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D L Cutler

Publications and source records attributed to D L Cutler.

At least 37 records · Page 2Linked to original sources
PubMed1998

Spontaneous and inducible cytokine responses in healthy humans receiving a single dose of IFN-alpha2b: increased production of interleukin-1 receptor antagonist and suppression of IL-1-induced IL-8.

The present study was to determine whether the administration of a single dose of interferon-alpha2B (IFN-alpha2B) to healthy humans affects endogenous (or basal level) or inducible cytokines in a whole blood, ex vivo culture. Twenty-four healthy volunteers received an s.c. injection of IFN-alpha2b (3 x 10(6)U), and 4 volunteers received the vehicle as placebo. The study was blinded. Blood was drawn before and 3, 6, 12, and 24 h after the injection and incubated in the presence or absence of lipopolysaccharide (LPS) or interleukin-1beta (IL-1beta). After 24 hs, the plasma was assayed for tumor necrosis factor-alpha (TNF-alpha), IFN-gamma, IL-1beta, IL-1 receptor antagonist (IL-1Ra), and IL-8. Treatment with IFN-alpha2b was associated with a 4.8-fold increase in the endogenous production of IL-1Ra in cultured blood sustained over 24 hs. In contrast, no change in endogenous IL-1Ra production was detected in the controls. A significant suppression (75%, p < 0.001) of IL-1beta-induced IL-8 production 3 and 6 h after IFN-alpha2b compared with control subjects was observed. These effects were also observed when IFN-alpha2b was added directly to whole blood cultures in vitro. In contrast to IL-1 stimulation, LPS stimulation of blood from IFN-alpha2b-treated subjects resulted in enhanced IL-1beta and TNF-alpha production. These results suggest that a single dose of IFN-alpha2b induces an anti-inflammatory state for endogenous stimuli but a proinflammatory state for exogenous endotoxin.

Adult↗
PubMed1998

A three-decade perspective on community and public psychiatry training in Oregon.

The public psychiatry training program at Oregon Health Sciences University, established in 1973, educates psychiatric residents to work in community mental health centers and state hospitals. The authors present a brief history of this program, which spans three decades, and describe recent developments in its operation, with special attention to financing, administrative structure, and educational elements. Several program graduates have chosen careers in public-sector work. The program is founded on the principle that just as dollars should follow patients in health care systems, so should residents in training follow patients. Administrative and fiscal arrangements must be flexible to support this mobility.

Career Choice↗
PubMed1997

Attenuation of proinflammatory response by recombinant human IL-10 in human endotoxemia: effect of timing of recombinant human IL-10 administration.

To determine the effects of IL-10 on cytokine and granulocyte responses during endotoxemia, two groups of eight healthy male volunteers were challenged with endotoxin (4 ng/kg) on two occasions, once in combination with placebo injection, and once in conjunction with i.v. administered recombinant human IL-10 (rhIL-10) (25 microg/kg). In group 1, rhIL-10 was administered 2 min before endotoxin challenge; in group 2, the intervention was delayed for 1 h after endotoxin administration. rhIL-10 pretreatment reduced the LPS-induced rises in temperature and release of TNF, IL-6, IL-8, and IL-1 receptor antagonist. Endotoxin-induced granulocyte accumulation in lungs, as determined by dynamic granuloscintigrams, was prevented by rhIL-10 pretreatment, whereas granulocyte recruitment in liver and spleen was only modestly reduced. In addition, granulocyte degranulation, as measured by plasma elastase/alpha1-antitrypsin complexes, was blunted significantly by rhIL-10 pretreatment. Post-treatment with rhIL-10 did not influence LPS-induced temperature responses, cytokine release, or granulocyte degranulation. Both rhIL-10 pretreatment and post-treatment reduced LPS-induced cortisol levels. These results indicate that pretreatment with rhIL-10 reduces endotoxin-induced febrile responses, cytokine responses, and granulocyte accumulation in lungs, while in this acute model post-treatment with rhIL-10 exerts limited anti-inflammatory effects.

Adult↗
PubMed1997

Interleukin-10 inhibits activation of coagulation and fibrinolysis during human endotoxemia.

