An inhibition enzyme immunoassay for estimating relative antibody affinity and affinity heterogeneity

A method to measure the relative affinity of antibodies using an inhibition enzyme immunoassay is described. It is validated using monoclonal antibodies of defined affinity characteristics and by comparison with conventional methods of affinity measurement. The method allows measurement of the relative affinity of low levels of antibody, and the calculation of an empirical estimate of the heterogeneity of affinity in antibody populations.     

Detection of penicillin tolerance in streptococci.

"Tolerance" to penicillin in streptococci was investigated by two different techniques. Of 70 strains examined, 35 appeared tolerant in conventional titrations and 31 appeared tolerant when tested by a recently-described disc method. There was 88% agreement between the two methods, but the disc test failed to detect tolerance shown by titrations in six strains of streptococci, including three beta-haemolytic strains belonging to Lancefield's group D. A significant relationship was observed between tolerance and Eagle's optimum dosage effect: 71% of tolerant strains examined displayed the Eagle effect, whereas only 17% of non-tolerant strains exhibited the effect.     

Aortocaval fistula: CT appearance with angiographic correlation

As CT is often the initial imaging method in the evaluation of suspected complications of abdominal aortic aneurysm, especially rupture of the aneurysm, it is important to be aware of other less common complications that can be detected by CT. A patient with an aortocaval fistula and renal venous hypertension is discussed. The constellation of CT findings that suggest this diagnosis is described as is the angiographic correlation. Awareness of these CT findings, including early equivalent enhancement of the inferior vena cava and aorta; enlarged, poorly functioning kidney; and perirenal "cobwebs," will lead to the appropriate confirmatory angiographic studies.     

Occurrence of circulating 7-deoxyaglycone metabolites of 4′-deoxydoxorubicin in man

Summary In five cancer patients we have determined the pharmacokinetics of 4-deoxydoxorubicin (4-DOX), its alcoholic metabolite 4-deoxydoxorubicinol and the occurrence of circulating 7-deoxyaglycone metabolites. The 7-deoxyaglycone of the alcohol metabolite, the major aglycone of Adriamycin (ADR) present in man, was not detected in any serum sample. The 7-deoxyaglycone of the parent drug, which appears in concentrations in excess of 30ng/ml after ADR administration, was detected in only 2/5 patients in trace amounts. These preliminary data indicate a difference in biotransformation between ADR and 4-DOX despite their close structural similarities.     

Routine preoperative biliary drainage: effect on management of obstructive jaundice

Dens fractures are frequently difficult to identify radiographically, particularly when it is only possible to obtain a lateral radiograph of the upper cervical spine. Further, when a dens fracture is identified in lateral projection, it is often difficult to distinguish the "high" (Type II) from the "low" (Type III) fracture. The authors describe an elongated "ring" density superimposed upon the body of the axis in the lateral cervical radiograph which, when horizontally disrupted, indicates a dens fracture and is a specific radiographic sign of the "low" variety.     

Bystander CD8 T-cell-mediated demyelination is interferon-gamma-dependent in a coronavirus model of multiple sclerosis

Mice infected with the coronavirus mouse hepatitis virus, strain JHM (JHM) develop a disease that shares many histological characteristics with multiple sclerosis. We previously demonstrated that JHM-infected mice that only have CD8 T cells specific for an epitope not in the virus develop demyelination on specific activation of these cells. Herein we show that this process of bystander T-cell-mediated demyelination is interferon-gamma (IFN-gamma)-dependent. The absence of IFN-gamma abrogated demyelination but did not change T-cell infiltration or expression levels of inflammatory cytokines or chemokines in the spinal cord. These results are consistent with models in which IFN-gamma contributes to CD8 T-cell-mediated demyelination by activation of macrophages/microglia, the final effector cells in the disease process.     

