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Biomedical subjects

B Friedman

Publications and source records attributed to B Friedman.

At least 19 recordsLinked to original sources
PubMed1995

Strategic responses by hospitals to increased financial risk in the 1980s.

OBJECTIVE: This research addresses the following types of responses by hospitals to increased financial risk: (a) increases in prices to privately insured patients (testing separately the effects of risk from the effects of "cost-shifting" that depends on level of Medicare payment in relation to case mix-adjusted cost); (b) changes in service mix offered and selectivity in acceptance of patients to reduce risk; and (c) efforts to reduce variation in resource use for those patients admitted. DATA SOURCES: The database includes a national panel of over 400 hospitals providing information from patient discharge abstracts, hospital financial reports, and county level information over the period 1980-1987. STUDY DESIGN: Econometric methods suitable to panel data are implemented, with tests for pooling, hospital-specific fixed effects, and possible problems of selection bias. PRINCIPAL FINDINGS: The prices paid by private insurers to a particular hospital were affected by the changes in risk imposed by Medicare prospective payment, the generosity of Medicare payment, state rate regulation, and ability of the hospital to bear risk. The risk-weighted measure of case mix did not respond to changes in payment policy, but other variables reflecting the management of care after admission to reduce risk did change in the predicted directions. CONCLUSIONS: Some of the findings in this article are relevant to current Medicare policies that involve risk-sharing, for instance, special allowances for "outlier" patients with unusually high cost, and for sole community hospitals. The first type of allowance appears successful in preserving access to care, while the second type is not well justified by the findings. State rate regulation programs were associated not only with lower hospital prices but also with less risk reduction behavior by hospitals. The design of regulation as a sort of risk-pooling arrangement across payers and hospitals may be attractive to hospitals and help explain their support for regulation is some states.

Cost Allocation↗
PubMed1995

BDNF and NT-4/5 exert neurotrophic influences on injured adult spinal motor neurons.

Adult motor neurons, like their immature antecedents, express the mRNA for the signaling receptor for brain-derived neurotrophic factor (BDNF) and for neurotrophin-4/5 (NT-4/5). However, while both BDNF and NT-4/5 support the survival of axotomized developing spinal motor neurons in vitro or in vivo, it is not known whether these factors continue to influence spinal motor neurons in adulthood. The present study tests if BDNF or NT-4/5 modulate the reactive responses of adult spinal motor neurons to nerve injury. We utilize sciatic nerve transection to axotomize the spinal motor neurons that form the retrodorsal lateral nucleus (RDLN) and show that, after axotomy, RDLN motor neurons lose ChAT immunoreactivity and also reexpress p75Ingfr, the low affinity receptor for all neurotrophin family members. Treatment with BDNF or NT-4/5 alters these effects of sciatic nerve transection. Both BDNF and NT-4/5 attenuate the loss of ChAT expression in axotomized RDLN motor neurons; thus, as compared to vehicle treatments, BDNF and NT-4/5 produce statistically significant increases in the optical density of ChAT immunostaining. Furthermore, BDNF and NT-4/5 also significantly increase the RDLN reexpression of p75Ingfr after sciatic nerve transection. Interestingly, essentially identical increases in RDLN ChAT and p75Ingfr immunostaining are produced by sciatic nerve crush injuries in the absence of exogenous neurotrophin treatment. These data show that treatment with exogenous BDNF and NT-4/5 changes the response of adult spinal motor neurons to sciatic nerve transection. Furthermore, these neurotrophins elicit reactive responses in axotomized motor neurons that mimic those produced by endogenous agents in regenerating crushed peripheral nerve.

Animals↗
PubMed1994

Pharmacokinetics and pharmacodynamics of multiple oral doses of MK-0591, a 5-lipoxygenase-activating protein inhibitor.