Interleukin-10 (IL-10) has been found to inhibit lipopolysaccharide (LPS)-induced tissue factor expression by monocytes in vitro. To determine the effects of IL-10 on LPS-induced activation of the hemostatic mechanisms in vivo, we performed a placebo-controlled, cross-over study of human endotoxemia. Two groups of eight volunteers were challenged with LPS (4 ng/kg) on two occasions: once in conjunction with placebo, and once with recombinant human IL-10 (rhIL-10; 25 microg/kg). In group 1, placebo or rhIL-10 was given 2 minutes before LPS challenge, group 2 received placebo or rhIL-10 1 hour after LPS administration. Pretreatment with rhIL-10 reduced both LPS-induced activation of the fibrinolytic system (plasma concentrations of tissue type plasminogen activator, plasmin-alpha2-antiplasmin complexes, and D-dimer), and inhibition of fibrinolysis (plasma levels of plasminogen activator inhibitor 1), whereas posttreatment only inhibited the latter response. Both IL-10 pre- and posttreatment attenuated activation of the coagulation system (plasma levels of prothrombin fragment F1 + 2 and thrombin-antithrombin complexes). These results indicate that rhIL-10, besides its well-described inhibitory effects on cytokine release, potently modulates the fibrinolytic system and inhibits the coagulant responses during endotoxemia.

Adult↗
PubMed1997

Pharmacodynamics of subcutaneous recombinant human interleukin-10 in healthy volunteers.

Interleukin-10 inhibits T-lymphocyte activation and proliferation and lipopolysaccharide-induced monocyte production of proinflammatory cytokines. Fifty-four healthy volunteers received single doses of recombinant human interleukin-10 (1.0, 2.5, 5.0, 10, 25, or 50 micrograms/kg) or placebo by subcutaneous injection (randomized double-blind assignment). Clinical adverse events were infrequent at doses below 50 micrograms/kg (five of six subjects had mild flu-like syndrome). Mean serum interleukin-10 concentrations were dose related. The mean terminal-phase half-life ranged from 2.7 to 4.5 hours, and the apparent volume of distribution ranged from 0.70 to 1.35 L/kg. Hematologic changes included transient mild to moderate increases of neutrophil counts, decreases of lymphocyte counts, and a delayed decrease of platelet counts. Recombinant human interleukin-10 significantly suppressed production of the proinflammatory cytokines interleukin-1 beta and tumor necrosis factor-alpha by whole blood stimulated ex vivo with Escherichia coli lipopolysaccharide.

Adult↗
PubMed1996

Pharmacokinetics and immunomodulatory properties of intravenously administered recombinant human interleukin-10 in healthy volunteers.

Normal volunteers received single doses of recombinant human interleukin-10 (rhIL-10; n = 6 per group) or placebo (n = 3 per group) by intravenous injection to characterize pharmacokinetics, tolerability, and immunomodulatory effects. Dosages were 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 25.0, 50.0, and 100.0 micrograms/kg. Dose-related adverse effects consisted of a mild-to-moderate flu-like syndrome characterized by fever with chills, headache, and myalgias at the highest dose. The mean terminal phase t1/2 ranged from 2.3 +/- 0.5 to 3.7 +/- 0.8 hours. Dose-related effects of rhIL-10 included transient increases of circulating neutrophils and monocytes and decreases of lymphocytes. rhIL-10 markedly suppressed, in a time- and dose-dependent manner, the synthesis of the inflammatory cytokines IL-1 beta and tumor necrosis factor alpha by whole blood stimulated ex vivo with bacterial lipopolysaccharide. Circulating numbers of CD14+/HLA-DR+ cells at 24 hours after the dose were increased in a dose-dependent manner. Effects on expression of HLA-DR by CD14+ cells were variable. There was no apparent effect on HLA-DR expression by CD20+ cells. The immunomodulatory effects of rhIL-10 merit further clinical investigation.

Adolescent↗
PubMed1996

Clinical, hematologic, and immunologic effects of interleukin-10 in humans.

