‘Just 17 if you know what I mean’ … but what do we really mean to say about Th17 immunity?

Th17-derived IL-17 might be considered the archetypal pro-inflammatory cytokine of adaptive immunity, to be targeted by new therapeutics for alleviation of autoimmune and inflammatory disease. However, the IL-17 family of cytokines is produced by diverse innate and adaptive cells, including Th17, Tc17, ILC3, NK cells and γδ T-cells. These responses are appreciated to underpin diverse aspects of protective, physiological immunity, from dialogue with the gut microbiota to bacterial and fungal immunity in the lung.     

The immune regulatory role of neutrophils

Neutrophils are appreciated to perform a wide range of pro- and anti-inflammatory effector functions in diverse settings. These go far beyond the response to acute infection, encompassing sterile injury, autoimmunity, allergy and tumours. There is growing appreciation of the nuances of their modes of action, especially elucidation of the nature and consequences of NETosis. New work suggests that it is time to give greater consideration to the anti-inflammatory role of neutrophils, such as in the control of cytokine release during sepsis.     

Hemorrhagic tumor necrosis during a pilot trial of tumor necrosis factor-alpha and anti-GD3 ganglioside monoclonal antibody in patients with metastatic melanoma

Hemorrhagic tumor necrosis is an inflammatory event that leads to selective destruction of malignant tissues, with both potentially toxic and beneficial consequences. A pilot clinical trial was undertaken combining tumor necrosis factor-alpha (TNF-alpha) with the monoclonal antibody R24 (MoAb R24) against GD3 ganglioside in patients with metastatic melanoma. Patients received MoAb R24 to recruit leukocytes to the tumor followed by low doses of recombinant TNF-alpha to activate leukocytes. Eight patients were treated and seven patients had mild toxicity. One patient with extensive metastatic melanoma developed tumor lysis syndrome within hours after treatment with almost complete necrosis of bulky tumors in multiple visceral sites. To our knowledge, this is the first documented case of hemorrhagic tumor necrosis in a patient with metastatic cancer in multiple visceral sites.     

Paternal effects on offspring fitness in a multimale primate society

When females mate with multiple males, paternal care is generally expected to be negligible, because it may be difficult or impossible for males to discriminate their own offspring from those of other males, and because engaging in paternal care may reduce male mating opportunities. Consequently, males in multimale societies are not predicted to provide direct benefits to their offspring. We have recently demonstrated, however, that males in a typical multimale primate society (yellow baboons, Papio cynocephalus) discriminate their own offspring from those of other males and provide care to them in the form of repeated support during agonistic encounters. This observation raises the question of whether fathers enhance offspring fitness in this species. Here we use 30 years of data on age at maturity for 118 yellow baboons with known fathers. We show that the father's presence in the offspring's social group during the offspring's immature period accelerated the timing of physiological maturation in daughters. Sons also experienced accelerated maturation if their father was present during their immature period, but only if the father was high ranking at the time of their birth. Because age at reproductive maturity has a large impact on lifetime reproductive success, our results indicate a direct effect of paternal presence on offspring fitness. This relationship in turn suggests that the multiple roles that males play in multimale animal societies have not been sufficiently examined or appreciated and that paternal effects may be more pervasive than previously appreciated.     

Amidolytic assay of human factor XI in plasma: comparison with a coagulant assay and a new rapid radioimmunoassay

The traditional coagulant assay for plasma factor XI suffers from a relatively high coefficient of variation, the need for rare congenitally deficient plasma, and a poor correlation between precision and sensitivity. We have developed a simple functional amidolytic assay for factor XI in plasma using the chromogenic substrate PyrGlu-Pro-Arg- p-nitroanilide (S-2366). After inactivation of alpha 1-antitrypsin, CI inhibitor, and other plasma protease inhibitors with CHCI3, plasma was incubated with kaolin, in the absence of added calcium, which limited the enzymes formed to those dependent on contact activation. Soybean trypsin inhibitor was used to minimize the action of kallikrein on the substrate. Once the reaction was complete, corn trypsin inhibitor was used to inactive factor XIIa, the enzyme generated by exposure of plasma to negatively charged surfaces, which had activated the factor XI. The assay is highly specific for factor XI, since plasma totally deficient in that zymogen yielded only 1%-3% of the enzymatic activity in normal plasma under identical conditions. The requirements for complete conversion of factor XI to XIa in plasma within 60 min were, respectively, factor XII, 0.6 U/ml, and high molecular weight kininogen, 0.2 U/ml. Prekallikrein was not an absolute requirement for complete activation but did accelerate the reaction. The intraassay coefficient of variation was 3.4%, and the mean of 35 normal plasmas was 1.00 U +/- 0.24 SD. In addition, a new rapid radioimmunoassay was devised using staphylococcal protein A as the precipitating agent for a complex of factor XI antigen with monospecific rabbit antibody. The mean was 1.01 U +/- 0.30 SD. The correlation coefficients for amidolytic versus coagulant and amidolytic versus radioimmunoassay were r = 0.95 for the former and 0.96 for the latter. Thus, a simple, accurate amidolytic assay and a radioimmunoassay have been devised for measuring factor XI in plasma that correlate well with the coagulant activity of factor XI, as determined in our laboratory.     

