‘Distensibility’ of the papaverine-relaxed vascular bed in human subcutaneous tissue

The effect of an increase in vascular transmural pressure upon the blood flow in two subcutaneous vascular beds, maximally dilated by papaverine was studied in 6 healthy humans. Blood flow was measured on the dorsum of the hand and at the lateral malleolus by the local ¹³³Xe washout technique. Increase in vascular transmural pressure was induced by lowering the labelled area various distances below heart level. Lowering the area caused an increase in blood flow. The increase was less pronounced in the legs than in the hand. As arterial perfusion pressure head remained constant during lowering, this indicates that the relative decrease in vascular resistance was smaller in the leg than in the hand. Experimental edema did not influence the relative decrease in vascular resistance. The results suggest that ‘distensibility’ of the resistance vessels is smaller in the leg than in the hand. This might be due to a structural adaptation of the vascular wall in vessels often subjected to increased hydrostatic pressure.     

Interaction between blood type,smoking and factor V Leiden mutation and risk of venous thromboembolism: a Danish case‐cohort study

See also Lowe GDO. Epidemiology of venous thromboembolism: the need for large (including prospective) studies and meta‐analyses. This issue, pp 2186–8 and Rosendaal FR. Etiology of venous thrombosis: the need for small original studies. This issue, pp 2189–90.     

Gender differences in randomised,controlled trials in intensive care units

There is a male dominance among patients in intensive care units (ICUs). Potentially, this will increase the risk of a skewed male/female distribution in randomised, controlled trials (RCTs). We have evaluated if this has in fact happened when randomising and whether the authors have been aware of that. We performed a systematic search on PubMed from 1 January 2011 to 31 May 2012 using the mesh terms ‘randomized controlled trial’ and ‘intensive care unit’. Twenty‐five RCTs with a total of 12,788 patients met the inclusion criteria, with an overall male dominance of 63.6% (P < 0.0001). Eighteen of the 25 papers had an individually statistically significant gender difference in their total trial population. None of the 18 trials with a significant gender difference in their overall trial population had calculated the P‐value for this overall difference. In the randomised groups, there was a significant gender difference in five papers. Seventeen had no significant gender difference in the randomised groups, and three papers did not state gender in the randomised groups. This study show that there is a marked male dominance in RCTs conducted in ICUs. We recommend that when planning future RCTs, the authors contemplate if their results can be used indiscriminately among ICU patients if the distribution of males and females is much skewed. It is relevant to determine if ones endpoint can be influenced by gender differences and if there is a risk of gender influence on data, proportional allocation or stratification should be considered.     

Pharmacokinetics,pharmacodynamics and safety of recombinant canine FVIIa in a study dosing one haemophilia A and one haemostatically normal dog

Summary. Recombinant human FVIIa (rhFVIIa) corrects the coagulopathy in hemophilia A and B as well as FVII deficiency. This is also the case in dogs until canine anti‐human FVIIa antibodies develop (～2 weeks). Recombinant canine factor VIIa (rcFVIIa), successfully over‐expressed by gene transfer in haemophilia dogs, has provided long‐term haemostasis (>2 years). However, pharmacokinetics (PK), pharmacodynamics (PD) and safety of rcFVIIa after pharmacological administration have not been reported. We therefore wanted to explore the safety, PK and PD of rcFVIIa in dogs. A pilot study was set up to evaluate the safety as well as PK and PD of rcFVIIa after a single intravenous dose of 270 μg kg^?1 to one HA and one haemostatically normal dog and to directly compare rcFVIIa with rhFVIIa in these two dogs. Single doses of rcFVIIa and rhFVIIa were well tolerated. No adverse events were observed. Pharmacokinetic characteristics including half‐life (FVIIa activity: 1.2–1.8 h; FVIIa antigen 2.8–3.7 h) and clearance were comparable for rcFVIIa and rhFVIIa. Kaolin‐activated thromboelastography approached normal in the HA dog with the improvement being most pronounced after rcFVIIa. This study provided the first evidence that administering rcFVIIa intravenously is feasible, safe, well tolerated and efficacious in correcting the haemophilic coagulopathy in canine HA and that rcFVIIa exhibits pharmacokinetic characteristics comparable to rhFVIIa in haemophilic and haemostatically competent dogs. This strengthens the hypothesis that rcFVIIa can be administered to dogs to mimic the administration of rhFVIIa to humans.     

