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Biomedical subjects

S M Wolff

Publications and source records attributed to S M Wolff.

At least 37 records · Page 2Linked to original sources
PubMed1991

Taurolidine, an analogue of the amino acid taurine, suppresses interleukin 1 and tumor necrosis factor synthesis in human peripheral blood mononuclear cells.

Taurolidine (Geistlich Pharm, AG, Wolhusen, Switzerland), a derivative of the amino acid taurine, is commonly used in some parts of the world as an adjunctive therapy for various infections. Its mechanism of action is thought to be related to its antimicrobial properties, including its ability to interfere with some of the biological activities of endotoxin (lipopolysaccharide, LPS). For example, taurolidine has been shown to protect animals against endotoxic shock and death. In this study we examined the ability of taurolidine to block LPS-induced tumor necrosis factor (TNF) and interleukin 1 (IL-1) synthesis in human peripheral blood mononuclear cells (PBMC) from 27 donors. We observed a dose-dependent reduction in the synthesis of these two cytokines when taurolidine was preincubated with LPS before being added to PBMC. This reduction was independent of the molar ratio of taurolidine to LPS but was related to the concentration of taurolidine present in the PBMC cultures. There was a 80 to 90% reduction in total IL-1 and TNF synthesis induced by LPS at concentrations of taurolidine of 40 to 100 micrograms/mL; the vehicle was without effect. Following a 30-min preincubation with PBMC, taurolidine could be washed from the cells and still suppress cytokine synthesis induced by LPS. Using release of lactic acid dehydrogenase, 100 micrograms/mL of taurolidine was not toxic for PBMC. Taurolidine also reduced IL-1 and TNF synthesis induced by the Staphylococcus aureus-derived toxic shock syndrome toxin-1 as well as that induced by nontoxic heat-killed Staphylococcus epidermidis organisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetyltransferases↗
PubMed1989

In vitro production of IL 1 beta, IL 1 alpha, TNF and IL2 in healthy subjects: distribution, effect of cyclooxygenase inhibition and evidence of independent gene regulation.

Numerous studies have reported altered in vitro cytokine production in various diseases. In the present study we used specific immunoassays to quantitate production of interleukin 1 beta (IL 1 beta), IL 1 alpha, tumor necrosis factor (TNF) and IL 2 from human peripheral blood mononuclear cells (PBMC). The distribution of cell-associated and secreted cytokines was studied in PBMC of 21 individuals; in response to lipopolysaccharide (LPS) the proportion of cell-associated IL 1 beta ranged from 13% to 56%, for IL 1 alpha 29% to 98%, and for TNF 2% to 17%. In a larger cohort of 32 subjects, the total amount of immunoreactive cytokines produced in response to LPS or phytohemagglutinin was normally distributed within the study group. Mean production of IL 1 alpha in response to LPS was 10.1 ng/ml and exceeded production of IL 1 beta (5.6 ng/ml) and TNF (2.2 ng/ml). The distribution pattern was characterized by high intersubject variability extending over two orders of magnitude and the presence of high and low "producers". Production of IL 1 alpha and IL 1 beta correlated (R = 0.69). In contrast, production of IL 1 beta did not correlate with production of TNF or IL 2. Indomethacin present during stimulation of PBMC increased the amount of IL 1 beta produced and showed a high correlation (R = 0.83) compared to cultures without indomethacin. Thus, low production of IL 1 beta in certain subjects appears not to be due to inhibitable levels of cyclooxygenase products. In a retrospective study, PBMC from 12 subjects who had taken oral cyclooxygenase inhibitors during the preceding 7 days produced 43% more IL 1 beta than subjects who did not take these drugs (p less than 0.05). These studies demonstrate that the amount of cytokine synthesized by PBMC (a) is regulated independently for IL 1, TNF and IL 2; (b) correlates for IL 1 beta and IL 1 alpha; (c) is intrinsic for low and high "producers", and (d) production of IL 1 beta increases with the use of oral cyclooxygenase inhibitors.

Adult↗
PubMed1988

Detection of circulating tumor necrosis factor after endotoxin administration.