We conducted a double-blind, placebo-controlled study to investigate the safety, pharmacokinetics, and immunological properties of interleukin-10 (IL-10) administration in healthy humans. Volunteers received a single intravenous bolus injection of recombinant human IL-10 (1, 10, or 25 micrograms/kg) or placebo. Cytokine production in whole blood and peripheral blood mononuclear cells (PBMC) was assessed before and 3, 6, 24, and 48 hr after the injection. Peak serum concentrations of IL-10 (15 +/- 1.1, 208 +/- 20.1, and 505 +/- 22.3 ng/ml) occurred after 2-5 min for 1, 10, and 25 micrograms/kg IL-10, respectively. The terminal-phase half-life was 3.18 hr. A transient leukocytosis (24-63% above baseline) was observed 6 hr after injection, which coincided with a dose-dependent decrease (12-24%) in neutrophil superoxide generation. There was a marked inhibition (60-95%) of endotoxin-induced IL-6 production from whole blood in each group receiving IL-10. Production of IL-8 in endotoxin-stimulated blood was reduced in the 10 micrograms/kg group. In PBMC stimulated with phytohemagglutinin and phorbol ester, there was a decrease (72-87%) in interferon-gamma (IFN gamma) production 6 hr after IL-10 with a return to pre-IL-10 levels after 24 hr. This reduction was only partially associated with a decrease in the number of CD2-bearing cells. We conclude that IL-10 administration into humans is without significant side effects, and a single injection reduces ex vivo production of IL-6, IL-8, and IFN gamma.

Adolescent↗
PubMed1995

Oral and intravenous zidovudine pharmacokinetics: the effect of granulocyte-macrophage colony stimulating factor.

Combination therapy with zidovudine and recombinant human granulocyte-macrophage colony stimulating factor (rHu GM-CSF) may be warranted, owing to the bone marrow suppressive effects of zidovudine. A study of 16 patients, 8 of whom had acquired immune deficiency syndrome (AIDS) and 8 of whom were infected with human immunodeficiency virus (HIV) but were asymptomatic, was conducted. The effect of 4 days of rHU GM-CSF versus placebo on intermittent zidovudine therapy (200 mg every 8 hours) was evaluated using a randomized, cross-over study design. Pharmacokinetics of oral and intravenous zidovudine were determined on days 1 (oral), 3 (oral), and 4 (intravenous) of rHu-GM-CSF (placebo) administration. After intravenous dosing, zidovudine plasma clearance for placebo and rHu GM-CSF averaged 1.4 +/- 0.2 and 1.3 +/- 0.2 L/hr/kg, respectively (P = 0.017), mean residence time averaged 1.5 +/- 0.5 and 1.9 +/- 0.6 hours, respectively (P = 0.012), and the steady-state volume of distribution was 2.0 +/- 0.7 and 2.3 +/- 0.7 L/kg, respectively (P = 0.027) for the two treatment arms. Stratified data for patients with AIDS and those with asymptomatic HIV infection revealed no significant difference in plasma clearance or mean residence time between the two patient groups. These pharmacokinetic results indicate that dosage adjustments for zidovudine are not warranted when administered with rHu GM-CSF owing to the small changes observed. However, the statistically significant increase in Vss suggests the possibility of enhanced zidovudine cellular uptake in the presence of rHu GM-CSF.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Low-carbohydrate diet alters intracellular glucose metabolism but not overall glucose disposal in exercise-trained subjects.

Dietary composition has been strongly implicated as an important determinant of in vivo insulin sensitivity. However, the metabolic alterations associated with extreme changes in diet have not been well described. We compared glucose metabolism after a standard diet ([STD] 35% fat, 51% carbohydrate, and 14% protein) with the effects of a 3-week adaptation to a low-carbohydrate, high-fat diet ([LCD] 75% fat, 8% carbohydrate, and 17% protein). Ten healthy men were studied using the euglycemic clamp technique, indirect calorimetry, and percutaneous vastus lateralis muscle biopsies for analysis of glycogen synthase (GS) and pyruvate dehydrogenase (PDH) activities in the basal and insulin-stimulated states. Insulin-stimulated glucose disposal was unchanged (STD 46.1 +/- 4.3 v LCD 46.0 +/- 4.3 mumol/kg.min, P = NS), but marked alterations in the routes of glucose disposal were noted. Insulin-stimulated glucose oxidation (Gox) was markedly reduced following LCD (STD 18.6 +/- 1.9 v LCD 8.23 +/- 1.9 mumol/kg.min, P = .0001), and nonoxidative glucose metabolism (Gnox) was enhanced by LCD (STD 24.9 +/- 0.9 v LCD 38.9 +/- 4.3 mumol/kg.min, P = .03). Following LCD, both the total and active forms of PDH (PDHt and PDHa) were significantly depressed. After LCD, GS activates (FV0.1, %I, and A0.5) were unaffected in the basal state, but were greater than for STD (P = .004) after insulin stimulation. The apparent increase in the sensitivity of GS to activation by insulin following LCD correlated strongly with maximal O2 consumption ([VO2max] r = .97, P = .001), suggesting that physical conditioning interacted with the metabolic impact of LCD. In summary, LCD did not induce changes in net glucose disposal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Training residents for community psychiatric practice: guidelines for curriculum development.

