Nitric oxide: a mediator in anaphylactic shock in guinea-pigs.

In this study we show that the pathophysiology of anaphylaxis includes generation of nitric oxide (NO), a very powerful, short-acting vasodilator. Guinea-pigs sensitized to ovalbumin were treated with 200 microgram/kg diphenylene iodonium (DPI), and NO synthase inhibitor, prior to antigen challenge. Mortality following the challenge fell from 71 to 39% (p < 0.001, n = 59). In the Langendorff preparation perfused isolated hearts from sensitized guinea-pigs were challenged to initiate cardiac anaphylaxis. The coronary flow rate (CFR), a direct reflection of coronary arterial resistance, was reduced by antigen challenge to 56 +/- 4% (n = 16) of the basal rate. DPI (2 micrograms/ml) intensified the antigen-induced fall in CFR to 13 +/- 3% of control (p < 0.005, n = 5), and the false substrate for NO, L-N-methylarginine, to 37 +/- 3% (p < 0.05, n = 4). Sodium nitroprusside (SNP), a NO generator, raised the basal CFR by 46% (from 11.2 +/- 1.7 ml/min to 16.3 +/- 1.9 ml/min) and blunted the antigen-induced fall in CFR. Paradoxically, DPI, which can inhibit flavoprotein enzymes other than NO synthase, potentiated the vasodilator effect of SNP, raising the basal CFR by 116%. Together these results strongly indicate that the vasodilator NO is generated in anaphylaxis. However, whereas in the heart it may function as a counterweight to the vasospasm of the coronary arteries, in the intact animal it appears to be a major contributor to the potentially lethal hypotension of anaphylactic shock.

[Effect of low-dose amiodarone on thyroid function].

Thyroid function was examined periodically in a group of 85 patients treated with low-dose amiodarone, and followed for 1-13 years (mean 3.6). Biochemical hypothyroidism (elevated thyroid stimulating hormone (TSH) only) developed in 8 patients and clinical hypothyroidism in 3, while hypothyroidism developed in 5. In the first 11 cases amiodarone was continued but 1-thyroxine was added. In the 5 that became hyperthyroid, amiodarone was stopped and thyroid function became normal within a few months. In the 69 patients without thyroid dysfunction, elevated thyroxine (T4) and free thyroxine index (FTI) were found in 20% and 17%, respectively, and elevated free T4 (FT4) in 28%; all had normal total tri-iodothyronine (TT3) and TSH. In practically all patients, reverse T3 (rT3) rose more than 30% above initial levels. It is concluded that in patients treated with low dose amiodarone: 1) thyroid function should be followed closely; 2) elevated levels of TT4, FTI and FT4 do not necessarily imply hyperthyroidism; 3) hypothyroidism may be biochemical only, without progression to overt hypothyroidism, despite continued treatment; 4) both the hypo- and the hyperthyroidism induced are usually reversible; 5) amiodarone may be continued despite onset of hypothyroidism, provided replacement therapy is given.

[Elevated thyroid hormone levels in the absence of hyperactivity].

Elevated blood levels of thyroid hormones may be due to causes other than glandular hyperactivity. We have seen transient increases in total thyroxine (TT4), free thyroxine index (FTI), free thyroxine (FT4), and total triiodothyronine (TT3) in 12 women and 3 men with subacute thyroiditis and 2 women with painless (silent) postpartum thyroiditis. Elevated TT4, FTI, and FT4 were found in 11 of 85 patients treated with amiodarone. High TT4, but not FTI or FT4, was seen in 4 women using contraceptives, in 2 pregnant women and in 2 men with liver dysfunction. All hormones, except TSH, were elevated in a patient in whom thyrotoxicosis factitia was later proved. High FTI, TT4 or FT4 but not TT3 were detected in 11 of 20 patients treated with l-throxine after surgical thyroidectomy and in 10 of 68 treated for hypothyroidism. To avoid treating when thyroxicosis is not present and to avoid reducing or stopping vital drug treatment, familiarity with these states which alter blood hormone levels is important.

