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Biomedical subjects

H J Fuchs

Publications and source records attributed to H J Fuchs.

At least 37 records · Page 2Linked to original sources
PubMed1990

Immunomodulatory and toxic effects of free and liposome-encapsulated tumor necrosis factor alpha in rats.

Tumor necrosis factor alpha has potent immunomodulatory and antitumor activity, but its therapeutic applications may be limited by its significant host toxicity. We showed that liposome-encapsulated recombinant human tumor necrosis factor alpha (rHuTNF-alpha) retained full anticellular activity in vitro. We then assessed the immunomodulatory and toxic effects of two different doses of i.v. free or liposome-encapsulated rHuTNF-alpha in normal rats. Both free and liposome-encapsulated rHuTNF-alpha significantly enhanced alveolar macrophage- and blood monocyte-mediated interleukin 1 release and tumor cell lysis, as well as natural killer cell cytotoxicity, when compared to buffer-treated controls. However, administration of rHuTNF-alpha in liposomes substantially reduced tumor necrosis factor alpha-mediated toxicity. Animals receiving liposome-encapsulated rHuTNF-alpha showed significantly less tissue injury, gastric retention, and circulating leukocyte shifts than animals receiving free rHuTNF-alpha. In addition, liposome-based delivery significantly increased lung and liver uptake of rHuTNF-alpha. Therefore, liposome-encapsulated rHuTNF-alpha retains immunomodulatory activity, significantly reduces toxic inflammatory effects, and may allow targeting of tumor necrosis factor alpha to selected organs after i.v. administration.

Adjuvants, Immunologic↗
PubMed1989

Interferon-gamma increases alveolar macrophage Ia antigen expression despite oral administration of dexamethasone to rats.

Corticosteroids have multiple effects on immune and inflammatory responses and decrease host resistance to a broad range of microorganisms. Resident tissue macrophages have been proposed as a target for the immunosuppressive effects of corticosteroids and are important in host defense against infections. During infection-induced immune responses, macrophages are activated after exposure to interferon-gamma (IFN-gamma), and class II major histocompatibility (Ia) antigens on their surface are increased. We investigated the effect of orally administered corticosteroids on alveolar macrophages, the resident macrophages of the lung parenchyma. We hypothesized that corticosteroids would inhibit the activation of alveolar macrophages and measured induction by IFN-gamma of Ia antigens as a marker of cell activation. Alveolar macrophages from normal and corticosteroid-treated rats were exposed to recombinant murine IFN-gamma (rMuIFN-gamma) in vitro and assayed for Ia transcription and surface Ia expression. Ia mRNA accumulation was induced in alveolar macrophages from normal and corticosteroid-treated rats after exposure in vitro to rMuIFN-gamma. Furthermore, rMuIFN-gamma increased surface expression of Ia proteins on alveolar macrophages from corticosteroid-treated rats, although to a lesser extent than on cells from control rats. Finally, surface Ia expression could also be increased in vivo by exposure of corticosteroid-treated rats to an aerosol containing rMuIFN-gamma. These results demonstrate that administration of oral corticosteroids, while establishing a state of immunosuppression in rats, does not abolish responsiveness of rat alveolar macrophages to rMuIFN-gamma. We speculate that IFN-gamma-induced augmentation of phagocytic cell function may constitute an important therapeutic modality to treat complications of immunodeficiency.

Administration, Oral↗
PubMed1988

Lung-specific delivery of cytokines induces sustained pulmonary and systemic immunomodulation in rats.

