Codeine-induced histamine release in intact human skin monitored by skin microdialysis technique: comparison ofintradermal injections with an atraumatic intraprobe drug delivery system

Background The skin microdiallysis technique makes it possible to measure histamine release in intact human skin in vivo directly. In this study we have used the microdialysis technique to characterize histamine release by codeine after intracutaneous injectioin and following skin challenge by a novel atraumatic delivery technique. Objective The purpose of the study was to compare histamine release in human skin by codeine. delivered by an intraprobe drug delivery system (IPD) and intracutaneous injections (ICT), with respect to dose-response relations, kinetics of histamine appearance and decay, corelations between histamine release and skin respones, and reproducibility. Methods Hollow dialysis fibres were inserted intradermally in 12 healthy subjects. Twelve fibres were inserted in each subjects, six fibres in each arm. Each fibre was perfused at a rate of 3 μL/min, and samples were collected in 2 min fractions. By the IPD technique, codeine was administrered to the skin by adding codeine to the perfusion medium. Sequential IPD challenges were performed in one arm. and ICTs were done on the other arm. Results Sixfold serial dilutions of codeine (0.01-3 mg/mL) caused a significant doserelated histamine release by ICT and IPD. Peak histamine release was found within the first 4 min after skin challenge by ICT and IPD, followed by a fast decline with a dialysate histamine half life of approximately 2-3 min. Peak hisamine release was linearly correlates with cumulative release of the 20 min sampling period, and histamine release correlated with weal soze. The coefficient of variation on peak histamine releae was 18.9% and 4.8% for codeine ICT and IPD, respectively. Conclusioin We have described in detail codeine-induced histamine release in intact human skin in vivo by the microdialysis technique. It was possible to administer codeine atraumaticallyl to the skin by intraprobe delivery. The skin microdialysis codeine atraumaticallly to the skin by intraprobe delivery. The skin microdialysis technique opens up possibilities for measurement of infllammatory mediators release in normal and diseases skin, and it will be possible to deliver immunopharmacologically active drugsto the skin by intraprobe delivery.     

Hereditary angio-oedema: new clinical observations and autoimmune screening, complement and kallikrein-kinin analyses

Objectives. To study clinical and laboratory manifestations of hereditary angio-oedema (HAE).
Subjects. Thirty-three affected members of a kindred of 63.
Results. Oedematous attacks in the skin, mucous membranes and gastrointestinal tract with fluid displacement were elicited by mental and physical stress, minor traumas, dental and surgical procedures, eruption of teeth, tonsillitis, pregnancies, and use of oestrogen-containing pills including menopausal substitution. Every adult woman with symptomatic HAE ( n =11) showed symptoms of urinary tract infections in conjunction with the attacks ( P = 0.010), and also experienced more spontaneous abortions or premature labours ( P =0.037) than healthy relatives. Patients with HAE of both sexes more frequently reported heartburn or peptic ulcers ( P =0.002). Rheumatic complaints were reported by 53% of HAE patients and 12% of their unaffected relatives ( P =0.013), but biochemical screening for 18 autoantibodies and quantitation of immunoglobulins did not reveal statistically significant differences between the two groups. C3, prekallikrein, total kininogen, high molecular weight kininogen (HK), alpha-2-macroglobulin and factor XII were not significantly different in HAE patients. In contrast, levels of C1-INH and C4 were depressed and cleaved HK increased in patients compared to unaffected relatives.
Conclusions. HAE manifests in a variety of ways, and may influence risk of spontaneous abortions and premature labour.     

Activation of the Complement, Coagulation, Fibrinolytic and Kallikrein–Kinin Systems During Attacks of Hereditary Angioedema

Five patients with hereditary angioedema (HAE) were studied during attacks and remission as were healthy controls. The high levels of C1/C1-INH complexes, low C4 and high ratio C4 activation products (C4bc)/C4 also differed significantly during remission compared to controls.During attacks C4bc/C4 increased (922–2007; P =0.022, remission versus attacks, median values throughout), C2 and CH50 dropped (111–31%; P =0.043 and 110–36%; P =0.016, respectively), TCC (C5b-9) increased (0.88–1.23 AU/ml; P =0.028). Cleavage of HK increased to be almost complete during attacks (20–90%; P =0.009). While factor XIa/serpin-complexes did not increase, a more than twofold rise in thrombin/antithrombin-complexes (0.20–0.50 μg/l; P =0.009) and in plasmin/alpha-2-antiplasmin-complexes (7.3–17 nmol/l; P =0.028) was observed. For the first time cascade activation in HAE was studied simultaneously, and corroborates that attacks lead to activation of the kallikrein-kinin system, fibrinolysis and early part of the classical complement pathway. In addition, the authors present novel data of terminal complement and coagulation activation, the latter apparently not via FXIa.     

