Biomedical subjects
Publications and source records attributed to M J Schultz.
Ingestion of thalidomide was associated with a reduction in the upregulation of the granulocyte activation marker CD11b and a reduced capacity to release elastase and lactoferrin after stimulation with lipopolysaccharide or lipoteichoic acid. A single oral dose of thalidomide attenuates neutrophil activation upon ex vivo stimulation with bacterial antigens.
Interferon (IFN-)gamma is thought to play a role in the resistance to various pathogens. To study the role of IFN-gamma in the pathogenesis of Pseudomonas pneumonia, IFN-gamma receptor (R) alpha-subunit-deficient [IFN-gammaR(-/-)] mice and wild type mice were intranasally inoculated with Pseudomonas aeruginosa (10(5) CFU). IFN-gammaR(-/-) mice demonstrated an enhanced clearance of P. aeruginosa from their lungs when compared to normal wild type mice (P < 0.05 at 24 hours after the infection), which was associated with a tendency towards an improved survival. These findings were not accompanied by a more effective activation of several components of the innate immune system known to contribute to host defense against pneumonia, i.e. the lung concentrations of cytokines and chemokines were similar in IFN-gammaR(-/-) and wild type mice, while the influx of neutrophils in bronchoalveolar lavage fluid (BALF) was even higher in wild type mice than in IFN-gammaR(-/-) mice. Remarkably, IFN-gammaR(-/-) mice had higher nitric oxide levels in the BALF at 24 hours after infection (P < 0.05). Endogenous IFN-gamma impairs rather than augments host defense during pneumonia caused by P. aeruginosa.
Monocytes from patients with sepsis have a reduced capacity to produce cytokines, a state referred to as immunoparalysis. To determine whether polymorphonuclear leukocytes (PMNL) can be rendered hyporesponsive, PMNL from 6 healthy volunteers intravenously challenged with lipopolysaccharide (LPS; 4 ng/kg) were stimulated ex vivo with heat-killed bacteria or LPS, and the release of the CXC chemokines interleukin-8, epithelial-derived neutrophil attractant-78, and growth-related oncogen-alpha was measured. At 1 and 2 h after LPS administration in vivo, PMNL produced fewer CXC chemokines after stimulation with bacteria or LPS (all P<.05). Serum obtained 2 h after in vivo administration of LPS did not influence chemokine production by PMNL from 6 healthy volunteers not previously exposed to LPS. Thus, intravenous injection of LPS induces a refractory state of PMNL that is not caused by soluble factors produced in response to in vivo exposure to LPS.
Macrolides may influence the inflammatory response to an infection by mechanisms that are unrelated to their antimicrobial effect. Indeed, erythromycin and other macrolides inhibit cytokine production and induce degranulation of neutrophils in vitro. CXC chemokines are small chemotactic cytokines that specifically influence neutrophil functions. To determine the effect of a clinically relevant dose of erythromycin on the production of CXC chemokines and neutrophil degranulation, six healthy humans received a 30 min iv infusion of erythromycin (1000 mg). Whole blood obtained before and at various times after the infusion was stimulated ex vivo with heat-killed Streptococcus pneumoniae. Ex vivo production of the CXC chemokines interleukin 8 (IL-8) and epithelial cell-derived neutrophil attractant 78 (ENA-78), in whole blood obtained after erythromycin infusion, was lower than that in blood drawn before erythromycin infusion (maximum inhibition post-infusion: 32.9 +/- 6.5% and 35.2 +/- 12.6% decrease in production, respectively, expressed as percentage change relative to production before infusion of erythromycin, both P < 0.05). In contrast, infusion of erythromycin was associated with an enhanced capacity of whole blood to release the neutrophil degranulation products bactericidal/permeability increasing protein (BPI), human neutrophil elastase (HNE) and human lactoferrin (HLF) upon stimulation with S. pneumoniae. Effects of erythromycin were greatest 4 h after infusion was stopped, when BPI, HNE and HLF concentrations were increased by +107.6 +/- 33.5%, +134.7 +/- 34.8% and +205.9 +/- 55.9 %, respectively (expressed as percentage change relative to production before infusion of erythromycin) (all P < 0. 05). These results indicate the ability of erythromycin to reduce CXC chemokine production and to enhance neutrophil degranulation in human blood.
To determine the effect of Pseudomonas aeruginosa exotoxin A (P-ExA) on cytokine production, we studied cytokine release induced by heat-killed P. aeruginosa (HKPA) in human whole blood in the presence or absence of P-ExA. P-ExA (0.01-1 microgram ml(-1)) caused a dose-dependent decrease in HKPA-induced production of tumor necrosis factor alpha (TNF), interleukin (IL-) 10, IL-6 and IL-8 (all P<0.05). P-ExA-induced inhibition of IL-10, IL-6 and IL-8 release was not dependent on reduced TNF concentrations, since the relative attenuation of the production of these cytokines was similar in the presence or absence of a neutralizing anti-TNF antibody. The effect of P-ExA on cytokine production may offer a disadvantage to the host with respect to clearance of the infection.