The pharmacodynamics, kinetics, and tolerability of a new orally active 5-lipoxygenase inhibitor were evaluated in healthy male volunteers. MK-0591, 50, 125, and 250 mg every morning and 250 mg every 12 hours, was administered for 10 days. Leukotriene B4 biosynthesis ex vivo in ionophore (A23187)-stimulated whole blood and leukotriene E4 levels in urine were determined. Leukotriene B4 production was inhibited up to 90% of baseline for 12 hours after administration at the highest dose. The degree of leukotriene B4 inhibition ex vivo in whole blood significantly correlated with plasma MK-0591 concentrations (0 to 1500 ng/ml; r = 0.73). Urinary leukotriene E4 was inhibited by > 80% at 24 hours after administration for all dose levels. Pharmacokinetics of MK-0591 were linear, with a half-life of approximately 6 hours. Very little accumulation was seen after multiple dosing. MK-0591 had no effect on testosterone levels, and good tolerability was shown at all dose levels of MK-0591 administered for up to 10 days.

5-Lipoxygenase-Activating Proteins↗
PubMed1992

Oligodendrocytes and myelin formation along the optic tract of the developing hamster: an immunohistochemical study using the Rip antibody.

The monoclonal antibody Rip recognizes an antigen specific to oligodendrocytes and their processes (Friedman et al: Glia 2:380, 1989). We have used this antibody to document the appearance of oligodendrocytes and the sequence of ensheathment of axons along the optic tract (OT) and within its major target areas in neonatal (P3-P21) and adult hamsters. Myelination of axons in the visual pathway follows an overall proximo-distal gradient. On P3, immunopositive, pre-ensheathing oligodendrocytes are detected in the OT ventral to the lateral geniculate body (LGB) whereas myelin segments are present around OT axons by P5. The first pre-ensheathing oligodendrocytes are detected medially in the LGB on P7 and myelinated axons in the overlying OT by P11. In the superior colliculus, pre-ensheathing oligodendrocytes are present in the optic fiber layer (SO) on P7, but not in the superficial gray layer (SGS) until P11. Myelination of axons within SO proceeds along a marked rostro-caudal gradient. On P14, axons in rostral SO are heavily myelinated; thereafter, ensheathment continues caudally within the SO and the SGS. The progressive invasion of oligodendrocytes along the proximo-distal axis of the optic pathway, and the corresponding myelination of OT axons, are discussed in the context of a possible inhibitory role of oligodendrocytes in regulating the regenerative propensity of retinotectal axons.

Animals↗
PubMed1992

Regulation of ciliary neurotrophic factor expression in myelin-related Schwann cells in vivo.

Adult rat sciatic nerve is known to express high levels of ciliary neurotrophic factor (CNTF) mRNA and protein. Here we examine the cellular localization of CNTF protein and mRNA in peripheral nerve and the regulation of CNTF expression by peripheral axons. In intact nerve, CNTF immunoreactivity is found predominantly in the cytoplasm of myelin-related Schwann cells. After axotomy, CNTF immunoreactivity and mRNA levels fall dramatically and do not recover unless axons regenerate. This behavior is similar to the pattern of myelin gene expression in these nerves. We conclude that the expression of CNTF in Schwann cells depends on axon-Schwann cell interactions.

Animals↗
PubMed1992

The neurotrophins BDNF, NT-3, and NGF display distinct patterns of retrograde axonal transport in peripheral and central neurons.

The pattern of retrograde axonal transport of the target-derived neurotrophic molecule, nerve growth factor (NGF), correlates with its trophic actions in adult neurons. We have determined that the NGF-related neurotrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), are also retrogradely transported by distinct populations of peripheral and central nervous system neurons in the adult. All three 125I-labeled neurotrophins are retrogradely transported to sites previously shown to contain neurotrophin-responsive neurons as assessed in vitro, such as dorsal root ganglion and basal forebrain neurons. The patterns of transport also indicate the existence of neuronal populations that selectively transport NT-3 and/or BDNF, but not NGF, such as spinal cord motor neurons, neurons in the entorhinal cortex, thalamus, and neurons within the hippocampus itself. Our observations suggest that neurotrophins are transported by overlapping as well as distinct populations of neurons when injected into a given target field. Retrograde transport may thus be predictive of neuronal types selectively responsive to either BDNF or NT-3 in the adult, as first demonstrated for NGF.

Animals↗
PubMed1992

Bronchodilator properties of an inhaled leukotriene D4 antagonist (verlukast--MK-0679) in asthmatic patients.