DRG-based cost analysis of inpatient conservative treatment of stage III/IV peripheral arterial occlusive disease

DRG-based cost analysis of inpatient conservative treatment of PAD stage III/IV BACKGROUND: In a prospective study carried out by the German Society of Angiology and the DRG Competence Center, Munich, the question was investigated whether the costs of conservative treatment of patients with PAOD stage III/IV (DRG F65) are adequately represented within the current G-DRG system. METHODS UND PATIENTS: Between September 1 and December 16, 2002, a total of 704 patients with DRG F65 (peripheral vascular diseases) were evaluated at 8 angiologic centers in Germany. Apart from the length of hospital stay, the total costs (cost equivalents) were calculated using a method developed by the DRG Research Group at the University of Münster. Moreover, the study population was compared with a German calculation sample for the DRGs F65A/B, as published by InEK. RESULTS: As it turned out, conservatively treated patients with PAOD stage III or IV (DRGs F65A/B) cause significantly (p < 0.001) higher costs and have significantly (p < 0.001) greater lengths of hospital stay than patients who were also assigned to DRG F65 because of other vascular diseases. At the same time it became clear that angiologic centers treat twice as many patients with critical limb ischemia in comparison with the German average. The reimbursement hitherto estimated by InEK covers not even half the cost actually produced by conservative treatment of PAD stage III/IV. CONCLUSION: To ensure a performance-related reimbursement, a new basis DRG for patients with PAD stage III/IV has to be created, as has ben proposed by the German Society of Angiology. Otherwise, adequate conservative therapy in accordance with existing guidelines, of patients who cannot be treated surgically or interventionally will not be possible any more in the future.     

Influence of tissue affinity of angiotensin-converting enzyme inhibitors on left ventricular remodeling after myocardial infarction

Background: The demonstration of local renin-angiotension systems has raised the question of whether angiotensinconverting enzyme (ACE) inhibitors with different tissue affinities differ with regard to their effects on postinfarction remodeling. Hypothesis: The study was undertaken to investigate the influence of ACE inhibitors with different tissue affinity on morphology and function of the infarcted left ventricle. Methods: In all, 52 patients (17 women, 35 men, 38-73 years) with large acute myocardial infarction were randomized to receive either 25-75 mg/day captopril or 10-20 mg/day fosinopril beginning on the Day 7 after infarction. Of these, 28 had anterior and 24 had posterior wall infarctions. Infarct size was determined by the creatine kinase integral method. Fifty patients were examined by cinemagnetic resonance imaging (CMRI) 1 and 26 weeks after infarction. The following parameters were determined: left ventricular enddiastolic and end-systolic volume index (LVEDVI, LVESVI), ejection fraction (LVEF), infarct weight, and muscle mass (LVMM). The volume-to-mass ratio (VMR) was calculated and the clinical status according to the guidelines of the New York Heart Association (NYHA) was documented at each examination time. The results were compared with those of a historical sample without ACE-inhibitor therapy examined in an identical manner (n = 31, 10 women, 21 men, 36-75 years). Results: LVEDVI and LVESVI increased in the first 6 months after infarction by 24.9 and 36.6%, respectively, in the historical sample; by 11.0 and 7.8%, respectively, under captopril; and by 13.1 and 10.7%, respectively, under fosinopril. LVEF decreased by 14.9% in the untreated sample, by 3.7% under captopril and by 5.0% under fosinopril. Infarct weight and LVMM increased by 12.7 and 15.3%, respectively, without ACE inhibition, by 5.7 and 10.1%, respectively, in patients treated with captopril, and by 6.1 and 9.3%, respectively, in patients treated with fosinopril. The VMR increased by 7.4% in the historical sample, by 3.5% in the captopril group, and by 1.8% in the fosinopril group. The NYHA clinical status improved by 18.2% without ACE inhibition, by 42.9% in the captopril group, and by 26.3% in the fosinopril group. The differences between the two ACE-inhibitor groups and the reference group were all significant, while the differences between the captopril group and the fosinopril group were significant only for VMR (p<0.01) and NYHA class (p < 0.05). Conclusions: Both captopril and fosinopril have a comparable positive influence on postinfarction remodeling and on clinical status. Lipophilicity and tissue affinity do not seem to play a clinically important role in ACE-inhibitor therapy after infarction.