Exploration of a new model of care in a psychiatry unit.

The model established at Orillia Soldiers Memorial Hospital involves family physicians as the most responsible physician. They act as "admission gatekeeper" for all unattached patients who are admitted to the psychiatry in-patient unit. A PubMed, EBSCO, OVID Medline, Embase, CINAHL, and Web of Science database review of the last 10 years (2006-2016) was undertaken. A satisfaction survey was undertaken. An intensive literature review found this model to be unique. The model has proved to be extremely efficient and cost-effective.

Artificial membranes: a new type of cell for measuring diffusional resistance.

A novel technique allows determination of membrane diffusivities and eliminates the complications of the fluid resistance to mass transfer on either side of the membrane. Results on the permeability of a dialysis membrane of the type used in artificial kidneys agree with previous data and are obtained in much shorter time. The measured activation energy for diffusion demonstrates that the transport of salt through the membrane occurs by the same mechanism as the diffusion of salt in water, but that only 10 percent of the membrane surface is effective.

p38 pathway kinases as anti-inflammatory drug targets.

Mitogen-activated protein kinases (MAPK) are intracellular signaling molecules involved in cytokine synthesis. Several classes of mammalian MAPK have been identified, including extracellular signal-regulated kinase, c-jun N-terminal kinase, and p38 MAP kinase. p38alpha is a key MAPK involved in tumor necrosis factor alpha and other cytokine production, as well as enzyme induction (cyclooxygenase-2, inducible nitric oxide synthase, and matrix metalloproteinases) and adhesion molecule expression. An understanding of the broad biologic and pathophysiological roles of p38 MAPK family members has grown significantly over the past decade, as has the complexity of the signaling network leading to their activation. Downstream substrates of MAPK include other kinases (e.g., mitogen-activated protein-kinase-activated protein kinase 2) and factors that regulate transcription, nuclear export, and mRNA stability and translation. The high-resolution crystal structure of p38alpha has led to the design of selective inhibitors that have good pharmacological activity. Despite the strong rationale for MAPK inhibitors in human disease, direct proof of concept in the clinic has yet to be demonstrated, with most compounds demonstrating dose-limiting adverse effects. The role of MAPK in inflammation makes them attractive targets for new therapies, and efforts are continuing to identify newer, more selective inhibitors for inflammatory diseases.

Conformations of lysine-sensitive aspartokinase.

1. The technique of differential thermal and proteolytic inactivation has been employed as a conformational probe for the lysine-sensitive aspartokinase (EC 2.7.2.4) of Escherichia coli B. 2. L-Amino acid inhibitors of this enzyme each induce a characteristic enzyme conformation. This is evidenced by rates of thermal and proteolytic inactivation and Arrhenius activation energies for thermal inactivation which are characteristic of the amino acid present. 3. Phenylalanine and leucine binding are mutually exclusive as evidenced by competitive behavior in thermal inactivation experiments, suggesting a hydrophobic amino acid binding site with broad specificity. 4. The phenylalanine-dependent conformation and the leucine-dependent conformation differ considerably. In comparison with the native enzyme, the former is more labile to proteolysis by trypsin whereas the latter is more stable. First-order rate constants for thermal inactivation of the phenylalanine- and leucine-dependent conformations are, respectively, about one-half and one-tenth that of the native enzyme. 5. Items 3 and 4 taken together suggest that the conformations are ligand induced and do not arise via ligand stabilization of spontaneously arising conformers.

Regulatory properties of lysine-sensitive aspartokinase under equilibrium conditions.

The regulatory properties of the lysine-sensitive aspartokinase (ATP : L-aspartate 4-phosphotransferase, EC 2.7.2.4) have been studied under equilibrium conditions by determining the effects of modifiers on the rate of equilibrium isotope exchange between ADP and ATP. The extent of inhibition by lysine, leucine or phenylalanine is almost independent of substrate concentration but is influenced by the substrate/product ratio. Inhibition by a given concentration of inhibitor is increased when the ADP/ATP ratio is increased indicating a regulatory interaction between end products and cellular energy metabolism. Lysine inhibition is cooperative under equilibrium conditions and the parameters of the Hill equation are nearly identical to those obtained in initial velocity studies. A cooperative heterotropic interaction between lysine and leucine is also observed by the ATP-ADP exchange assay just as it is in initial velocity assays. Thus, the regulatory features of aspartokinase that are observed in initial velocity studies are also manifest under equilibrium conditions as revealed by equilibrium isotope exchange rates.