The safety, tolerability and bronchodilator properties of inhaled verlukast (MK-0679), a new potent and selective LTD4-receptor antagonist, were studied in 12 asthmatic subjects with more than 15% increase in FEV1 after salbutamol inhalation. On three separate study days the patients inhaled placebo, verlukast 2 mg and verlukast 8 mg from a metered dose inhaler according to a randomized, double-blind, cross-over allocation schedule. Pulmonary function and tolerability were assessed regularly and after 8 h a second dose of test drug was inhaled. Thirty minutes later a beta 2-agonist dose-response curve was performed by inhaling salbutamol in cumulative doses of 200, 400 and 800 micrograms. Verlukast (8 mg) caused significant improvement in mean FEV1 from 1.5 through 8 h after inhalation as compared to placebo (P less than 0.05). The maximum change in FEV1 occurred at 2 h after inhalation with mean percent increases above baseline of 3.5, 7.7, and 9.2% after placebo, verlukast 2 mg and 8 mg, respectively. The bronchodilator response to inhaled salbutamol was significantly larger after verlukast 8 mg than after placebo pretreatment (P less than 0.05), whereas verlukast 2 mg afforded no additive bronchodilator effect. We conclude that inhalation of the LTD4-antagonist verlukast induces modest but significant bronchodilatation and may be beneficial in the treatment of asthma.

Administration, Inhalation↗
PubMed1992

Production of granulocyte/macrophage colony-stimulating factor in human airways during allergen-induced late-phase reactions in atopic subjects.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) are hematopoietic growth factors that have been shown to induce proliferation and activation of inflammatory cells, and may play a role in allergic reactions. Since little is known about the involvement of cytokines in allergic inflammation in the lung, the levels of GM-CSF and IL-3 were measured in bronchoalveolar lavage (BAL) fluids obtained in the late phase after segmental lung antigen (Ag) challenge in 14 allergic rhinitis subjects with or without bronchial asthma. BAL fluids either after Ag (ragweed, dust mite, or timothy) or saline control challenge were recovered 19 h later. In 6 of the 14 patients, BAL fluids were concentration-dialyzed (20x) and assayed for cytokine activity. Cytokine assays were performed using the human megakaryocytic leukemic cell line M-07e, which is responsive to either GM-CSF or IL-3. The level of GM-CSF-equivalents was approximately 25 times higher in Ag-challenged sites (49.9 +/- 12.7 pg/ml; mean +/- SEM), compared to saline challenge sites (2.2 +/- 1.0, p < 0.01, n = 9). Neutralization experiments using a polyclonal specific antibody (Ab) against GM-CSF and IL-3 revealed that the bulk of the activity was GM-CSF. BAL fluids from Ag- and saline-challenged sites in one nonatopic subject contained no significant GM-CSF activity. Furthermore, the level of GM-CSF in Ag-challenged BAL fluid and the percentage of eosinophils in BAL from each subject correlated significantly (r = 0.73, p < 0.005, n = 14).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Production of granulocyte-macrophage colony-stimulating factor by cultured human tracheal epithelial cells.

We have evaluated the capacity of cultured human respiratory epithelial cells (HTE) to produce granulocyte-macrophage colony-stimulating factor (GM-CSF) and have examined the ability of proinflammatory stimuli and of glucocorticoids to modulate the production of GM-CSF by these cells. Conditioned medium (CM) was obtained after 24-hr culture of HTE in the presence or absence of serum (5%) and was assayed for GM-CSF activity using the M-07e cell line, which proliferates in response to GM-CSF and interleukin-3 (IL-3). HTE produced 1.1 +/- 0.7 and 2.1 +/- 1.5 ng GM-CSF/10(6) cells in the presence or absence of serum, respectively (n = 4). The identity of this activity as GM-CSF was established by neutralization with specific antibody to GM-CSF, while antibody to IL-3 was without effect. Dexamethasone (10(-6) M) inhibited basal GM-CSF release to below the limit of detection of the assay (0.12 ng GM-CSF/ml conditioned media). GM-CSF release was significantly enhanced by 10(-6) M histamine (1.6 +/- 0.7 versus 2.13 +/- 0.8 ng GM-CSF/10(6) cells; n = 9) and 5 ng/ml interleukin-1 (IL-1) (0.6 +/- 0.2 versus 3.2 +/- 0.5 ng GM-CSF/10(6) cells; n = 3). Stimulation of GM-CSF release by IL-1 was dose-dependent. A significant increase in GM-CSF activity was observed with 0.1 ng/ml, while maximal stimulation occurred at 5 ng/ml IL-1. In kinetic studies, GM-CSF activity was first detected in CM from cells incubated in the absence of stimulus at 8 hr of incubation, and continued to increase up to 24 hr. IL-1 stimulated GM-CSF activity was detected in CM as early as 4 hr and continued to increase significantly up to 24 hr. Thus, human tracheal epithelial cells release GM-CSF and this release is regulated by inflammatory mediators and glucocorticoids.