CD4+CD25+ regulatory T cells: I. Phenotype and physiology

The immune system protects us against foreign pathogens. However, if fine discrimination between self and non-self is not carried out properly, immunological attacks against self may be launched leading to autoimmune diseases, estimated to afflict up to 5% of the population. During the last decade it has become increasingly clear that regulatory CD4⁺CD25⁺ T cells (T_reg cells) play an important role in the maintenance of immunological self-tolerance, and that this cell subset exerts its function by suppressing the proliferation or function of autoreactive T cells. Based on human and murine observations, this review presents a characterization of the phenotype and functions of the Treg cells in vitro and in vivo . An overview of the surface molecules associated with and the cytokines produced by the Treg cells is given and the origin, activation requirements and mode of action of the Treg cells are discussed. Finally, we address the possibility that Treg cells may play a central role in immune homeostasis, regulating not only autoimmune responses, but also immune responses toward foreign antigens.     

Reproducibility of responsiveness to a standardized bronchial allergen provocation—Rt compared to FEV1 as measurement of response to provocation

Standardized bronchial allergen provocation was performed twice in nineteen extrinsic, well defined, stable asthmatic patients, with an interval of median 15 days (range 14–19) to study the reproducibility of the bronchial response. Smoking and medications were withheld prior to the provocation after a rigid scheme. Ten-fold increasing concentrations of allergen solution 0.9 ml were inhaled by tidal volume breathing for 5 min with intervals of 10 min. The bronchial response to inhaled allergen was determined by forced expiratory volume in the first sec (FEV₁) and by total resistance to breathing (R_t) determined by an opening interrupter method. The provocation was continued until an allergen concentration causing at least 20% decrease of the postsaline FEV₁ or a 40% increase in R_t was reached. A PC₂₀-FEV₁ and a PC₄₀-R_t was calculated by interpolation on the log-dose-response curve. The reproducibility of PC₂₀-FEV₁ allergen was high with a 95% confidence interval (CI) for a single determination being the observed value ±0.83, ten-fold concentration difference, the intraclass correlation (IC) was 0.99 and the coefficient of variation 8.46%. Concerning PC₄₀-R_t a 95% CI for a single determination was calculated being the observed value ±0.58, ten-fold concentration difference, IC was 0.99 and the coefficient of variation was 5.79%. No significant correlation was found between differences in pre-challenge FEV₁ and R_t values and the corresponding PC₂₀-FEV₁ and PC₄₀-R_t values. Least square regression between PC₂₀-FEV₁ and PC₄₀-R₁ was performed for the first and the second provocation (P < 0.05). We conclude that bronchial allergen challenge performed in stable asthmatics is highly reproducible and as such a valuable test in the diagnosis of allergic asthma when connected with anamnesis, skin-prick test and the level of specific immunoglobulin E in peripheral blood.     

Effects of dynamic leg exercise on subcutaneous blood flow rate in the lower limb of man

Subcutaneous blood flow (SBF) was studied simultaneously in the upper arm at heart level and in the lower limb during positional changes and during leg exercise in seven healthy males. SBF was estimated by local clearance of ‘“Xenon registered by portable cadmium telluride detectors. Venous pressure was recorded directly on dorsum on the foot. Changinr the position from supine to head-up tilt, SBF decreased by 43 % (P < 0.01) at the arm level, 40% at the thigh (P < 0.01), 47% at the calf (P < 0.01) and decreased by 51 % at the ankle level (P < 0.01). Performing 20 heel-raisings per min in nearly erect posture, SBF increased by 96% at the thigh (P < 0.01), 25% at the calf (P > 0.1) and increased by 18% at the ankle level (P > 0.1). At 40 heel-raisings per min SBF increased by 99% at the thigh (P < 0.0 1), 121 % at the calf (P < 0.0 1), but only 44% at the ankle level (P > 0.1). During leg exercise subcutaneous vascular resistance was significantly increased at arm and ankle levels. In contrast, a vasodilatory response was noticed at the thigh and calf levels and seemed associated with a decrease in local venous pressure to below the trigger level of the sympathetic veno-arteriolar reflex mechanism. In conclusion, SBF in the lower limb of man was increased during exercise. The increase in SBF could only partly be ascribed to the concomitant increase in perfusion pressure. The local blood flow response seemed modified by changes in sympathetic nervous activity and metabolic rate.     