Cytokines, products of stimulated macrophages, are thought to mediate many host responses to bacterial infection, but increased circulating cytokine concentrations have not been detected consistently in infected patients. We measured plasma concentrations of circulating tumor necrosis factor alpha (cachectin), interleukin-1 beta, and gamma interferon, together with physiologic and hormonal responses, in 13 healthy men after intravenous administration of Escherichia coli endotoxin (4 ng per kilogram of body weight) and during a control period of saline administration. Eight additional subjects received ibuprofen before receiving endotoxin or saline. Plasma levels of tumor necrosis factor were generally less than 35 pg per milliliter throughout the control period, but increased 90 to 180 minutes after endotoxin administration to mean peak concentrations of 240 +/- 70 pg per milliliter, as compared with 35 +/- 5 pg per milliliter after saline administration. Host responses were temporally associated with the increase in circulating tumor necrosis factor at 90 minutes, and the extent of symptoms, changes in white-cell count, and production of ACTH were temporally related to the peak concentration of tumor necrosis factor. Ibuprofen pretreatment did not prevent the rise in circulating tumor necrosis factor (mean peak plasma level, 170 +/- 70 pg per milliliter) but greatly attenuated the symptoms and other responses after endotoxin administration. Concentrations of circulating interleukin-1 beta and gamma interferon did not change after endotoxin administration. We conclude that the response to endotoxin is associated with a brief pulse of circulating tumor necrosis factor and that the resultant responses are effected through the cyclooxygenase pathway.

Adrenocorticotropic Hormone↗
PubMed1988

Inhibition of cyclo-oxygenase attenuates the metabolic response to endotoxin in humans.

Acute infection initiates fever, acute-phase changes, and catabolic responses in the host, resulting in weight loss, hypermetabolism, and accelerated proteolysis. To test the hypothesis that cyclo-oxygenase inhibition might attenuate these responses, we administered Escherichia coli endotoxin intravenously to seven normal volunteers and to seven additional subjects pretreated with a cyclo-oxygenase inhibitor (ibuprofen). Control studies were also performed following administration of saline and ibuprofen alone. Vital signs, metabolic rate, and concentrations of pituitary and stress hormones, as well as those of other substrates, were serially measured. Endotoxin administration produced a response similar to an acute illness, with flulike symptoms, fever, tachycardia, increased metabolic rate, and stimulation of stress hormone release. These changes were markedly attenuated by cyclo-oxygenase inhibition. The leukocytosis, hypoferremia, and elevation of the C-reactive protein level induced by endotoxin were unaffected by cyclo-oxygenase inhibition. These data indicate that activation of the cyclooxygenase pathway is necessary to produce many of the metabolic changes observed during critical illness.

Adult↗
PubMed1988

A low dose of recombinant interleukin 1 protects granulocytopenic mice from lethal gram-negative infection.

Natural and synthetic immunomodulators that increase nonspecific resistance to infection induce interleukin 1 (IL-1) production. Therefore, we investigated the effect of the administration of IL-1 on the survival of lethally infected granulocytopenic mice. Mice with cyclophosphamide-induced granulocytopenia were injected with approximately 10(7) Pseudomonas aeruginosa in the thigh muscle at time 0; gentamicin was administered 6 hr and 23 hr later. When recombinant human IL-1 beta (one of the two forms of IL-1) was given as a single i.p. injection 24 hr before the infection, survival was increased. Using 80 ng of IL-1 beta per mouse, survival compared to control animals was 98% vs. 71% at 24 hr, 98% vs. 60% at 30 hr, 86% vs. 36% at 36 hr, and 61% vs. 11% at 48 hr (P less than 0.001) after the infection. No effect of IL-1 was observed when it was given 0.5 hr before or 6 hr after the infection. Animals not treated with gentamicin also benefited from the IL-1. Administration of the cyclooxygenase inhibitor ibuprofen did not affect the activity of IL-1. Numbers of bacteria cultured from the blood, thigh muscle, liver, spleen, and kidney were similar in IL-1-treated and control animals. Superoxide production by peritoneal macrophages was also similar in the two groups. These studies demonstrate that IL-1 pretreatment protects granulocytopenic mice against lethal pseudomonas infection and suggest that this protection occurs through a noncellular mechanism.

