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.     

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.     

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.     

Detection of Nocturnal Hypoglycemia in Insulin-treated Diabetics by a Skin Temperature - Skin Conductance Meter

ABSTRACT The efficacy and credibility of a skin temperature - skin conductance meter (Teledyne Sleep Sentry) for detecting hypoglycemia was studied during night-time in 22 adult insulin-treated diabetics. Capillary blood glucose concentration was measured 99 times (when the alarm sounded, in case of hypoglycemic symptoms, and at 3 a.m.). Hypoglycemia was defined as a capillary blood glucose concentration of ≤3 mmol/l. Blood glucose was measured 61 times in connection with sounding of the alarm and 38 times without the alarm sounding. At 3 a.m. the Sleep Sentry sounded the alarm 22 times, of which hypoglycemia was present 6 times giving a diagnostical specificity or diagnostical true positive rate of 0.27 (95 % confidence limits 0.11–0.50). In 35 of 38 cases of no alarm the blood glucose was >3 mmol/l, giving a diagnostical sensitivity of 0.92 (95 % confidence limits 0.79–0.98). The Sleep Sentry sounded the alarm in 6 of 9 cases of hypoglycemia, giving a nosological sensitivity of 0.67 (95 % confidence limits 0.30–0.93). The Sleep Sentry did not sound the alarm in 35 of 51 cases of non-hypoglycemia, giving a nosological specificity of 0.69 (95 % confidence limits 0.54–0.81). In other words, the Sleep Sentry detects about 2/3 of blood glucose values ≤3 mmol/l, but in addition it sounds a false alarm in 2/3 of the cases.     

Low-dose Cytosine Arabinoside Therapy in a Patient with Myelofibrosis during Transformation to Acute Non-lymphocytic Leukemia

ABSTRACT. A patient with myelofibrosis transforming into acute non-lymphocytic leukaemia (ANLL) was treated with low doses of cytosine arabinoside (ARA-C). Complete remission was obtained twice without serious toxicity. It is suggested that low-dose ARA-C may be an effective and rather non-toxic therapy in patients with myeloproliferative disorders transforming to ANLL.     

The effect of budesonide (Rhinocort®) in the treatment of small and medium-sized nasal polyps

The objectives of this study were to determine if the size of nasal polyps could be assessed in a reproducible way and to study the effect of budesonide in patients suffering from eosinophilic nasal polyposis with small and medium sized polyps. Ninety-one patients entered the study. Budesonide 200 μg b.i.d. (aerosol or aqua) and placebo (aerosol or aqua) were compared in a 3-month double-blind, multi-centre, randomized study. Efficacy was measured by an assessment of polyp size, nasal peak-flow index and the patient's assessment of nasal symptoms. The conclusions were that the size of polyps could be assessed in a reproducible way, and that budesonide delivered either as a water-based suspension or as an aerosol is effective in the treatment of patients with small and medium sized polyps.