Saccharic acid 1.4-lactone protects against CPT-11-induced mucosa damage in rats

Purpose To evaluate the ability of D-saccharic acid 1.4-lactone (SAL), a -glucuronidase inhibitor, to prevent irinotecan hydrochloride (CPT-11) from inducing mucosal damage as a cause of diarrhea in rats.Methods Wistar rats were divided into six groups of three animals each, administered 1.0 ml isotonic solution intraperitoneally once daily for up to three consecutive days, respectively for up to six days. The series were as follows: (1) On days 1–3: saline; (2). On days 1–3: 200 mg CPT-11/m²; (3) On days –3 to –1 relative to the first administration of CPT-11: 10 mg/ml SAL; on days 1–3: 200 mg CPT-11/m²; (4) On days –3 to +3 relative to the first administration of CPT-11: 10 mg/ml SAL, and on days 1–3: additional 200 mg CPT-11/m²; (5) On days 1–3: 200 mg CPT-11/m² (0.5 ml) + 10 mg/0.5 ml SAL; (6) On days –3 to –1 relative to the first administration of CPT-11: 3 mg/ml SAL, and on days 1–3: 200 mg CPT-11/m². Luminal mucosa damage of the small intestine was detected by histology 24 h after the last intraperitoneal application. Peptidase activities of the proximal jejunum were measured by using an in situ perfusion model.Results Following intraperitoneal CPT-11 treatment, using conventional histology of paraffin sections, we observed severe mucosal damage. This was reflected by a decrease of the villi/crypt ratio, an increase of apoptotic cells, as well as an increase of mitotic figures in the crypt region. There was a concomitant increased lymphatic infiltration in mucosa of CPT-11 treated rats. This damage pattern could be clearly reduced by co-treatment with the -glucuronidase inhibitor, SAL, independent of the treatment schedule. In contrast to our expectations based on previous reports, the intraperitoneal application of CPT-11 alone or in combination with SAL did not cause significant differences in luminal enzyme liberation in comparison with controls in the in situ perfusion assay.Conclusions The -glucuronidase inhibitor SAL is able to significantly reduce CPT-11-induced mucosal damage in the small intestine of rats. This observation might soon have a clinical impact for the treatment of patients with CPT-11.     

How conflicted authors undermine the World Health Organization (WHO) campaign to stop all use of asbestos: spotlight on studies showing that chrysotile is carcinogenic and facilitates other non-cancer asbestos-related diseases

The silicate mineral asbestos is categorized into two main groups based on fiber structure: serpentine asbestos (chrysotile) and amphibole asbestos (crocidolite, amosite, anthophyllite, tremolite, and actinolite). Chrysotile is used in more than 2 000 applications and is especially prevalent in the construction industry. Although its use is banned or restricted in more than 52 countries, an estimated 107 000 workers die from asbestos exposure each year, and approximately 125 million workers continue to be exposed. Furthermore, ambient exposures persist to which the public is exposed, globally. Today, the primary controversies regarding the use of asbestos are the potencies of different types of asbestos, as opposed whether or not asbestos causes morbidity and mortality. The asbestos industry has promoted and funded research based on selected literature, ignoring both clinical and scientific knowledge. In this piece, we highlight a prominent example of a conflicted publication that sought to undermine the World Health Organization (WHO) campaign to stop the use of all forms of asbestos, including chrysotile asbestos. Independent and rigorous scientific data provide sufficient evidence that chrysotile asbestos, like other forms of asbestos, is a cause of asbestos-related morbidity and premature mortality     