There is a critical need to recruit and retain more psychiatrists with the required skills and interest to work with seriously mentally ill and/or socially disadvantaged patients within organized programs in community settings. More residency training programs having the capacity to prepare psychiatrists for community practice can help to meet this need. A consensus definition of the clinical, administrative, consultative and academic areas of contemporary community psychiatric practice developed by the American Association of Community Psychiatrists is used to determine the goals of the training curriculum described in this paper. A comprehensive list of knowledge, skill, and attitude objectives, as well as suggestions for structuring clinical training assignments are provided as guidelines for curriculum development.

Adult↗
PubMed1992

Severe insulin resistance and diabetes mellitus in mandibuloacral dysplasia.

Mandibuloacral dysplasia (MAD) is a syndrome with onset in midchildhood. The predominant characteristics of MAD include flexion contractures; mandibular hypoplasia; loss of body fat; atrophic, speckled skin; and progressive osteolysis of the clavicles. We studied three males with MAD. Each had lipodystrophy of the extremities, with sparing of the face and neck. All had moderate hyperlipidemia. In response to oral glucose, each had a diabetic response, with peak insulin levels between 2870 and 22,960 pmol/L. Insulin-stimulated glucose disposal was determined in two patients with MAD. At an insulin infusion rate of 120 mU/m2 per minute, glucose disposal was less than 25% of that measured at similar levels of insulinemia in nondiabetic control subjects, indicating marked insulin resistance in patients with MAD. The insulin resistance occurred without obesity, excessive levels of counterregulatory hormones, or anti-insulin-receptor antibodies. We suggest that MAD is a previously undescribed form of lipodystrophic insulin-resistant diabetes mellitus.

Abnormalities, Multiple↗
PubMed1992

The cost of fragmented mental health financing: is it worth it?

Three major aspects of mental health systems--the way they are financed, the configuration of services, and the outcome of services--are discussed. Problems of resource consumption, fragmentation of goals, and deleterious impacts due to financing systems, per se, are described. Levels of staff involvement in the financing system (as distinct from direct services) influence staff attitudes toward financing, services, and clients. Financing schemes appear to both influence the effectiveness of mental health systems and provide the dubious "advantage" of costing more. Studies are suggested that will compare comprehensive systems with an eye toward reform.

Chronic Disease↗
PubMed1992

Psychiatry in community mental health centers: everyone can win.

The purpose of this paper is to describe the psychiatrist's role in community mental health programs, beginning with the evolution of psychiatric involvement in community mental health centers (CMHCs). There is a discussion of the current state of psychiatry in community mental health programs with descriptions of the types of roles psychiatrists occupy and their thoughts about those roles. The concluding sections focus on the ways psychiatrists can be utilized in community mental health programs so that both the psychiatrist and the agency benefit and are satisfied.

Community Mental Health Centers↗
PubMed1991

Insulin-resistant diabetes mellitus and hypermetabolism in mandibuloacral dysplasia: a newly recognized form of partial lipodystrophy.

Mandibuloacral dysplasia (MAD) is a syndrome characterized by partial lipodystrophy and a distinct phenotype, which includes progressive osteolysis of the mandible and clavicles, cutaneous atrophy, joint contractures, and diabetes mellitus. We now describe the results of hyperinsulinemic glucose clamps performed in conjunction with indirect calorimetry in two subjects with MAD. At a glucose level of 5 mmol/L and insulin concentration of over 6.5 x 10(4) pmol/L, glucose disposal rates were less than 20% of maximum insulin-stimulated glucose disposal in five nondiabetic controls. Basal hepatic glucose output was elevated in the two patients and was incompletely suppressed by a 1200 mU/m2.min infusion of insulin. Glucose and lipid oxidation rates were inappropriately elevated, reflecting marked hypermetabolism. Pharmacological concentrations of insulin failed to normally suppress lipid oxidation, diminish FFA levels, or adequately suppress glucagon levels. In summary, MAD is a unique form of lipodystrophic diabetes characterized by typical somatic features, extreme insulin resistance, and marked hypermetabolism.

Adolescent↗
PubMed1989

Education and training in public psychiatry.

The Public Psychiatry Training Program offers an education in the unique knowledge, attitudes, and skills essential for working with persons with severe and chronic illness in both hospital and community settings.

Community Mental Health Services↗