Adult↗
PubMed1991

Selective metal binding to Cys-78 within endonuclease V causes an inhibition of catalytic activities without altering nontarget and target DNA binding.

T4 endonuclease V is a pyrimidine dimer-specific DNA repair enzyme which has been previously shown not to require metal ions for either of its two catalytic activities or its DNA binding function by virtue of its ability to function in the presence of metal-chelating agents. However, we have investigated whether the single cysteine within the enzyme was able to bind metal salts and influence the various activities of this repair enzyme. A series of metals (Hg2+, Ag+, Cu+) were shown to inactivate both endonuclease Vs pyrimidine dimer-specific DNA glycosylase activity and the subsequent apurinic nicking activity. The binding of metal to endonuclease V did not interfere with nontarget DNA scanning or pyrimidine dimer-specific binding. The Cys-78 codon within the endonuclease V gene was changed by oligonucleotide site-directed mutagenesis to Thr-78 and Ser-78 in order to determine whether the native cysteine was directly involved in the enzyme's DNA catalytic activities and whether the cysteine was primarily responsible for the metal binding. The mutant enzymes were able to confer enhanced ultraviolet light (UV) resistance to DNA repair-deficient Escherichia coli at levels equal to that conferred by the wild type enzyme. The C78T mutant enzyme was purified to homogeneity and shown to be catalytically active on pyrimidine dimer-containing DNA. The catalytic activities of the C78T mutant enzyme were demonstrated to be unaffected by the addition of Hg2+ or Ag+ at concentrations 1000-fold greater than that required to inhibit the wild type enzyme. These data suggest that the cysteine is not required for enzyme activity but that the binding of certain metals to that amino acid block DNA incision by either preventing a conformational change in the enzyme after it has bound to a pyrimidine dimer or sterically interfering with the active site residue's accessibility to the pyrimidine dimer.

Blotting, Western↗
PubMed1991

Episodic eosinophilia-myalgia-like syndrome in a patient without L-tryptophan use: association with eosinophil activation and increased serum levels of granulocyte-macrophage colony-stimulating factor.

We have studied a patient with recurrent bouts of angioedema, myalgia, and eosinophilia that was not due to L-tryptophan ingestion. Peripheral blood eosinophils (EOSs) during exacerbations of his illness displayed characteristics of "activation," including hypodense phenotype and increased responsiveness to platelet-activating factor (PAF) in vitro with respect to expression of CD11b surface adhesion proteins. Elevated serum levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) bioactivity were also detected, whereas interleukin-3 and interleukin-5 levels were not increased. During treatment with glucocorticoids, all clinical symptoms resolved, EOSs decreased in number and became normodense, PAF responsiveness diminished, and GM-CSF levels returned to normal. During glucocorticoid tapering, a subsequent clinical relapse was again associated with EOS hypodensity, increased PAF responsiveness, and increased serum GM-CSF levels. Although this patient satisfies the diagnostic criteria for eosinophilia-myalgia syndrome, the episodic and profound nature of exacerbations and response to therapy in the absence of L-tryptophan usage suggests a possible overlap with the syndrome of episodic angioedema and eosinophilia. In vitro studies suggest that GM-CSF may play a role in the eosinophilia, EOS activation, and pathophysiology of disease in this patient and demonstrate resolution of these abnormalities during glucocorticoid therapy. The efficacy of glucocorticoid therapy in some hypereosinophilic states may therefore be mediated, at least in part, via reduction of GM-CSF production and/or EOS activation.

