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.     

Skeletal Muscle Adaptations to Physical Training in Type II (Non-insulin-dependent) Diabetes Mellitus

Seven middle-aged men with manifest type II diabetes mellitus underwent an endurance training programme for 10–15 weeks. The maximal aerobic capacity, as well as the endurance capacity, was improved by 10% (p<0.05). The intramuscular glycogen store increased by more than 80% (p<0.05) from 350 μmol/g dw (dry weight), and the activities of citrate synthase and 3-hydroxy-acyl-CoA dehydrogenase increased by more than 50% (p<0.05) and 30% (p<0.05). The activity of glycogen synthase was decreased by approximately 20% (p<0.05), whereas lactate dehydrogenase remained unchanged. Capillaries/fibre and fibre area increased by more than 50% (p<0.05) and 30% (p<0.05) leaving the area of supply constant. Training did not influence fasting blood lipids and glucose, glycosylated hemoglobin, oral glucose tolerance, and insulin response to an oral glucose load measured 72 hours post-exercise. It is concluded that patients with manifest type II diabetes, as normoglycaemic individuals, adapt to physical training. However, no persistent effect on glucohomeostasis and lipaemia is produced by short-term training in the diabetic patients.     

A Decrease in Pulmonary Vein Diameter After Radiofrequency Ablation Predicts the Development of Severe Stenosis

A decrease in ostial pulmonary vein (PV) diameter was observed in patients on the day after radiofrequency ablation of atrial fibrillation (AF). This study examined whether a relative reduction in PV diameter on day 1 (RRPVD1) after the procedure predicts the late development of severe PV stenosis (PVS). The study included 104 consecutive patients (mean age = 55 years, range 46–61, 34 women) with drug refractory AF. Pulmonary vein diameter was measured using MR angiography (MRA) on the day before and on day 1 after the ablation procedure. The MRA was repeated every 3 months after the procedure. Severe PVS was defined as a >70% diameter reduction from the initial ostial diameter. The cut-off of RRPVD1 was prespecified as 25% decrease in initial diameter. The data are presented as medians and interquartile range. A total of 357 PV were treated. The RRPVD1 was 0.0% (0.0–11.1%). Severe PVS was found in 18 PV during a follow-up of 12 months (range 6–13). The log-rank analysis confirmed a strong association between a RRPVD1 ≥25% and the development of PVS (hazard ratio: 7.1; 95% confidence interval 3.8–13.5, P < 0.0001). By multivariate Cox regression model, after adjustment of procedure variables, RRPVD1 was the strongest predictor of development of severe PVS. RRPVD1 ≥25% was a strong independent predictor of development of severe PVS.     

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.     

Deleterious effect of exogenous angiotensin-I on the extent of regional ischaemia and its inhibition by captopril

The endogenous activity of the local renin-angiotensin system(RAS) and the anti-ischaemic properties of captopril were investigatedin electrically driven rabbit Langendorff hearts (constant pressure:70 cmH₂O, Tyrode solution, Ca²⁺ 1.8 mmol.l^–1). Cumulativeconcentration-response curves showed no significant difference(P>0.05) between the reduction of the global coronary flow(CF) by exogenous angiotensin-I or angiotensin-II (EC₅₀ = 10^–10mol.l^–1). It is concluded that the local RAS in isolatedrabbit hearts is highly sensitive, whereas its endogenous activityis very low due to very low endogenous angiotensin-I content.Myocardial ischaemia (MI) was induced by the occlusion of aleft coronary artery branch and MI was quantified from NADHsurface fluorescence photography. MI was significantly enlarged(+35%) (P <0.05) by exogenous angiotensin-I (6x10^–9mol.l^–1). The reduction in CF and the increment in MIby angiotensin-I could be completely prevented by adding captoprilat a low concentration (10^–6 mol.l^–1) to the perfusionbuffer. In the absence of exogenous angiotensin-I, captoprilalone (10^–6 mol.l^–1) neither significantly enhancedCF (P >0.05), nor diminished MI (P >0.05), supportingthe finding of very low endogenous activity of tile local RASin this model. We, moreover, conclude that at a low concentration(10^–6 mol.l^–1) captopril does not possess directcardioprotective properties independent of its ACE inhibitingaction.     

Pharmacokinetic evaluation of ipamorelin and other peptidyl growth hormone secretagogues with emphasis on nasal absorption

1. The pharmacokinetics of three new peptidyl growth hormone secretagogues, ipamorelin (NNC 26-0161), NNC 26-0194 and NNC 26-0235, were compared with two well-known hexapeptides, GHRP-2 and GHRP-6, in the male rat following different routes of administration. 2. Following i.v. bolus injection, plasma concentrations of the peptides declined biexponentially. Ipamorelin differed markedly from the other peptides investigated, demonstrating a systemic plasma clearance 5-fold lower than that of GHRP-6. Ipamorelin was mainly excreted in the urine, whereas GHRP-6 was predominantly excreted in the bile. NNC 26-0194 and NNC 26-0235 also showed high biliary excretions. Ipamorelin and the two NNC peptides were moderately resistant towards metabolism as 60-80% of the administered dose could be recovered from bile and urine as intact peptide. 3. After intranasal application, the bioavailability of ipamorelin was estimated at ～ 20%. Higher bioavailabilities of ～ 50% were determined for NNC 26-0235, NNC 26- 0194 and GHRP-2, whereas the nasal absorption of GHRP-6 was somewhat lower. Thus, the peptides could be easily transported across the nasal epithelium suggesting that the nasal route seems promising for systemic delivery of this family of peptidyl growth hormone secretagogues.     

When to suspect and how to diagnose pulmonary lymphangioleiomyomatosis

Abstract The objective of this study was to present clinical and radiological data of eight women with histologically proven lymphangioleiomyomatosis (LAM) diagnosed between 1984 and 1994, and to suggest a diagnostic strategy when LAM is suspected. A review of case reports, including results of biopsies, lung function and radiological procedures was undertaken. The mean age of the women at start of symptoms was 36 years, and the mean age at time of diagnosis 42 years. The most frequent presenting complaint was dyspnea, either in conjunction with pneumothorax (3), chylothorax (2) or on exertion (2). All patients had airflow limitation and markedly reduced gas transfer. Five patients had 16 episodes of pneumothorax. In seven patients multiple cysts were observed on the surface of the lung during thoracotomy while computerized tomography (CT) scans revealed numerous cysts evenly distributed throughout the lung parenchyma. The procedures that confirmed the diagnosis included transbronchial lung biopsy (4), open lung biopsy (2), thoracoscopy (1), thoracotomy (3) and autopsy (1). Three specimens had to be revised before the histological diagnosis was confirmed. It was concluded that the important clues to a diagnosis of LAM are recurrent episodes of pneumothoraces in fertile women, progressive air-flow limitation, markedly reduced gas transfer and characteristic findings on thoracic CT scans. A specific request to the pathologist to stain lung tissue specimens for smooth muscle cells is mandatory.