Metabolic effects of forskolin in chick chondrocytes.

The effects of forskolin on parameters of energy metabolism and proteoglycan synthesis have been investigated in chick embryo sternal chondrocyte cultures. After 8 h exposure to 100 microM forskolin, ATP levels and oxygen consumption were unaltered. Protein synthesis was unaffected up to 50 microM forskolin and protein degradation was unaffected by forskolin up to 100 microM. In contrast, incorporation of the proteoglycan precursors, 35SO4 and [3H]glucosamine, was more sensitive to forskolin. Inhibition was linear with dose between 10 and 100 microM, reaching 70% at 100 microM. Incorporation of 35SO4 into glycosaminoglycan chains initiated on an artificial beta-xyloside acceptor was inhibited in the same manner. cAMP accumulation was maximal at 10 microM forskolin, a concentration which did not alter proteoglycan synthesis. We conclude that a major, acute effect of forskolin in these short-term experiments is inhibition of proteoglycan synthesis in a cAMP-independent manner.

Effect of forskolin on synthesis of xyloside-initiated glycosaminoglycans in embryonic chick chondrocytes.

The synthesis of sulfated glycosaminoglycan (GAG) chains has been studied in the presence of various concentrations of the artificial acceptor 4-methylumbelliferyl beta-D-xyloside and of forskolin. Sulfated GAG chains formed in the presence of forskolin had a smaller hydrodynamic radius than controls, as revealed by chromatography on Sepharose CL-6B. Sulfated GAGs from both control and treated cultures behaved identically when chromatographed on DEAE.

Systems of care and treatment outcomes for alcoholic patients.

All admissions to the Singer Mental Health Center, Rockford, Ill, with a diagnosis of alcoholism in a one-year period (N = 466) were randomly assigned to one of two inpatient programs. One program, "intensive incare," had a high staff-patient ratio with the operating assumption that intensive staff-patient interaction is significant in patient outcome. The other, "peer-oriented incare," was of low staff density with the assumption that patient-patient interaction is critical in rehabilitation. In addition, the patients resided in communities with outpatient services classified as either "network" (an organized set of community services) or "no-network" (no special funding or deliberate outreach effort). Thus, each patient could be treated in one of four systems of care. Data on treatment outcomes were collected via semistructured interviews at 3, 6, 12, and 18 months after admission. The "peer-oriented incare" system showed superiority to the "intensive incare" treatment approach in improved drinking behavior. There were no other significant differences among the four systems on the outcome criteria for alcoholic patients. Along with other recent studies, these findings have implications for policy planning, particularly with today's emphasis on cost effectiveness.

The enhanced in vitro hematopoietic activity of leridistim, a chimeric dual G-CSF and IL-3 receptor agonist.

The in vitro activity of leridistim was characterized for cell proliferation, generation of colony-forming units (CFU) and differentiation of CD34+ cells. In AML-193.1.3 cells, leridistim exhibited a significant increase in potency compared to rhG-CSF, SC-65303 (an IL-3 receptor agonist) or an equimolar combination of rhG-CSF and SC-65303. CFU-GM assays demonstrated that at 50% of the maximum response, the relative potency of leridistim was 12-fold greater than the combination of rhG-CSF and rhIL-3 and 44-fold more potent than rhG-CSF alone. In multi-lineage CFU assays, a combination of erythropoietin (rhEPO) and leridistim resulted in greater numbers of BFU-E, CFU-GEMM and CFU-Mk than rhEPO alone. Ex vivo culture of peripheral blood or bone marrow CD34+ cells with leridistim substantially increased total viable cells over cultures stimulated with rhG-CSF, SC-65303, or a combination of rhG-CSF and SC-65303. Culture with leridistim, resulted in a greater increase in myeloid (CD15+/CD11b+), monocytic (CD41-/CD14+) and megakaryocytic (CD41+/CD14-) precursor cells without depleting the progenitor pool (CD34+/CD15-/CD11b-). These results demonstrate that leridistim is a more potent stimulator of hematopoietic proliferation and differentiation than the single receptor agonists (rhG-CSF and SC-65303) either alone or combined. These unique attributes suggest that leridistim may enhance hematopoietic reconstitution following myelosuppressive chemotherapy.