PIP: Elevation of the thyroid hormone levels might be induced by causes not reflecting overexpressivity of the gland. According to the authors' experience in Israel, mistakes have been encountered frequently in the averaging of the results, which on occasion brought about withdrawal of therapy without any justified reason, or therapy administration without need. 15 patients diagnoses with subcutaneous thyroiditis were treated with aspirin, prednisone, and propranolol, and reached normal levels of hormones in 6-8 weeks of time. In postpartum thyroiditis, normal levels of thyroid hormone were reached in 3-4 months without pharmacological intervention. Extrinsic overdose of iodine (aniodaron administration) was completed in all patients without any sign of thyroid overactivity. Alleged high levels of TT4 (total thyroxin) were diagnoses in women taking oral contraceptives and in men with cirrhotic liver disease but with normal levels of free thyroxin index and TT3. Overactivity of the thyroid gland was suspected in a patient receiving up to 100 mcg dose of eltroxin who tried to lose weight according to this method. Patients who used L-thyroxine after complete/partial thyroidectomy had high levels of TT4 but in all the TT3 and thyroid stimulating hormone levels were normal. The need for recognition of these cases is emphasized in order to avoid any over treatment which is harmful and depressive or from lowering the dose and halting the use of valuable drugs without obvious reason.

[Complications of low-dose amiodarone].

Complications of low-dose amiodarone in 83 patients, in whom the drug was effective and who were followed for 1-13 years, are presented. Hypothyroidism was diagnosed in 11 (in 8 by the finding of elevated TSH). In 2 of the 3 in whom clinical signs of hypothyroidism were evident, amiodarone was continued, but thyroxine was also given. In 5 others thyrotoxicosis ensued. Propylthiouracil (PTU) was given and amiodarone was discontinued. PTU was then stopped within 4-8 months, without recurrence of the hyperthyroidism. In 1 patient pneumonitis resolved spontaneously a few weeks after stopping amiodarone. Because of gastrointestinal distress amiodarone was stopped in 1 patient. In none were liver enzymes elevated, nor was the nervous system affected clinically. Photosensitivity in 6 patients and skin discoloration in 2 did not necessitate discontinuation of the drug. Blurred vision was reported by 4, but its connection with amiodarone was not proven. There was sinus bradycardia in 2. There was no arrhythmic effect of amiodarone seen on ECG nor on Holter monitoring, nor was there any mortality. We conclude that amiodarone in low doses causes many complications, most of them mild and transient. However, in only a few cases is discontinuation of the drug indicated.

Phosphofructokinase deficiency (Tarui disease) associated with hepatic glucuronyltransferase deficiency (Gilbert's syndrome): a case and family study.

Tarui disease is a rare, genetically determined glycogen storage myopathy caused by the total lack of phosphofructokinase (PFK) enzymatic activity in the muscles and partially deficient enzymatic activity in the erythrocytes. We describe a patient with this disorder, who presented with exercise intolerance, painful cramps, elevation of muscle enzyme levels in the serum, compensated hemolysis with paradoxically elevated hemoglobin levels and gout with overproduction of uric acid. This patient had a partial hepatic uridine diphosphoglucuronate-glucuronyltransferase deficiency (Gilbert's syndrome). The coexistence of these two enzymatic deficiencies resulted in a complex clinical picture, especially during and after muscular effort. Screening of the patient's family revealed asymptomatic PFK deficiency in the erythrocytes of both parents and sister.

Nesidioblastosis in adults.

A 75-year-old woman with hyperinsulinemic hypoglycemia who died of acute myocardial infarction with ventricular rupture is reported. The microscopic examination of the pancreas revealed that the cause of hyperinsulinemic hypoglycemia was nesidioblastosis characterized by the presence of enlarged, irregular islets of Langerhans and clusters of islet cells in close proximity to the ducts. To our knowledge, nesidioblastosis in adults has not been previously reported in Israel.

[Well-differentiated thyroid carcinoma].