To determine the effects of penicillin and erythromycin on cytokine production induced by heat-killed Streptococcus pneumoniae (HKSP), we studied the effects of those drugs on cytokine production induced by S. pneumoniae in human whole blood in vitro and ex vivo. In whole blood in vitro, erythromycin, but not penicillin, caused a dose-dependent decrease in HKSP-induced production of tumor necrosis factor alpha (TNF) and interleukin 6 (IL-6), while the production of IL-10, IL-12, and gamma interferon was inhibited only at the highest erythromycin concentration tested (10(-3) M). The production of TNF and IL-6 in whole blood obtained from healthy subjects after a 30-min infusion of erythromycin (1,000 mg) was lower after ex vivo stimulation with HKSP than that in blood drawn before the infusion. Inhibition of TNF contributed to erythromycin-induced inhibition of IL-6 synthesis. Inhibition of TNF and IL-6 production by erythromycin may have a negative impact on host defense mechanisms during pneumococcal pneumonia.
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Cholera is a disease rarely imported in the Netherlands. Recently a 34-year-old woman who had returned from a trip through Thailand was admitted to our hospital with complaints of vomiting, watery stools and moderate dehydration. Vibrio cholerae OI serotype Ogawa biotype El Tor was isolated from the faeces. She recovered after antimicrobial and fluid therapy. Her 29-year-old travelling companion had only mild symptoms of diarrhoea, but the bacterium was isolated from her stool also. Cholera should be considered in travellers with vomiting and diarrhoea coming back from Thailand.
The recently developed artemisinin derivative arteether was administered by intramuscular injection to healthy male subjects in a single dose (n = 23) and a multiple dose study (n = 27). The drug was well tolerated. Clinical, neurological, electrocardiographic and biochemical monitoring did not reveal significant toxicity. Apart from some increase in eosinophil numbers, no haematological abnormality was seen. Preliminary pharmacokinetic data showed a long elimination half life of 25-72 h and marked accumulation in the multiple dose study.
Transcutaneous PCO2 studies were performed in 21 healthy preterm infants and in 12 preterm infants with respiratory problems, in order: I. to evaluate the feasibility of transcutaneous PCO2 measurements in the clinical situation; 2. to collect normal values for preterm infants, and 3. to compare transcutaneous tcPCO2 values with PCO2 measured in capillary or arterial blood samples. Normal tcPCO2, measured in 21 healthy preterm infants, mean gestational age 32.5 +/- 2.3 weeks (range 26 6/7-36 1/7, mean birth weight 1547 +/- 498 gram (range 820-2840), postnatal age 2.2 +/- 2.1 days (range 0-6) was 41.2 +/- 5.5 mm Hg. The relation between transcutaneous PCO2 and PCO2 in arterial or capillary blood samples was studied in 12 patients with respiratory problems, 7 boys and 5 girls, mean gestational age 31 4/7, birth weight 1600 gram (range 885-3050). We found a good linear relation between tcPCO2 and arterial PaCO2 (regression coëfficient between 0.66 and 0.96) and a bad correlation between tcPCO2 and capillary PCO2 (regression coefficient 0.14-0.89). We conclude that tcPCO2 measurement is reliable and feasible for clinical use and is more reliable than PCO2 measurement in capillary blood.
Present therapy for Hodgkin's disease which primarily affects young patients may produce long term remissions in more than 50% of cases. Potential injuries to the reproductive system from radiation or chemotherapy are significant considerations in therapeutic planning. Assessment of the effects of infradiaphragmatic radiation on germ cells may avoid ovarian ablation in women of reproductive age. This report addresses ovarian function and fertility following lateral oophoropexy and repositioning for Hodgkin's disease.
Eighteen patients with small cell carcinoma of the lung treated with doxorubicin hydrochloride and hexamethylmelamine are presented. Fifteen of these patients had extensive disease at presentation. Four patients in this group died after one or fewer courses of chemotherapy. The median duration of survival for the entire group of patients is 15 months. Six patients are alive from 18 to 56 months without evidence of disease. Drug toxicity was minimal and well tolerated, which permitted this regimen to be given in an outpatient setting.
In an elderly nursing home resident who had taken excessive dosages of bulk laxative for many years, small-bowel obstruction developed, requiring surgical intervention. A carcinoma of the ascending colon probably was the immediate cause of the obstruction, which resulted in the accumulation and inspissation of the bulk laxative throughout the small bowel. Great care should be exercised in the long-term use of these laxatives.
Sixty-five patients with malignant brain tumors were treated with a combination of BCNU (100 mg/m2 qd X 1) and procarbazine (100 mg/m2 qd X 14); the cycle was repeated in 1 month and then on a 6-week schedule with procarbazine being given for 21 days. Forty-five patients had malignant gliomas (glioblastoma multiforme, anaplastic astrocytoma, malignant glioma, or gemistocytic astrocytoma) and were evaluated as a group. All patients had either shown evidence of tumor regrowth after previous surgery and/or radiotherapy, or had deep unbiopsied tumors presumed to be malignant gliomas. Of these 45 patients, 13 of 45 (30%) were judged to be unequivocal responders and an additional eight of 45 (17%) were designated as probable responders. The median duration of clinical response was 34 weeks for responders and 20 weeks for probable responders. The combination of BCNU and procarbazine, therefore, was somewhat inferior to a previous combination of procarbazine, CCNU, and vincristine.
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