The recombinant cytokines IFN-gamma and TNF-alpha stimulate several macrophage-mediated functions important in host defense. However, systemic administration of cytokines may be limited by significant host toxicity. We investigated whether aerosolized cytokines can stimulate alveolar macrophage and blood monocyte function, and whether they induce an inflammatory response in the lungs of normal rats. We found that aerosolized murine rIFN-gamma or recombinant human TNF-alpha increased IL-1 production by both alveolar macrophages and blood monocytes for at least 5 days after administration. Furthermore, murine rIFN-gamma increased the expression of Ia Ag on alveolar macrophages and human rTNF-alpha increased alveolar macrophage- and blood monocyte-mediated tumor lysis. Sequential aerosolization of IFN-gamma and TNF-alpha significantly increased both IL-1 release and Ia expression compared to either cytokine administered alone. Aerosolized human rTNF-alpha achieved lung levels comparable to those produced by an i.v. TNF-alpha dose reported to cause diffuse organ injury and death in rats. However, plasma TNF-alpha levels were several thousand-fold lower after aerosol administration. Aerosolized cytokines did not induce lung edema or an inflammatory cell infiltrate within the airways or alveoli. Aerosolized human rTNF-alpha alone, or murine rIFN-gamma and human rTNF-alpha, induced margination of leukocytes in pulmonary blood vessels 1 day after aerosolization, and a few small foci of pulmonary hemorrhage 5 days later. We conclude that aerosol administration of IFN-gamma or TNF-alpha enhances both pulmonary and systemic monocyte function, and that the combination of IFN-gamma and TNF-alpha produce additive or synergistic effects. Aerosolized cytokines induce only a minimal pulmonary inflammatory response. Aerosolized TNF-alpha produces high cytokine levels in the lung but very low uptake into the circulation.

Adjuvants, Immunologic↗
PubMed1988

Cellular influx and activation increase macrophage cytotoxicity and interleukin-1 elaboration during pulmonary inflammation in rats.

This study was undertaken to investigate the effects of pulmonary inflammation induced by bacillus Calmette-Guérin (BCG) on the density distribution of lavaged alveolar macrophages. We sought to determine macrophage cytotoxicity and interleukin-1 elaboration in density-defined subpopulations of macrophages during tissue inflammation. At all time points after intravenously administered BCG, lavaged alveolar macrophages contained increased percentages of higher density cells. Alveolar macrophage cytotoxicity against the rat sarcoma cell line XC increased maximally 2 to 6 days after intravenous administration of BCG before declining on Day 13. Macrophage interleukin-1 elaboration increased maximally 14 days after administration of BCG before declining on Day 23. Additionally, macrophage cytotoxicity and interleukin-1 elaboration were increased above normal in cells from each of five density fractions. We conclude that a subpopulation of higher density macrophages, probably recently derived from blood monocytes, accumulates in inflammatory sites. Cellular activation increases the cytotoxicity and interleukin-1 elaboration by macrophages in all density-defined subpopulations and obscures the relationship between cellular density and function that is present in normal animals.

Animals↗
PubMed1988

Use of allophycocyanin allows quantitative description by flow cytometry of alveolar macrophage surface antigens present in low numbers of cells.

Autofluorescence has limited quantitative description by flow cytometry of certain alveolar macrophage surface antigens. Autofluorescence is most significant when macrophages are excited by blue light and emission is monitored in the green-yellow light range. Because of recent advances in flow cytometry and in the development of fluorescent labeling compounds, such as allophycocyanin, autofluorescence can be minimized by the use of red excitation and emission wavelengths. We have developed a three-step labeling technique that discretely identifies the minor subpopulation of normal rat alveolar macrophages that express Class II major histocompatibility (Ia) antigens. Using this technique, we observed that alveolar macrophage Ia antigen expression increases at least fourfold after intravenous administration of bacillus Calmette-Guerin to previously primed rats. Additionally, we observed that in vitro treatment of alveolar macrophages by exposure to gamma interferon results in an increase in Ia antigen expression. This new method is significant because flow cytometry is a powerful tool with which to analyze quickly, accurately, and reproducibly alveolar macrophage surface antigens.

Animals↗
PubMed1983

Affinity inactivation of bovine Cu,Zn superoxide dismutase by hydroperoxide anion, HO2-.