18 cases of well-differentiated thyroid carcinoma are described, of which 5 were papillary or mixed carcinomas and 3 were follicular. In 12 of 14 in whom radio-isotope scanning was performed, a cold or indeterminate nodule was found. Fine needle aspiration was positive and concordant with the operative histological findings in half the cases examined. In 4 hemithyroidectomy was performed, and in 14 total thyroidectomy. Thyroid remnants were found on scanning in all of the 14. These remnants were ablated with radioactive iodine (131I). An ablative dose of 30 millicurie was insufficient in almost all cases and a second dose was required. 3 cases with regional spread of the tumor were reoperated, and large ablative doses of 131I(150-170 mCi) were given. In 14 cases clinical remission was achieved. Followup included ultrasonography and total body 131I scans.

Mycotic aneurysms of the aortic root. A pathologic study of 20 cases.

Twenty specimens of heart with mycotic aneurysms at the aortic root were studied. In ten cases, mycotic aneurysm followed infection of the aortic valve. In one case, it developed following infection of an aortic jet lesion, and in nine patients, the aneurysm was at the seat of a prosthetic aortic valve. In seven of the 11 cases with a natural aortic valve, the valve was either unicuspid or bicuspid. A retrospective evaluation of the data on the clinical records of the 20 patients revealed that infective endocarditis or noncardiac postoperative sepsis was present in 11. The most frequently isolated microorganism was Staphylococcus aureus. Conduction disturbances were found in six patients, all of them with involvement of the atrioventricular node by the aneurysm. Perforation into intracardiac cavities was found in four, two into the right ventricular infundibulum and one each into each atrium. Pericardial tamponade was caused by bleeding from the aneurysm in two cases, and myocardial infarction was a probable consequence of coronary arterial compression by the aneurysm in two cases. Mycotic aneurysms of the aortic root, in spite of their being partially or completely healed of active infection, carry a high risk of the complications enumerated. Among the 20 cases, cultures were positive in 11 and negative in nine. Staphylococcus aureus was cultured from five of the cases.

Alkaloids from dendrobatid frogs: structures of two omega-hydroxy congeners of 3-butyl-5-propylindolizidine and occurrence of 2,5-disubstituted pyrrolidines and a 2,6-disubstituted piperidine.

Forty alkaloids were detected and characterized from skin extracts of high- and low-elevation populations of the poison frog Dendrobates histrionicus from northwestern Colombia. Combined gc/ms with NH3 or ND3 in a chemical ionization mode detected protonated parent ions and determined the number of exchangeable NH and OH hydrogens. Six previously unknown dendrobatid alkaloids were characterized. Two were 2,5-disubstituted pyrrolidines, which included pyrrolidine 197B, a trans-2-butyl-5-pentylpyrrolidine, while a third was a 2,6-dipentylpiperidine. Indolizidines 239AB and 239CD had the same relative configuration as the parent alkaloid 223AB [(5E,9E)3-butyl-5-propylindolizidine] and contained, respectively, a omega-hydroxy group in the propyl or butyl side chain. The profiles of alkaloids in the new northern populations of D. histrionicus are typical of the species in containing a set of about eight histrionicotoxins, in marked contrast to a related species, Dendrobates lehmanni, which does not contain histrionicotoxins.

Accessory tissue of the tricuspid valve protruding into the left ventricle through a septal defect.

We report the pathologic findings in 13 cases with accessory tissue originating from the tricuspid valve and protruding into the left ventricular outflow tract through a ventricular septal defect (VSD). In eight cases the accessory tissue formed a pouch, the walls of which were similar to the tissue of the normal tricuspid valve. In five cases, papillarylike masses of young connective tissue formed the accessory tissue. The degree of left ventricular outflow tract obstruction was mild in five cases, intermediate in five, and severe in three. Adhesions to the rims of the VSD causing obstruction of the VSD were seen in ten cases. Associated anomalies were present in all cases. The most frequent associated anomalies other than the tricuspid valvular anomalies and the VSDs were transposition of the great arteries and a variety of vascular anomalies.

Severe thyrotoxicosis caused by an ectopic intrathoracic goiter.