Akuttherapie lebensbedrohlicher tachykarder Rhythmusstörungen

Life-threatening supraventricular tachyarrhythmias include atrial fibrillation, atrial flutter, AV-nodal reentrant tachycardia with rapid ventricular response and preexcitation syndromes combined with atrial fibrillation. Ventricular tachyarrhythmias still remain one of the leading causes of death; these arrhythmias include monomorphic and polymorphic ventricular tachycardia, torsade de pointes tachycardia, ventricular fibrillation and ventricular flutter. In all patients with tachycardias, an attempt should be made to differentiate between narrow (QRS duration < 0.12 s) or wide QRS complex (QRS duration ≥ 0.12 s) tachycardias. In the assessment of patients (pts) with supraventricular/ventricular tachyarrhythmias, attention should be given to identify whether the tachycardia is associated with worsening angina or low cardiac output. In pts with narrow QRS complex tachycardias or pts with atrial fibrillation and preexcitation syndromes immediate synchronized cardioversion should be performed if signs or symptoms of instability (hypotension, evidence of end-organ dysfunction, worsening angina) exist. In pts with a stable hemodynamic situation, vagal maneuvers, adenosine or calcium channel blockers can be used. Management of atrial flutter usually centers on cardioversion or rapid atrial pacing to normal sinus rhythm. In the treatment of patients with deemed unstable ventricular tachycardia (VT), electrical cardioversion is the treatment of choice. In more stable patients, ajmaline is the preferred agent after myocardial infarction and lidocaine if myocardial ischemia is present. In pts with torsade de pointes tachycardias aggressive steps must be taken to prevent degeneration of this rhythm to ventricular fibrillation (VF). Magnesium sulfate has recently been demonstrated efficacious and is currently considered first-line drug therapy. Transcutaneous overdrive pacing should be attempted if magnesium is unsuccessful. The pt with pulseless VT or VF demands early electrical countershock.     

Analysis of lymphocyte subsets in patients with aplastic anemia before and during immunosuppressive therapy

Summary To define the contribution of T-lymphocyte subsets in the development of aplastic anemia (AA), T-cell subpopulations including T cells, T cells, and TCS1-positive T cells, were analyzed by cytophotometry in the peripheral blood (PB) and bone marrow (BM) of patients with AA before and after 6 weeks of therapy with anti-lymphocyte globulin (ALG), methylprednisolone, and cyclosporin A (CSA). In nine patients with AA a significant decrease of PB- and BM-derived T cells was observed after 6 weeks of therapy as compared with normal controls. At diagnosis, the CD4/CD8 ratio in PB and BM of the patients did not differ from the ratio in the control population; however, a reversed ratio (< 1) was present in PB as well as in BM after weeks of therapy. Interestingly, lymphocytes expressing the T-cell receptor (TCR) were significantly decreased both before (PB 1.2±0.1%; BM 0.8±0.1%) and after 6 weeks of therapy (PB 0.7±0.1%; BM 0.7±0.1%) as compared with healthy controls (PB 2.4±0.2%; BM 2.3±0.2%). However, the proportion of the -T-cell subpopulation expressing the TCS1 phenotype was markedly increased before (PB 42±3.5%; BM 31±3%) and especially after 42 days of therapy (PB 77±12%; BM 45±2%) as compared with that in normal subjects (PB 19±2%; BM 9.7±0.8%). At present, follow-up is under evaluation to correlate these findings with hematological response. The pathophysiological significance of the observed alterations within the T-cell subsets and especially the T-cell populations will require further functional analyses, in particular since TCS1-positive T cells exhibit autoimmunological capacity.Presented at the annual meeting of the German Society for Hematology and Oncology, 4–7 October 1992, Berlin     

Neutrophil Extracellular Trap-Related Extracellular Histones Cause Vascular Necrosis in Severe GN

Severe GN involves local neutrophil extracellular trap (NET) formation. We hypothesized a local cytotoxic effect of NET-related histone release in necrotizing GN. In vitro, histones from calf thymus or histones released by neutrophils undergoing NETosis killed glomerular endothelial cells, podocytes, and parietal epithelial cells in a dose-dependent manner. Histone-neutralizing agents such as antihistone IgG, activated protein C, or heparin prevented this effect. Histone toxicity on glomeruli ex vivo was Toll-like receptor 2/4 dependent, and lack of TLR2/4 attenuated histone-induced renal thrombotic microangiopathy and glomerular necrosis in mice. Anti–glomerular basement membrane GN involved NET formation and vascular necrosis, whereas blocking NET formation by peptidylarginine inhibition or preemptive anti-histone IgG injection significantly reduced all aspects of GN (i.e., vascular necrosis, podocyte loss, albuminuria, cytokine induction, recruitment or activation of glomerular leukocytes, and glomerular crescent formation). To evaluate histones as a therapeutic target, mice with established GN were treated with three different histone-neutralizing agents. Anti-histone IgG, recombinant activated protein C, and heparin were equally effective in abrogating severe GN, whereas combination therapy had no additive effects. Together, these results indicate that NET-related histone release during GN elicits cytotoxic and immunostimulatory effects. Furthermore, neutralizing extracellular histones is still therapeutic when initiated in established GN.     