Bovine liver Cu,Zn superoxide dismutase (SOD) is inactivated by hydrogen peroxide at alkaline pH, and full inactivation correlates with the loss of 1.1 histidine/subunit. At each pH utilized, saturation of the rate of inactivation is observed. This process is characterized by a half-saturation constant for peroxide and a maximum pseudo-first-order rate constant for inactivation. At 25 degrees C, the former decreases from 15.7 to 3.2 mM as the pH is increased from 9.0 to 11.5, while the latter increases from 0.83 to 2.43 per min over the same pH range. We have previously (Arch. Biochem. Biophys. 224, 579 (1983] proposed that the true affinity reagent for the inactivation of yeast SOD is the hydroperoxide anion, and we now believe the same is true for bovine SOD. However, a subtle difference between the two enzymes exists, for while the maximum pseudo-first-order rate constant for inactivation of bovine SOD increases with increasing pH, the same parameter for the yeast enzyme is pH-independent.

Animals↗
PubMed1983

[Comparative circulatory studies during implantation of total endoprostheses using methylmethacrylate and BDF cement].

In every ten patients undergoing elective surgery for total hip prosthesis methylmethacrylate and BDF cement respectively were used for the implantation of the prosthesis. The results of the haemodynamic investigation demonstrate that improvement of the surgical procedure may reduce the incidence of haemodynamic parameters: After implantation of methylmethacrylate into the femoral shaft the arterial pressure decreased from 95.9 +/- 13 to 86 +/- 11 torr (P less than 0.05); the left ventricular stroke work index dropped from 49.9 +/- 5 to 42.1 +/- 7 g.m/m2 (P less than 0.01). While total peripheral resistance decreased slightly in the methylmethacrylate group, there was a small increase after implantation of BDF cement into the femoral shaft. In both groups, however we found a slight elevation of pulmonary vascular resistance after cement implantation into the femur. The determination of the serum concentration of the cement monomer did not yield any measurable serum concentrations. Heat production by polymerisation of BDF cement (maximum 45.8 +/- 6.5 Centigrade) was much less compared with the temperature which developed during the polymerisation of methylmethacrylate (maximum 63 +/- 16.4 Centigrade); therefore, the safety of clinical application seems to be greater with the new BDF cement.

Aged↗
PubMed1980

[Effect of metoprolol on the circulation after head trauma. Studies during continuous intravenous administration (author's transl)].

The influence of continuous intravenous administration of metoprolol on heart rate and haemodynamics was tested in ten unconscious patients who, after sustaining a head injury, developed sinus tachycardia due to increased sympathicotonia. In preliminary studies on three patients the effective dosage for heart rate reduction was determined. Following this, seven patients received 0.15 mg/kg . h of metoprolol over 36 hours. Heart rate decreased from an average of 127.5 to 78.8/min, a statistically significant reduction. Stroke volume index significantly rose from an average of 35.5 to 52.3 ml/m2, while other haemodynamic variables were not or only slightly changed. Cardiac index fell (not significantly) from 4.51 to 3.81/min . m2, peripheral vascular resistance rose (not significantly) form 942.4 to 1061.7 dyn . s . cm-5. Arterial and pulmonary artery pressures as well as filling pressures of right and left ventricle and left ventricular work index were not altered. Total oxygen consumption and oxygen extraction rate also remained unchanged. Measurement of metoprolol plasma levels in four patients excluded the possibility of a cumulative effect.

Adult↗
PubMed1980

[Haemodynamic measurements during controlled hypotension by nitroglycerin (author's transl)].