Agranulocytosis↗
PubMed1988

Tumor necrosis factor and endotoxin induce similar metabolic responses in human beings.

After injury, infection, or major operations a number of predictable metabolic responses occur. It has been proposed that the cytokine tumor necrosis factor (TNF)/cachectin is a primary mediator of these host responses. To test this hypothesis, we studied 16 tumor-bearing humans with normal renal and hepatic function, who received 24-hour continuous intravenous infusions of escalating doses of recombinant TNF (4 to 636/micrograms/m2/24 h). Serial measurements were made of vital signs and plasma concentrations of TNF, interleukin-1, adrenocorticotropic hormone, cortisol, iron, glucose, and C-reactive protein. Low doses of TNF had minimal metabolic effects, but infusions of greater than or equal to 545 micrograms/m2/24 hr (n = 8) resulted in fever, pituitary, and stress hormone release and acute phase changes. These alterations were compared with the changes that occurred in healthy humans (n = 13) receiving intravenous bolus injections of Escherichia coli endotoxin (4 ng/kg). TNF infusion in doses greater than or equal to 545 micrograms/m2/24 hr produced peak plasma TNF concentrations and metabolic responses that were similar to those after endotoxin injection. Interleukin-1 concentrations remained basal after TNF or endotoxin administration. TNF may represent the primary afferent signal that initiates many of the metabolic responses associated with sepsis and endotoxemia.

Acute-Phase Proteins↗
PubMed1987

Branch retinal vein occlusion. A clinicopathologic case report.

The eyes of a 72-year-old woman with a history of two branch retinal vein occlusions involving the left eye, were obtained postmortem and studied histopathologically. Prior to her death, she had been enrolled in the multicentered, prospective, randomized clinical trial on branch vein occlusion and treated with peripheral argon laser photocoagulation for disc neovascularization. Routine fluorescein angiograms and fundus photographs were available for clinical correlation. Despite photocoagulation, the patient had frequent recurrent episodes of vitreous hemorrhage. On histologic examination, both venous occlusions were found at arteriovenous crossings and associated with moderately sclerotic retinal arterioles. One occlusion was recanalized. Retinal inner ischemic atrophy was observed distal to the site of both venous occlusions and corresponded to areas of nonperfusion. Cystoid macular edema was not present. Three areas of neovascularization were found; one at the optic nerve head, one at the peripapillary retina, and one at the fovea. It is likely the patient's repeated vitreous hemorrhages were from one or all three areas of neovascularization demonstrated histopathologically.

Aged↗
PubMed1986

Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1.

Recombinant human tumor necrosis factor (rTNF alpha) injected intravenously into rabbits produces a rapid-onset, monophasic fever indistinguishable from the fever produced by rIL-1. On a weight basis (1 microgram/kg) rTNF alpha and rIL-1 produce the same amount of fever and induce comparable levels of PGE2 in rabbit hypothalamic cells in vitro; like IL-1, TNF fever is blocked by drugs that inhibit cyclooxygenase. At higher doses (10 micrograms/kg) rTNF alpha produces biphasic fevers. The first fever reaches peak elevation 45-55 min after bolus injection and likely represents a direct action on the thermoregulatory center. During the second fever peak (3 h later), a circulating endogenous pyrogen can be shown present using passive transfer of plasma into fresh rabbits. This likely represents the in vivo induction of IL-1. In vitro, rTNF alpha induces the release of IL-1 activity from human mononuclear cells with maximal production observed at 50-100 ng/ml of rTNF alpha. In addition, rTNF alpha and rIFN-gamma have a synergistic effect on IL-1 production. The biological activity of rTNF alpha could be distinguished from IL-1 in three ways: the monophasic pyrogenic activity of rIL-1 was destroyed at 70 degrees C, whereas rTNF alpha remained active; anti-IL-1 neutralized IL-1 but did recognize rTNF alpha or natural cachectin nor neutralize its cytotoxic effect; and unlike IL-1, rTNF alpha was not active in the mitogen-stimulated T cell proliferation assay. The possibility that endotoxin was responsible for rTNF alpha fever and/or the induction of IL-1 was ruled-out in several studies: rTNF alpha produced fever in the endotoxin-resistant C3H/HeJ mice; the IL-1-inducing property of rTNF alpha was destroyed either by heat (70 degrees C) or trypsinization, and was unaffected by polymyxin B; pyrogenic tolerance to daily injections of rTNF alpha did not occur; levels of endotoxin, as determined in the Limulus amebocyte lysate, were below the minimum rabbit pyrogen dose; and these levels of endotoxin were confirmed by gas chromatography/mass spectrometry analysis for the presence of beta-hydroxymyristic acid. Although rTNF alpha is not active in T cell proliferation assays, it may mimic IL-1 in a T cell assay, since high concentrations of rTNF alpha induced IL-1 from epithelial or macrophagic cells in the thymocyte preparations. These studies show that TNF (cachectin) is another endogenous pyrogen which, like IL-1 and IFN-alpha, directly stimulate hypothalamic PGE2 synthesis. In addition, rTNF alpha is an endogenous inducer of IL-1.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Both inflammatory and endocrine mediators stimulate host responses to sepsis.