The case of a 71-year-old woman with severe thyrotoxicosis due to an ectopic multinodular intrathoracic goiter is described. Previously reported cases with intrathoracic ectopic thyroid tissue were either nontoxic, or, if thyrotoxic, were a direct continuation of the tissue of the normally located gland. This mass was proved to be of thyroid origin using Tc-99m sodium pertechnetate scanning.

Binding of [3H]perhydrohistrionicotoxin and [3H]phencyclidine to the nicotinic receptor-ion channel complex of Torpedo electroplax. Inhibition by histrionicotoxins and derivatives.

Histrionicotoxin, a spiropiperidine alkaloid, and twenty-two analogs inhibited binding of [3H]perhydrohistrionicotoxin [( 3H]H12-HTX) and of [3H]phencyclidine [( 3H]PCP) to sites on the acetylcholine receptor-ion complex of Torpedo electroplax membranes. Structural alterations to the nitrogen (secondary amine) or oxygen (alcohol) functions or to the five carbon and four carbon side chain of histrionicotoxin altered the potency versus [3H]H12-HTX and [3H]PCP binding measured in the presence or absence of a receptor agonist, carbamylcholine. Histrionicotoxin itself was 3-fold more potent versus [3H]PCP binding than versus [3H]H12-HTX binding. N-Methylation or O-acetylation increased this difference, while alterations to the side chains either slightly decreased or markedly increased this difference. Histrionicotoxin was some 3.5-fold more potent versus [3H]H12-HTX binding in the presence of carbamylcholine than in its absence. O-Acetylation increased this selectivity for the carbamylcholine-activated state of the receptor channel complex, while alterations in the side chains either reduced or increased the selectivity. Histrionicotoxin was some 2.2-fold more potent versus [3H]PCP binding in the presence of carbamylcholine than in its absence. N-Methylation of O-acetyl-histrionicotoxin greatly increased this selectivity, while alterations in the side chains either reduced or had no effect on selectivity.

[In vitro and in vivo studies with interleukin 2 (IL-2) and various immunostimulants in a patient with AIDS]. / In-vitro- und In-vivo-Studien mit Interleukin-2 (IL-2) und verschiedenen Immunstimulanzien bei einer Patientin mit AIDS.

We report on a lethal course of an acquired immunodeficiency syndrome (AIDS) in a young female patient. She had spent her vacancies six years before diagnosis in Haiti, where a sexual intercourse with a Haitian man had occurred. Leading clinical symptoms consisted of recurrent Herpes simplex infections of the genital and perianal region as well as unexplained high temperatures. There were some typical laboratory and immunologic features of this disease with leukopenia, hypergammaglobulinemia, cutaneous anergy, a reduction of peripheral T-lymphocytes (OKT 3) and an almost complete loss of OKT 4 (helper cells) positive lymphocytes. The mitogenic response upon stimulation with allogeneic cells (MLC) or with the mitogens PHA, Con A and PWM was significantly reduced. There was no measurable interleukin-2 (IL-2) secretion of peripheral blood lymphocytes. Several immunostimulators (thymopentin, inosiplex, bestatin) were tested in lymphocyte proliferation assays in vitro. The mitogenic response could not be enhanced by neither of these substances. A clinical trial with Delimmun (inosiplex) for 14 days did not show any clinical or immunologic improvement in this patient. The intravenous application of high dose immunoglobulin G was without any observable effect. The proliferation inducing capacity of a highly purified IL-2 preparation on the AIDS cells in vitro led us to a clinical trial with this substance. We applied 100 Bödeker units of IL-2 per kg body weight and day subcutaneously for 16 days. A therapeutical effect, however, could not be observed. Cell marker analyses did not show significant changes in lymphocyte subpopulation composition under IL-2 therapy. There was an increase in the spontaneous cell proliferation 14 days after start of IL-2 therapy. The PHA- and IL-2 response of the AIDS cells, however, was unchanged. It cannot be excluded that an administration of IL-2 in earlier stages of AIDS may have beneficial effects.