The pharmacokinetic characteristics of amiodarone suggest extensive tissue deposition. We confirmed this by measuring tissue concentrations of the drug and of its major metabolite, desethylamiodarone, in human tissues. These were obtained at autopsy (n = 9), surgery (n = 7), or biopsy (n = 2) from 18 patients who had been treated with amiodarone for varying periods of time. (89 and 470). and lymph node (83 and 316). We also found high concentrations of amiodarone (306 mg/kg wet weight) and desethylamiodarone (943 mg/kg wet weight) in abnormally pigmented ("blue") skin from patients with amiodarone-induced skin pigmentation. These values were 10-fold higher than those in unpigmented skin from the same patients. These high concentrations were associated with lysosomal inclusion bodies in dermal macrophages in the pigmented skin. The inclusion bodies were intrinsically electron dense and were shown to contain iodine by energy dispersive xray microanalysis. Lysosomal inclusion bodies shown by electron microscopy to be multilamellar were seen in other tissues. These tissues included terminal nerve fibers in pigmented skin, pulmonary macrophages. blood neutrophils. and hepatocytes and Kupffer cells. These characteristic ultrastructural findings occur in both genetic lipidoses and lipidoses induced by other drugs, e.g., perhexiline. We conclude that during therapy with aniodarone, widespread deposition of amiodarone and desethylamiodarone occurs. This leads to ultrastructural changes typical of a lipidosis. These changes are seen clearly in tissues associated with the unwanted effects of amiodarone, e.g., skin, liver and lung. Circulation 72, No. 5, 1064-1075, 1985 AMIODARONE is recognized as an orally effective agent in the treatment of atrial and ventricular arrhythmias refractory to conventional therapy. It is a benzofuran derivative containing two iodine atoms per molecule. In man, only one major metabolite has been identified, desethylamiodarone.' During long-term therapy this compound reaches similar plasma concentrations to amiodarone, and both compounds show long terminal elimination half-lives reflecting a com-

Objective To compare and quantify, in a morphological (91), 81 (20) and 74 (38) nerves/mm2 in the three defined areas, respectively. In the neuropathic tissues study, the changes that occur in the connective tissue elements (elastin and collagen), muscle fibre diameters the nerve profile densities were 672 (249), 57 (23) and 37 (28) nerves/mm2, respectively. Fibre diameter, and nerve densities between normal, idiopathic and neuropathic bladders.elastin and collagen content and nerve density were measured in normal and unstable bladder tissue using Materials and methods Bladder tissue was obtained from 27 patients undergoing cystectomy for carcithese three defined areas. The mean (sem) fibre diameter was 6.81 (0.52) in normal bladder; in idiopathic noma, from 12 with idiopathic instability and from seven neuropathic patients who were undergoing ileobladder tissue the fibre diameters in the three areas were 6.72 (0.62), 7.06 (0.62) and 7.34 (1.15) mm, cystoplasty. A combination of histochemical and immunohistochemical techniques were used to detect respectively, and in neuropathic bladders were 6.75 (0.62), 8.24 (0.62) and 9.35 (0.62) mm, respectively. detrusor muscle, connective tissue and nerve profiles in the bladder tissue.The relative areas of elastin were 0.79 (0.70), 0.56 (0.45) and 18.3 (4.1)% for the control, normal and Results In both idiopathic and neuropathic bladder tissue the structural changes were highly punctate. From aCected areas of the neuropathic bladders, respectively, and the relative areas of collagen were 3.5 (1.3), 6.15

SUMMARY A new method for the analysis of small-intestinal crypt-cell kinetics using routine peroral diagnostic biopsies is described. Untreated patients with childhood and adult coeliac disease and adults with the gluten-sensitive enteropathy of dermatitis herpetiformis were studied, together with groups of adult and childhood controls. In the classical flat avillous mucosae the increase in crypt size was found to be three-dimensional. The number of proliferating cells per crypt was shown to be markedly increased, and an even greater rise in the crypt-cell production rate was demonstrated. A significant increase in the mitotic index was also confirmed in the avillous mucosae.

The labelling index is commonly used as a measure of proliferation. However, the use of tritiated thymidine or BrdU labelling of S-phase cells is limited to prospective samples. We have employed an oligonucleotide cocktail complementary to the mRNA species encoding the replication-dependent histones H2B, H3 and H4 for non-isotopic in situ hybridization (NISH), and have compared the resultant proliferation indices in normal skin with those obtained by bromodeoxyuridine (BrdU) incorporation and by Ki67 immunohistochemistry (IHC) using the monoclonal antibody MIB1. In addition, we compared the staining characteristics of histone NISH and Ki67 IHC in a further 25 samples from a variety of inflammatory dermatoses and neoplastic conditions, as well as from normal skin. In normal skin, S-phase (histone NISH and BrdU) and cycling (Ki67) cells were confined to the basal and low suprabasal layers. The labelling indices determined by histone NISH and BrdU incorporation were similar, whereas that of Ki67 IHC was four times greater. In biopsies from hyperproliferative dermatoses and dysplastic or malignant lesions, the number of histone NISH- and Ki67 IHC-positive cells was generally elevated; in accordance with the differential expression of these two markers during the cell cycle, MIB1 consistently gave higher results. The advantage of histone NISH over Ki67 IHC is that it is a marker of the same part of the cell cycle as BrdU incorporation. However, the combined use of both histone NISH and Ki67 IHC to measure two cell cycle parameters, namely S-phase and the number of cycling cells, allows more detailed retrospective study of epidermal proliferation than has been possible previously.