Host responses to sepsis and trauma are complex and their mediators are not well understood. To examine the roles of "endocrine" and "inflammatory" mediators, we studied healthy volunteers in four experimental groups: continuous 72-hour infusion of normal saline; continuous 72-hour infusion of hydrocortisone, glucagon, and epinephrine; daily intramuscular injection of the inflammatory agent etiocholanolone; and combined etiocholanolone injection--hormone infusion. In this model hypermetabolism, hyperglycemia, hyper-insulinemia, insulin resistance, negative nitrogen balance, and accelerated protein flux were mediated predominantly by infusion of the counterregulatory hormones. Etiocholanolone injection resulted in fever, acute-phase--protein synthesis, and hypoferremia. Leukocyte, temperature, and C-reactive--protein responses reflected major interactions between these stimuli. Both inflammatory and endocrine mediators are necessary for the complete manifestation of host responses to critical illness.

Adult↗
PubMed1986

Hemangiopericytoma of the conjunctiva. Two cases.

Two patients with hemangiopericytoma of the conjunctiva are reported. The first patient, a 40-year-old woman with a six-month history of a conjunctival mass, presented with a lesion confined to the conjunctiva. The second patient, a 43-year-old man, presented with a one-year history of a conjunctival mass. Excisional biopsy and histopathologic examination showed both lesions to be a hemangiopericytoma; an uncommon tumor of the conjunctiva.

Adult↗
PubMed1986

Expression of biologically active human interleukin 1 subpeptides by transfected simian COS cells.

"Interleukin 1" (IL-1) is a term used to describe the family of macrophage-derived proteins that mediate many immune and inflammatory reactions. We have previously described the molecular cloning and sequencing of the cDNA encoding the predominant (neutral) form of human IL-1, which has been designated IL-1 beta. We report here that transfection of simian COS cells with this cDNA clone results in the transcription of IL-1 mRNA and the synthesis of antibody-neutralizable intracellular IL-1 biological activity. In addition, selective deletion of regions of the IL-1 cDNA judged not to be essential for function, on the basis of conserved sequence homology, resulted in localization of a "core" region responsible for a majority of the biological activity. These results permit mapping the active site of IL-1 to a peptide of 6970 molecular weight located within the carboxyl third (between Met-136 and Gln-197) of the IL-1 precursor.

Animals↗
PubMed1986

Presentation of Wegener's granulomatosis in young patients.

