cloning of the melanocyte-stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH) receptors (MC1-R and MC2-R, respectively) recently has led to the identification of three additional melanocortin receptors, MC3-R, MC4-R, and MC5-R. The MC2 receptor primarily recognizes only ACTH peptides, but the other four receptors all recognize alpha-melanocyte-stimulating hormone (alpha-MSH) and potent alpha-MSH agonists such as [Nle4,D-Phe7]alpha-MSH-NH2 and Ac-Nle4-c[Asp5,D-Phe7,Lys10]alpha-MSH-(4-10)-NH2 as well as ACTH. The absence of any known physiological role for these new receptors, expressed both in the brain (MC3-R and MC4-R) and throughout a number of peripheral tissues (MC5-R), has necessitated as search for potent and receptor selective agonists and antagonists. We report here that analogues of the superpotent cyclic agonist analogue Ac-Nle4-c[Asp5,D-Phe7, Lys10]alpha-MSH-(4-10)-NH2, in which a bulky aromatic amino acid is substituted in the 7-position, can produce potent and selective antagonists for melanocortin receptors. Thus, the D-p-iodophenylalanine7-containing analogue Ac-Nle4-c[Asp5,D-Phe(pI)7,Lys10]alpha-MSH-(4-10)-NH2 is a potent antagonist (pA2 = 10.3) in the classical frog skin (Rana pipiens) assay (MC1-R), as is the D-2'-naphthylalanine7 (D-Nal(2)7)-containing analogue Ac-Nle4-c[Asp5,D-Nal(2)7,Lys10]alpha-MSH-(4-10)-NH2 (pA2 > 10.3). Interestingly, the D-p-chloro- and D-p-fluorophenylalanine7-containing analogues lacked antagonist activities at all melanotropin receptors, and both exhibited full agonist potency in the frog skin assay. The activity of these analogues also was examined at four mammalian melanocortin receptors. Interestingly, Ac-Nle4-c[Asp5,(D-Nal(2)7,Lys10] alpha-MSH-(4-10)-NH2 was found to be a potent antagonist of the MC4-R (pA2 = 9.3) with minimal agonist activity, a less potent antagonist of the MC3-R (pA2 = 8.3) with minimal agonist activity, and a full agonist of the MC1 and MC5 receptors. Surprisingly, Nle4-c[Asp5,D-Phe(pI)7,Lys10]alpha-MSH was found to be a potent agonist at the cloned human MC1-R (EC50 = 0.055 nM) and mouse MC1-R (EC50 = 0.19 nM) but had potent antagonist activities at the human MC4-R (pA2 = 9.7) and human MC3-R (pA2 = 8.3) with significant partial agonist activities (EC50 = 0.57 and 0.68 nM, respectively) as well. Thus, highly potent and receptor selective antagonist analogues can arise from substitution of the D-Phe7 residue with a bulky aromatic amino acid. These analogues can be used to help determine the functional roles of these receptors.
TL;DR: This combined fractographic and mathematical analysis of FPD connectors suggests that the core-veneer interface is an important failure source and that the veneering ceramic overwhelmingly controls load-bearing capability.
Abstract: Hertzian cone cracks visible at the loading site of 20 all-ceramic fixed partial dentures (FPDs), tested in vitro, led to the hypotheses that failure was due to the propagation of localized contact damage crack systems (Hertzian stress state) and that such damage was an unlikely clinical failure mode. Fractographic analysis of the 20 laboratory-failed and nine clinically-failed all-ceramic FPDs allowed for definitive testing of these hypotheses and a comparison between in vitro and in vivo failure behavior. In all cases, failure occurred in the FPD connectors (none from contact damage), with approximately 70 to 78% originating from the interface between the core and veneer ceramics. The coincidence between failure origins provides strong evidence that the in vitro test modeled aspects of structural behavior having clinical importance. The fractographic observations, coupled with the in vitro failure load data, furnished very specific boundary conditions which were applied to constrain mathematical models ...
TL;DR: The axonal regenerative properties of the new immunosuppressant drug FK506 (tacrolimus) are further explored and some axons were shown to reinnervate muscle spindles and inhibit the activity protein phosphatase 2B (calcineurin).
Abstract: The axonal regenerative properties of the new immunosuppressant drug FK506 (tacrolimus) are further explored in this continuing study. In an initial report (Gold et al., 1994a), we described the ability of FK506 to reduce the time until return of function in the hind feet of rats following a sciatic nerve crush. In the present study, we examined the morphological correlate underlying this enhancement of functional recovery. In rats receiving daily subcutaneous injections of FK506 (1.0 mg/kg) for 18 d following a sciatic nerve crush the regenerating axons appeared larger in size compared to saline-injected control animals. Morphometric analysis of axonal calibers in the soleus nerve demonstrated that mean axonal areas for the largest 30% of axons were increased over axotomized control values by 93% in the FK506-treated animals. Next, the rate of axonal regeneration was determined by radiolabeling the L5 dorsal root ganglion (DRG) at 9 and 14 d following axotomy. Regression analysis of the outgrowth distances for sensory axons between 10 and 15 d revealed a 16% increase in regeneration rate. Electron microscopy of intramuscular nerve branches in the interosseus muscles confirmed that the axons in the FK506-treated animals were further advanced toward their targets; in some instances, axons were shown to reinnervate muscle spindles. The results are discussed in terms of the known ability of FK506 to inhibit the activity protein phosphatase 2B (calcineurin).