Toxicokinetics of Nickel in Mice Studied with the {gamma}-Emitting Isotope 57Ni

The -emitting isotope ⁵⁷Ni was generated in a cyclotron to allowwhole-body counting of laboratory animals dosed with nickel.⁵⁷NiCl₂ was administered either orally by gastric intubationor by intraperitoneal injection to groups of mice in doses equivalentto the average human daily dietary nickel intake per mass unit.When given orally, the whole-body retention (WBR) was 0.02–0.36%of the administered dose at 45–75 hr. When given intraperitoneally,the WBR was 1–6% at 20–50 hr. After adjustment forthe rapid excretion of systemic nickel, the intestinal absorptioncould be estimated to be 1.7–10%. The relative WBR didnot vary with the magnitude of the dose within 0.05–5µmol Ni/kg given orally or 0.005–0.5 µmol/kggiven intraperitoneally. At 8 hr, the tissue concentration washighest in the kidneys, followed by the carcass, lungs, testicles,liver, and the spleen. After 20 hr, the highest concentrationswere still found in the kidneys followed by the lungs, the liver,and the carcass. At 20 hr after oral administration, 50–70%of ⁵⁷Ni retained in the body was within the carcass. The secondhighest nickel content was found in the kidneys, followed bythe liver and lungs. Whereas nickel in the kidneys was rapidlyexcreted, the elimination from the lungs and liver was relativelyslow, thereby, after 40 hr, resulting in a higher nickel contentin the liver than that in the kidneys. When nickel was givenintraperitoneally, practically no nickel was transported viathe portal vein to the liver after 20 hr, resulting in a lownickel content in the liver and a higher content in the kidney.These results document that the use of ⁵⁷Ni for studies on nickeltoxicokinetics is feasible and useful, and that the method isespecially well suited for comparative studies with a durationof up to 6 days.     

Residual myocardial ischaemia in first non-Q versus Q wave infarction: maximal exercise testing and ambulatory ST-segment monitoring

In a prospective study of 123 consecutive survivors of a firstmyocardial infarction (43 non-Q wave, 80 Q wave), we determinedthe total residual ischaemic burden by use of pre-dischargemaximal exercise testing and post-discharge 36 h ambulatoryST-segment monitoring initiated 11 ± 5 days after theinfarction. The prevalence of exercise-induced ischae-mic manifestations in the infarct types was similar: chest pain 14%vs 16% and ST-segment depression 54% vs 54%. The ischaemic thresholddid not differ either (heart rate at 1 mm of ST-segmnent depression120 ± 27 vs 119 ± 25 beats. min^–1). Duringearly post-discharge daily activities, more patients with non-Qwave infarction demonstrated transient episodes of ST-segmentdepression: 28% vs 14% (ns). Furthermore, ischaemic episodeswere significantly longer (42.5±50.1 vs 22.0 ±20.6 min; p <0.001), and the ischaemic threshold was significantlylower in non-Q wave infarction (heart rate at onset of ST-segmentdepression 84±11 vs 88±9 beats.min^–1; p<0.05). During 3.5±0.9 years of follow-up the proportionof patients with 1 ischaemic event (non-fatal reinfarction,angina pectoris, revascularization) was significantly higherin non-Q wave infarction (51%) as compared to Q wave infarction(31%) (P<005). In both infarct types the presence of ST-segmentdepression on ambulatory recording and exercise testing significantlypredicted the development of future angina pectoris, whereaspatients at increased risk for subsequent non-fatal reinfarctionor cardiac death were not identified.