Angioedema↗
PubMed1991

Clinical and biochemical effects of an oral leukotriene biosynthesis inhibitor (MK886) in psoriasis.

Antipsoriatic agents have been shown to decrease skin levels of arachidonic acid and its metabolites including 12-monohydroxy-eicosatetranoic acid (12-HETE), and leukotriene B4 (LTB4). In addition, specific systemic and topical lipoxygenase inhibitors have been reported to be effective in the treatment of psoriasis. The objective of this study was to investigate the effect of a potent oral leukotriene biosynthesis inhibitor (MK886) in patients with chronic plaque psoriasis. Clinical response together with the changes of LTB4 levels in lesional skin biopsy specimens, and urinary leukotriene E4 (LTE4) excretion were evaluated. In addition, markers of inflammation, proliferation and keratinization were studied immunohistochemically. No change in clinical scores or lesional LTB4 levels were observed with a 10 1/3-day course of MK886. A statistically significant reduction in urinary LTE4 excretion was observed: mean LTE4 (ng/h) were 5.14 before treatment and 1.51 on day 11 with MK886; and 7.55 before treatment and 6.57 on day 11 with placebo treatment. Epidermal accumulation of polymorphonuclear leukocytes (PMN) tended to diminish in the MK886 treatment group. These results indicate that although a reduction (greater than 70%) in urinary LTE4 excretion was found, and a slight decrease of epidermal PMN accumulation was observed, no correlative changes in clinical scores or LTB4 levels in skin lesion were found with a short course of MK886.

Administration, Oral↗
PubMed1991

The neurotrophins and CNTF: specificity of action towards PNS and CNS neurons.

The availability of relatively large amounts of nerve growth factor (NGF) has allowed extensive in vitro and in vivo characterization of the neuronal specificity of this neurotrophic factor. The restricted neuronal specificity of NGF (sympathetic neurons, neural crest-derived sensory neurons, basal forebrain cholinergic neurons) has long predicted the existence of other neurotrophic factors possessing different neuronal specificities. Whereas there have been many reports of "activities" distinct from NGF, full characterization of such molecules has been hampered by their extremely low abundance. The recent molecular cloning of brain-derived neurotrophic factor (BDNF) revealed that this protein is closely related to NGF and suggested that these two factors might be members of an even larger gene family. A PCR cloning strategy based on homologies between NGF and BDNF has allowed us to identify and clone a third member of the NGF family which we have termed neurotrophin-3 (NT-3). The establishment of suitable expression systems has now made available sufficient quantities of these proteins to allow us to begin to establish the neuronal specificity of each member of the neurotrophin family, and the role of each in development, maintenance and repair of the PNS and CNS. Using primary cultures of various PNS and CNS regions of the developing chick and rat, and Northern blot analysis, we describe novel neuronal specificities of BDNF, NT-3 and an unrelated neurotrophic factor-ciliary neurotrophic factor (CNTF).

Animals↗
PubMed1991

Case management: a randomized controlled study comparing a neighborhood team and a centralized individual model.

This randomized controlled study compared two types of case management for skilled nursing level patients living at home: the centralized individual model and the neighborhood team model. The team model differed from the individual model in that team case managers performed client assessments, care planning, some direct services, and reassessments; they also had much smaller caseloads and were assigned a specific catchment area. While patients in both groups incurred very high estimated health services costs, the average annual cost during 1983-85 for team cases was 13.6 percent less than that of individual model cases. While the team cases were 18.3 percent less expensive among "old" patients (patients who entered the study from the existing ACCESS caseload), they were only 2.7 percent less costly among "new" cases. The lower costs were due to reductions in hospital days and home care. Team cases averaged 26 percent fewer hospital days per year and 17 percent fewer home health aide hours. Nursing home use was 48 percent higher for the team group than for the individual model group. Mortality was almost exactly the same for both groups during the first year (about 30 percent), but was lower for team patients during the second year (11 percent as compared to 16 percent). Probable mechanisms for the observed results are discussed.

Aged↗