We have reviewed 50 cases of Wegener's granulomatosis, seen at the New England Medical Center Hospital between 1970 and 1984, and were impressed that 10 (20%) of these patients were under 25 years of age, with ages ranging from 13 to 23 years. Closer examination of this younger group revealed striking differences in their presenting symptoms and organ involvement when compared to the older group of patients. The presentation of these young patients was varied, with no single predominant symptom. Patients presented with otalgia and otitis media or hearing loss, fulminant sinusitis, arthralgias, and even corneal ulcers. Only one patient had "typical" rhinitis and nasal congestion. This group also had a disproportionate number of patients with involvement of the oral cavity, skin, and trachea. Biopsy of these sites frequently demonstrated necrotizing vasculitis. Three of our 50 patients had intracranial involvement, leading to transient hemiplegia in the first, permanent hemiplegia in the second, and a seizure disorder in the third. Two of these patients were in the younger age group. The proportion of patients with limited and generalized Wegener's granulomatosis was the same in both the younger and older age groups. All the younger patients, however, had manifestations of the disease in the head and neck, while four of the older patients had no symptoms in the upper respiratory tract. The number of young patients in our study emphasizes the fact that Wegener's granulomatosis, indeed, occurs in the younger patient and with a greater frequency than previously supposed. This study suggests that in the teenager and young adult, with an unusual constellation of symptoms of the head and neck and accompanying systemic problems, a diagnosis of Wegener's granulomatosis should be seriously considered.

Adolescent↗
PubMed1985

Malignant lymphoma and malignant angioendotheliomatosis: one disease.

A patient was diagnosed as having angioendotheliomatosis proliferans systemisata (APS) based on characteristic clinical and histologic features. A few days later, malignant lymphoma involving the gut was discovered. Immunohistochemical and electronmicroscopic studies confirmed the nonendothelial and lymphoid nature of intravascular tumor cells. This is the sixth case in which malignant lymphoma has been shown to involve the vessels of the skin (and probably of other organs) in a pattern identical to that seen in APS.

Aged↗
PubMed1985

The induction of interleukin-1 in humans and its metabolic effects.

To investigate the metabolic effects of interleukin-1 and its role as a mediator of host responses to trauma and sepsis, we injected seven healthy male subjects with etiocholanolone, an inflammatory agent that stimulates systemic responses thought to be mediated by interleukin-1. The subjects were fed a constant diet during each 4-day study and received three daily intramuscular injections of etiocholanolone, 0.10 mg/kg. Etiocholanolone injection resulted in inflammation, fever, leukocytosis, increased serum C-reactive protein, hypoferremia, and increased plasma activity of interleukin-1/lymphocyte-activating factor. Plasma concentrations of the counterregulatory hormones were normal. Protein metabolism, as reflected in nitrogen balance, 15N turnover, and forearm flux of alanine and glutamine, was unaltered. Serum glucose and insulin levels and tissue responsiveness to insulin were normal. This dissociation of acute-phase and catabolic responses may reflect the magnitude of the stimulus; higher levels of interleukin-1 may initiate catabolic responses. Alternatively, other mediators such as the counterregulatory hormones may direct the catabolic responses that occur after injury and sepsis.

Adult↗
PubMed1984

Nucleotide sequence of human monocyte interleukin 1 precursor cDNA.

Interleukin 1 (IL-1) is a protein with several biological activities regulating host defense and immune responses. We report here the isolation of human IL-1 cDNA. It encodes a precursor polypeptide of 269 amino acids (30,747 Mr). mRNA isolated by hybridization to this cDNA was translated in a reticulocyte cell-free system, yielding immunoprecipitable IL-1. Furthermore, this hybrid-selected mRNA was injected into Xenopus laevis oocytes, which subsequently secreted biologically active IL-1. The cDNA nucleotide sequence suggests that IL-1 is initially translated as a precursor molecule that is subsequently processed into the 15,000-20,000 Mr protein usually associated with IL-1 activity.

Amino Acid Sequence↗
PubMed1984

Sleep-promoting effects of endogenous pyrogen (interleukin-1).

When infused into the lateral cerebral ventricles of rabbits, human endogenous pyrogen (EP) preparations induced dose-dependent increases in slow-wave sleep concomitant with increasing body temperature. Heating EP to 70 degrees C destroyed its sleep-promoting and pyrogenic activity. Anisomycin (an antipyretic) prevented EP from increasing body temperature without affecting its sleep-promoting activity. Intravenous injection of EP induced fever and transient increases in slow-wave sleep but failed to induce prolonged increases in slow-wave sleep. We conclude that the somnogenic activity of EP is not secondary to its pyrogenic activity.

Animals↗