INTERLEUKIN-8 SECRETION AND 15-LIPOXYGENASE ACUVTTY IN RHEUMATOID ARTHRITIS: IN VITRO ANTI-INFLAMMATORY EFFECTS BY INTERLEUKIN-4 AND INTERLEUKIN-10, BUT NOT BY INTERLEUKIN-1 RECEPTOR ANTAGONIST PROTEIN

We have examined the ability of interleukin-4 (IL-4), interleukin-10(IL-10) and interleukin-1 receptor antagonist protein (IL-lra)to regulate spontaneous interleukin-8 (IL-8) production in culturedSF mononuclear cells (SFMC) from RA. Furthermore, we examinedwhether IL-4, IL-10, or IL-lra could influence the productionof the arachidonic acid products leukotriene B₄ (LTB₄), 12-hydroxy-eicosatetraenoicacid (12-HETE) and 15-hydroxy-eicosatetraenoic acid (15-HETE).IL-4 induced a maximal suppression of 75% in the IL-8 secretionin SFMC from 10.0 ng/ml down to 2.5 ng/ml after 24 h and from17.2 ng/ml to 4.2 ng/ml after 72 h of culture. IL-10 induceda 55% inhibition of the IL-8 secretion at 24 h and a 40% inhibitionat 72 h. IL-lra did not change the spontaneous IL-8 secretionfrom rheumatoid SFMC. We also examined, whether addition ofIL-4, IL-10 or IL-lra was able to modulate formation of thearachidonic acid products LTB₄,12-HETE and 15-HETE in culturedSF cells, stimulated with the calcium ionophore A23187. 15-HETEwas not detected in untreated cultures, nor in IL-10 or IL-lratreated cultures. IL-4, however, stimulated the formation ofthe anti-inflammatory mediator; 15-HETE (23 ng/10⁶ cells). Theseresults suggest that IL-4 or IL-10, could have beneficial anti-inflammatoryeffects in RA. KEY WORDS: Interleukin-4, Interleukin-10, Interleukin-1 receptor antagonist protein, 15-Hydroxy-eicosatetraenoic acid, Rheumatoid arthritis     

TARDBP mutations are not a frequent cause of ALS in Finnish patients

In previous studies 1-3 % of ALS patients have TARDBP mutations as the cause of the disease. TARDBP mutations have been reported in ALS patients in different populations but so far there are no studies on the frequency of TARDBP mutations in Finnish ALS patients. A cohort of 50 Finnish patients, 44 SALS and 6 FALS patients, were included in the study. Genomic DNA was extracted from venous blood or muscle tissue and a mutation analysis of TARDBP was performed. No definitely pathogenic mutations could be identified in TARDBP in our patient cohort. However, two previously unknown variations were found: one silent mutation in exon 2 and one relatively deep intronic single nucleotide insertion in intron 5. In addition, two previously known non-pathogenic polymorphisms in intron 5 were detected. The size of our cohort is obviously not large enough to conclusively exclude TARDBP mutations as a very rare cause of ALS in Finland. However, based on our results TARDBP mutations do not appear to be a frequent cause of familial or sporadic ALS in Finland.Key words: Amyotrophic lateral sclerosis, mutation screening, TARDBP     

Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease: reply to a rebuttal

See also Grove EL, Hvas AM, Mortensen SB, Larsen SB, Kristensen SD. Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease. J Thromb Haemost 2011; 9: 185–91; Ege MR, Zorlu A. Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease: a rebuttal. This issue, pp 888.     

Histamine-releasing serum factors as a predictor of the outcome of insect sting reactions. Results from a multicentre study*

Cord blood cells were incubated (passively sensitized) with sera from 27 patients with previous systemic reactions to insect stings. Histamine release (HR) from these cells was measured following exposure to venom extracts at increasing concentrations. The aim was to see whether this parameter could predict more efficiently than RAST and skin test the outcome of a subsequent re-sting. Results showed that HR from passively sensitized cells tended to reflect skin sensitivity and specific IgE levels. If patients were not re-stung during the follow-up period, HR from the passively sensitized cells frequently decreased whereas an increase was seen (in 6/13) when using sera collected after re-sting. In conclusion HR from passively sensitized cord blood cells could not satisfactorily predict re-sting reactions in the serum donors.