Promegapoietin, a family of chimeric growth factors, supports megakaryocyte development through activation of IL-3 and c-Mpl ligand signaling pathways.

OBJECTIVE: The signaling pathways induced by promegapoietin (PMP), a family of chimeric growth factors that activate the human IL-3 and c-Mpl receptors, were investigated. METHODS: The biological activity of PMP was examined by receptor binding, cell proliferation, ex vivo expansion of hematopoietic progenitor cells, and in vivo production of platelets. The activation of signaling pathways was examined by Western blot and Northern blot analyses. RESULTS: Two PMP molecules, PMP-1 and PMP-1a, induced proliferation of cells expressing the IL-3 receptor, c-Mpl, or both receptors and bound to the IL-3 receptor and c-Mpl with high affinity. Ex vivo expansion assays using human bone marrow CD34(+) cells suggested that PMP-1 induced greater total cellular expansion as well as expansion of CD41(+) megakaryocytic precursor cells than IL-3 or c-Mpl ligand alone. Subcutaneous administration of 50 microg/kg of PMP-1 for 10 days to rhesus monkeys resulted in increased platelet production in vivo from a baseline of 357 +/- 45 x 10(3) cells/mL to 1376 +/- 151 x 10(3) cell/mL. PMP-1 induced phosphorylation of the beta(c) subunit of IL-3 receptor and c-Mpl, JAK2, and STAT5b, but not STAT3. PMP-1 induced greater expression of Pim-1, c-Myc, and cyclin D2 than did either an IL-3 receptor agonist or c-Mpl receptor agonist alone. The magnitude of induction of early response genes was similar for PMP and the coaddition of IL-3 receptor agonist and c-Mpl receptor agonist. CONCLUSION: PMP combines the biological activities of IL-3 and c-Mpl ligand in a single molecule that can simultaneously activate signaling pathways induced by both these ligands.

The quality of life as opposed to the right to life.

PIP: Psychiatric reasons for advocating abortion at will derive in part from cumulative clinical experience of confronting the problems of unwanted children, abortion, and contraception. Consideration of the question of the "quality of life" may include consideration of the question of the right to life. According to this doctor, raising moral questions about abortion is not the same as fanaticism or primitiveness.^ieng

Effects of dideoxyforskolin on proteoglycan synthesis and structure in embryonic chick chondrocyte cultures.

1,9-Dideoxyforskolin inhibits proteoglycan synthesis and xyloside-initiated glycosaminoglycan (GAG) synthesis in chick embryo chondrocytes. Dideoxyforskolin does not affect the length of xyloside-initiated GAG chains secreted into the medium but chains from the dense proteoglycan secreted into the medium appear slightly longer. Incorporation of labeled serine into the dense proteoglycan and subsequent digestion with Pronase revealed a dramatic decrease in percent of total radioactivity associated with GAG chains in the proteoglycan from cultures treated with forskolin or dideoxyforskolin. These observations suggest that these diterpenes have a specific inhibitory effect on chain initiation reactions and thus may be useful tools in the study of proteoglycan synthesis and processing.

Application of an integrated rate equation to the inactivation of catalase.

A feature of catalase that has received scant attention in recent years and that may have physiological significance is the peroxide-dependent inactivation of the enzyme. In this article we show how to obtain the second-order rate constant for the inactivation reaction by fitting the reaction progress curve to an integrated rate equation. This method will simplify quantitation of the inactivation and reactivation of catalase. These measurements in tissues with altered metabolic states may reveal new information about the role of catalase in nutrition, aging, and pathology.

Analysis of preoperative intracavitary cesium application versus postoperative external beam radiation in stage I endometrial carcinoma.