Influence of different trigger techniques on twitch mouth pressure during bilateral anterior magnetic phrenic nerve stimulation

BACKGROUND: The trigger has a key role when assessing the twitch mouth pressure (Tw Pmo), since a "gentle" inspiratory or expiratory effort is needed for triggering to ensure an open glottis during twitch, but which also guarantees only very mild changes of transdiaphragmatic pressure following changes in lung volume. STUDY OBJECTIVES: To test if different trigger mechanisms cause different Tw Pmo values, if the predefined trigger criteria were accomplished, and if the breathing maneuver during triggering can influence the Tw Pmo. DESIGN: Experimental study. SETTING: Respiratory muscle and lung function laboratory of a university hospital. PARTICIPANTS: Twenty healthy men (mean age, 25.6 +/- 1.2 years [+/- SD]; mean FEV(1), 105.9 +/- 11.5% of predicted). MEASUREMENTS: Tw Pmo produced by bilateral anterior magnetic phrenic nerve stimulation was measured using an inspiratory flow trigger (40 mL/s), an inspiratory pressure trigger, and an expiratory pressure trigger (3.75 mm Hg). All trigger criteria were controlled. RESULTS: Unusable pressure-time curves occurred in 40% during expiratory triggering, but not during inspiratory triggering. For inspiratory pressure (flow) triggering, 10% (30%) of the predefined trigger criteria were exceeded by 50%, indicating that a "gentle" inspiratory effort was not warranted. The Tw Pmo was higher during inspiratory compared to expiratory triggering (analysis of variance, p < 0.05). The Tw Pmo during inspiratory pressure and flow triggering were comparable and significantly correlated (r = 0.70, p < 0.0001). The time between start of inspiration and trigger release, and the pressure-time product during that period ranged widely, but this could not predict the Tw Pmo (multiple linear regression). CONCLUSIONS: The trigger technique influences the Tw Pmo with higher values during inspiratory compared to expiratory triggering. Expiratory triggering more often produced unusable pressure-time curves. Inspiratory flow and pressure triggering is comparably useful in healthy subjects, but this might be different in patients. The trigger criteria need to be controlled to warrant a gentle breathing effort.     

Using Vascular Closure Devices Following Out-Of-Hospital Cardiac Arrest?

Objectives and Background: Despite a generally broad use of vascular closure devices (VCDs), it remains unclear whether they can also be used in victims from out-of-hospital cardiac arrest (OHCA) treated with mild therapeutic hypothermia (MTH).Methods: All victims from OHCA who received immediate coronary angiography after OHCA between January 1^st 2008 and December 31^st 2013 were included in this study. The operator decided to either use a VCD (Angio-Seal™) or manual compression for femoral artery puncture. The decision to induce MTH was based on the clinical circumstances.Results: 76 patients were included in this study, 46 (60.5%) men and 30 (39.5%) women with a mean age of 64.2 ± 12.8 years. VCDs were used in 26 patients (34.2%), and 48 patients (63.2%) were treated with MTH. While there were significantly more overall vascular complications in the group of patients treated with MTH (12.5% versus 0.0%; p=0.05), vascular complications were similar between patients with VCD or manual compression, regardless of whether or not they were treated with MTH.Conclusion: In our study, the overall rate of vascular complications related to coronary angiography was higher in patients treated with mild therapeutic hypothermia, but was not affected by the application of a vascular closure device. Therefore, our data suggest that the use of VCDs in victims from OHCA might be feasible and safe in patients treated with MTH as well, at least if the decision to use them is individually carefully determined.