Radioisotopic pulmonary lobectomy: feasibility study in dogs

In search for an alternate treatment for inoperable cancer of the lung in humans, we investigated the possibility that introduction of radioactive material into a selected lobe of the canine lung would effectively destroy that lobe without systemic effects or radiation injury to adjacent organs. Ten million ion exchange microspheres labeled with 740 MBq of phosphorus-32 (32P) were injected through a catheter placed in a selected lobar branch of a pulmonary artery in 12 anesthetized dogs. Six additional dogs served as controls and received 10 million microspheres not labeled with 32P. Organs were harvested from 1 wk to 12 mo after injection and examined grossly and histologically. There was progressive organization and contraction of each necrosed 32P treated lobe which was reduced to a scarred remnant by 12 mo, whereas only minimal inflammatory changes occurred in controls. Of the 32P injected dose, 94% remained in injected lobe, 4%-5% in nontargeted lobes and less than 0.08% in blood. Radioactivity in liver, kidneys, spleen, heart, and bone marrow was less than 0.1% for each organ. Thus, large doses of radiation in the order of 1,500 Gy can be effectively delivered to a selected lobe to produce a "radioisotopic pulmonary lobectomy."     

Phase I clinical study of LL-D49194α1 with retrospective pharmacokinetic investigations in mice and humans

Summary LL-D491941 is a new cytotoxic antibiotic selected for clinical phase I study because of its impressive pre-clinical anti-tumour activity and its low toxicity profile in experimental animals. A total of 15 patients were treated in centres in Glasgow and Amsterdam at doses ranging from 0.25 to 4 mg/m². One minor response was noted in a patient with colonic carcinoma. The study was suspended following the discovery of unexpected cardiotoxicity. As this toxicity was not consistent with the standard (EORTC) European Organisation for Research and Treatment of Cancer toxicology profile, we chose to investigate the pharmacokinetics of LL-D491941 in mice and humans in more detail to try to explain this phenomenon. A major difference in plasma protein binding was discovered between mice and patients, with a suggestion of non-linear kinetics being noted at higher doses in humans. It is likely that these differences in drug handling account for the unexpected and serious toxicity encountered in this trial.     

Modulation of immunoglobulin production and cytokine mRNA expression in peripheral blood mononuclear cells by intravenous immunoglobulin

Intravenous immunoglobulin (IVIG) has the potential to regulate Ig production, but the mechanism(s) responsible for this effect is unknown. In experiments reported here, we examined the ability of IVIG to regulate Ig production in human peripheral blood mononuclear cells (PBMCs) stimulated with pokeweed mitogen (PWM). IVIG (2–10 mg/ml) showed a potent (80–85%) inhibition of PWM-stimulated IgG, IgM, and IgA production. To determine more precisely how IVIG mediated the inhibition of Ig production, we studied Ig promoting cytokine gene expression after PWM stimulation with or without IVIG (2 and 10 mg/ml) using dot-blot techniques. RNA was isolated from PBMCs at predetermined time points and probed with cDNAs specific for human cytokines (IL-1-, IL-2, IL-2R, IL-4, IL-5, IL-6, -IFN, and TNF-). IL-6 mRNA accumulation was maximal at 4.5 hr post-PWM stimulation and was inhibited 64–75% when IVIG (10 mg/ml) was present. -IFN mRNA levels peaked at 72 hr poststimulation and were also 68–75% inhibited by IVIG. IL-2 mRNA levels peaked at 4.5 hr and were 23–46% inhibited by IVIG. The inhibitory effect of IVIG on production of these cytokines (IL-6 and -IFN) was also observed at the protein level in sonicated PBMCs after incubation with PWM and IVIG. The mRNA levels for other cytokines were not or only minimally inhibited by IVIG. Addition of IL-6, -IFN, or IL-2 partially restored Ig production in IVIG-treated PWM-stimulated cultures, suggesting that inhibition of other cytokines or another mechanism(s) independent of cytokine inhibition might also be involved, although inhibition of IL-6, -IFN, and IL-2 may be one of the critical factors in the suppression of Ig production by IVIG.