Two groups of patients with surgical Stage I endometrial carcinoma treated at the LDS Hospital in Salt Lake City are analyzed. Group 1 comprises 112 patients treated from 1974 through 1976, during which time preoperative intracavitary cesium was routinely used in all patients. Group 2 comprises 117 patients treated 1981 through 1983 under the treatment policy of hysterectomy without preoperative cesium. High risk patients from each group (grade 3 and/or deep myometrial invasion) generally received similar postoperative external beam pelvic radiotherapy (4500-5000 cGy). While 5-year actuarial disease-free survival rates were similar in each group (94% Group 1 vs 91% Group 2), multivariate analysis by the Cox Regression Method revealed that inclusion within treatment Group 2 carried independent adverse prognostic significance (p = 0.018). Other independent predictors of adverse 5-year disease-free survival included deep myometrial invasion and increasing histologic grade. Group 1 patients with grade 3 lesions had a superior 5-year actuarial disease-free survival (76% vs 53%) compared to those from Group 2. Group 1 patients with deep myometrial invasion also had a superior 5-year disease-free survival (84% vs 69%). The remaining low risk patients (grade 1 or 2, less than 1/3 myometrial invasion) had an excellent 5-year disease-free survival with or without preoperative cesium. Immediate preoperative intracavitary cesium was well tolerated, did not obscure pathologic findings and in our experience, reduced the probability of recurrence in high risk Stage I endometrial carcinoma patients.

Structure-activity relationship studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene A(4) (LTA(4)) hydrolase.

Leukotriene B(4) (LTB(4)) is a pro-inflammatory mediator that has been implicated in the pathogenesis of a number of diseases including inflammatory bowel disease (IBD) and psoriasis. Since the action of LTA(4) hydrolase is the rate-limiting step for LTB(4) production, this enzyme represents an attractive pharmacological target for the suppression of LTB(4) production. From an in-house screening program, SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) was identified as a potent inhibitor of LTA(4) hydrolase. Structure-activity relationship (SAR) studies around this structural class resulted in the identification of a number of novel, potent inhibitors of LTA(4) hydrolase, several of which demonstrated good oral activity in a mouse ex vivo whole blood assay.

Pregnancy-induced hyporesponsiveness to paternal alloantigens. II. Factors affecting altered expressions of immunity in parous rats.

It was previously demonstrated that female Fischer rats, primiparous by allogeneic DA males, produced only low levels of agglutinating antibody to a challenge skin graft bearing paternal alloantigens, although graft rejection was unimpaired. In this report, the phenomenon of pregnancy-induced hyporesponsiveness was further investigated with regard to factors responsible for its induction and maintenance. Increasing parity by DA males resulted in increased suppression of the Fischer females' agglutinating antibody production postpartum to a challenge skin graft bearing paternal antigens. Moreover, multiparity also resulted in impaired graft rejection, with greater numbers of litters causing more prolonged survival. Either humoral or cellular hyporesponsiveness, or both, persisted for several weeks or even months in many females. Removal of the iliac lymph nodes prior to pregnancy resulted in less severe suppression which was not maintained through the observation period (21 days postgrafting), whereas splenectomy either before mating or on day 7 of pregnancy had no effect. Tubal-ligated females exposed to multiple DA ejaculates, without pregnancy, manifested weakened humoral immunity similar to that of primiparous females, whereas those exposed to (Fischer X DA)F1 hybrid trophoblast multiple times in ectopic sites had not only somewhat suppressed antibody responses but also significantly impaired capacity to reject the challenge allograft. The potential roles of various antigenic stimuli and the complexities of intrauterine antigen processing during gestation are discussed in relation to this naturally induced allosuppression phenomenon.

Contrasting effects of two arachidonate 5-lipoxygenase inhibitors on formyl-methionyl-leucyl-phenylalanine (fMLP) and complement fragment 5a induced human neutrophil superoxide generation.