In nine patients undergoing neurosurgical operation for cerebral aneuryms haemodynamic measurements were made before, during and after continuous intravenous administration of Nitroglycerin at a mean dose of 6.5 micrograms/kg . min. Within 15 min of the start of the infusion mean arterial pressure fell from 94.2 +/- 10.5 to 73.4 +/- 11.1 mm Hg. A further decrease of mean arterial pressure even by a substantial raising of the Nitroglycerin dose was not possible. 15 min after the discontinuation of Nitroglycerin administration mean arterial pressure rose to the preinfusion level. The decrease of stroke volume index from 40.8 +/- 9.9 to 31.0 +/- 7.3 ml/m2 was partially compensated by an increase of heart rate from 65.9 +/- 9.6 to 77.7 +/- 19.4 beats/min. Consequently cardiac index fell only slightly from 2.9 +/- 0.6 to 2.5 +/- 0.5 ml/min . m2. The right atrial pressure decreased to 3.3 +/- 2.9 mm Hg, the mean pulmonary arterial pressure to 6.3 +/- 1.9 mm Hg and the pulmonary capillary wedge pressure to 2.3 +/- 2.1 mm Hg. The significant fall of total peripheral resistance to 983 +/- 194 dyn x s/cm5 (p less than 0.05) and the decrease of left ventricular stroke work index to 34.7 +/- 11.5 g . m/m2 contributed to reduce myocardial oxygen consumption. The authors conclude that, because of its effect on blood pressure, it reversibility of action and its absence of adverse side effects Nitroglycerin is a valuable agent for controlled hypotension.

Adult↗
PubMed1977

[Percutaneous puncture of the femoral vein for haemodialysis: report of 5000 punctures (author's transl)].

Using the Seldinger technique, a total of 5306 percutaneous femoral vein catheterisations were performed in the course of ten years. Two-catheter venovenous dialysis was performed 2357 times and single-needle technique 592 times. There were five important complications: severe retroperitoneal bleeding after perforation of the external iliac vein three times, fatal bleeding from the femoral artery once, and reversible damage to the femoral nerve once. The results indicate that for every 1000 percutaneous femoral-vein catheterisations one must expect one severe complication. However, by using the correct catheter technique, especially careful manipulation of the wire, complications can be largely avoided.

Adult↗
PubMed1976

[Multiple myeloma and terminal acute myeloid leukaemia (author's transl)].

A patient with multiple myeloma died of an acute myeloid leukaemia 15 years after onset of the former. At time of diagnosis the 39 year-old-patient had bone marrow infiltration of maximally 32 plasma cells/100 white bone marrow cells, a paraprotein (IgG, light-chain type lambda), osteoporosis of late onset and occasional osteolysis. The long survival time, as well as the acute myeloid leukaemia, are probably due to the effective treatment, first with cyclophosphamide (198 g over four years), later melphalan (3000 mg over eight years).

Cyclophosphamide↗
PubMed1976

[Thyroid hormones and thyrotropin in liver and kidney insufficiency].

In 22 patients with hepatic or renal insufficiency the serum concentrations of trijodothyronin, thyroxine and thyrotropin and also the T4-binding capacity of TBG were determined. The mean serum T3 concentration was found to be significantly lower in patients with hepatic coma when compared with euthyroid subjects. In the cases of renal insufficiency the serum T3 concentrations were in the normal range. Due to hormone loss through dialysis however, the mean value of the T3 concentrations was slightly lower than the average concentration of normal subjects. The obtained results agree with those of our earlier studies which showed that there are significant differences between liver artery and vein T3 concentrations in serum, whereas no such differences could be ascertained between serum concentrations in renal artery and vein. On the basis of these findings it is assumed that conversion of T4 into T3 occurs predominantly in the liver.

Hepatic Encephalopathy↗
PubMed1975

[Primary malignant nephrosclerosis (author's transl)].

Primary malignant nephrosclerosis shows a haemolytic-uraemic symptomatology and can be differentiated from secondary malignant nephrosclerosis on clinical and histological grounds. The disease was observed in 4 patients: a 25-year-old man and 3 women aged 19, 28 and 49 years. The disease is characterized by a fulminating course, malignant hypertension with progressive retinopathy, and development of progressive renal failure with subsequent irreversible anuria. In addition haemolytic anaemia or posthaemolytic states as well as consumption coagulopathy occur. In 2 cases schizozytes and in particular helmet-shaped forms could be demonstrated. On histology an obliterating necrotizing vascular change is seen which is limited to the kidneys as was demonstrated in one case by angiography. Therapeutic attempts included antibiotics, steroids, heparin, streptokinase, antihypertensive drugs, and haemodialysis. The 3 female patients died, the man survived after bilateral nephrectomy.

Acute Disease↗