SC-45662 and SC-41661A, selective arachidonate 5-lipoxygenase (5-LO) inhibitors, had markedly different effects on formyl-methionyl-leucyl-phenylalanine (fMLP) and complement fragment 5a (C5a) induced superoxide release from human neutrophils (PMNs). SC-45662 inhibited superoxide generation induced by fMLP and C5a with IC50 values of 12 and 5 microM, respectively. Furthermore, SC-45662 was capable of inhibiting fMLP and C5a induced superoxide release in PMNs primed with bacterial lipopolysaccharide, tumor necrosis factor-alpha and other priming agents. SC-41661A, a compound from the same chemical series as SC-45662, did not inhibit or induce superoxide generation, but instead primed PMNs for fMLP and C5a induced superoxide generation. The induced superoxide release was concentration dependently enhanced 2 to 4-fold at 5-50 microM. Superoxide release induced by phorbol myristate acetate or serum-activated zymosan was unaffected by either SC-45662 or SC-41661A. The regulation of superoxide generation by these compounds, both of which have the identical oxidation-reduction pharmacophore, was clearly independent of their effects on 5-LO activity. Furthermore, the mechanism by which SC-45662 and SC-41661A alter superoxide generation did not appear to depend on inhibition of xanthine oxidase, catalase or superoxide dismutase. These new compounds provide effective tools for further investigation of the relationship of these two biochemical oxidative systems.

Effect of a 5-lipoxygenase inhibitor on endotoxin-induced pulmonary dysfunction in awake sheep.

We studied the effects of a 5-lipoxygenase inhibitor, SC-45662, on endotoxin-induced pulmonary dysfunction in chronically instrumented unanesthetized sheep. Each sheep was studied with endotoxin alone, SC-45662 alone, and endotoxin after SC-45662 pretreatment. Endotoxin did not cause consistent increases in plasma or lung lymph concentrations of leukotriene B4 (LTB4). Ex vivo stimulation of whole blood from sheep before and after treatment with SC-45662 demonstrated no inhibition of cyclooxygenase metabolism but an approximately 80% inhibition of LTB4 production. At drug concentrations obtained in vivo, SC-45662 did not significantly inhibit in vitro A23187-stimulated whole blood thromboxane B2 production but did inhibit LTB4 production from ionophore-stimulated sheep granulocytes. SC-45662 attenuated the early changes in lung mechanics and pulmonary hypertension but did not attenuate the later increase in lung fluid and solute exchange observed after endotoxemia. We conclude that 5-lipoxygenase products are not measurably involved in the later increase in lung fluid and solute exchange observed after endotoxemia in sheep.

Carbamylated haemoglobin in chronic renal failure.

Carbamylated haemoglobin was measured by quantifying the release of isopropyl hydantoin by the acid hydrolysis of globin using gas liquid chromatography. Carbamylated haemoglobin was evaluated in 167 subjects including patients with a wide spectrum of renal disease. Grossly elevated concentrations of isopropyl hydantoin (mean values greater than 80 ng IPH/mg globin) were found in chronic renal failure, dialysis and transplant patients with renal failure compared to healthy subjects (15-39 ng IPH/mg globin). The elevated carbamylated haemoglobin correlated with renal function. Carbamylated haemoglobin may act as an indicator of uraemic status and has a potential clinical usefulness and may also have a pathophysiological significance.

Additional effects of monovalent cations on the lysine-sensitive aspartokinase of E. coli B.

The apparent specificity of activation of lysine-sensitive aspartokinase (E.C.2.7.2.4) from E. coli by monovalent cations differs depending on the assay used and on the Mg2+ concentration. Activity is nearly absolutely dependent on and is highly specific for a monovalent cation in the aspartate semialdehyde dehydrogenase coupled assay or the adenosine triphosphate-adenosine diphosphate exchange assay. Little specificity for monovalent cations is observed using the aspartyl hydroxamate assay. Activation and specificity are also altered by Mg2+ concentrations at a constant 5 mM nucleotide concentration. At a low (1.25 or 1.6 mM)Mg2+ concentration, monovalent cation activation and specificity are nearly absolute. Less dependence on monovalent cations and less specificity are observed at a higher Mg2+ concentration (6 mM). Li+ inhibits aspartokinase competitively with respect to either K+ or NH4+. Monovalent cations are also thermoprotective and differential thermal inactivation experiments at 56 degrees C reveal that NH4+ and K+, either of which will produce maximum catalytic activity, interact differently with aspartokinase. K+ interacts with positive cooperativity, whereas NH4+ does not. K+, NH4+, and Na+ are about equally effective in enhancing the dissociation of the aspartokinase-aspartylphosphate complex. Li+ is less effective.