Chediak-Higashi syndrome: hereditary gigantism of cytoplasmic organelles.

In the Chediak-Higashi syndrome, an anomalous hypopigmentation is associated with large lysosomal granules in the blood leukocytes. Since the inheritance pattern is that of an autosomal recessive trait, we postulated a common mechanism for these two primary features of the disease. Electron microscopy of melanocytes revealed that the pigmentary anomaly is indeed based on giant melanosomes. Since both types of granules, leukocytic and melanosomal, are characterized by limiting membranes, Chediak-Higashi disease may be a genetic disease of membranes.

The pattern of genetic transmission of the leukocyte defect in fatal granulomatous disease of childhood.

The leukocyte-phagocytic function test which was found to be abnormal in boys with fatal granulomatous disease of childhood has been found to be abnormal to an intermediate extent in their mothers. Nine of nine mothers were shown to be abnormal, whereas none of eight fathers and none of five healthy brothers exhibited a defect. 10 of 16 female siblings were abnormal to the same degree as their mothers, as were all three maternal grandmothers available for study. Assuming that this intermediate functional defect represents the heterozygous state, the nine family pedigrees are entirely compatible with the concept that the trait is transmitted on the X-chromosome.A tetrazolium dye-phagocytosis histochemical test was also abnormal in the carrier females and provided independent confirmation of the selection of the female siblings suspected of being carriers for the trait. In addition, this procedure gives indirect evidence that the gene in question is subject to the random inactivation that appears to affect many X-linked genes in mammalian females. The family members were also studied with two of the metabolic assays that have been shown to be abnormal in the cells of affected boys. One assay, the oxidation of the first carbon of glucose-1-(14)C by the isolated leukocytes, was significantly abnormal in the cells of carrier females. The other assay, the oxidation of formate-(14)C by leukocytes of heterozygotes was not significantly different from control values. The practical problem of diagnosing patients would appear to be best solved with a tetrazolium dye procedure, whereas the more subtle abnormality in carrier females is best detected with the leukocyte function test. Improved methods for the function test are being developed.

C1r deficiency: an inborn error associated with cutaneous and renal disease.

The studies of sera from two siblings with C1r deficiency are described. The brother (18 yr old) has shown clinical manifestations resembling lupus erythematosus for 5 yr, and the sister (24 yr old) has had arthralgia and recurrent episodes of rhinobronchitis since early childhood. Three siblings have died: one brother died at age 12 with symptoms similar to the disease of the male patient studied here, and two other siblings died in infancy, probably from infection. The low hemolytic C1 activity of the patients could be restored by the addition of purified C1r to their sera. Bactericidal activity and immune adherence were found to be impaired. When alternate pathways of the complement system were studied, both sera permitted activation of terminal components with endotoxin and cobra venom factor. These findings support the view that an alternate pathway for activation of the terminal portion of the complement cascade exists which does not utilize the conventional pathway operating through the usual early components.

Mucocutaneous candidiasis and thymoma.

The clinical, pathologic and immunologic features of 27 patients with chronic mucocutaneous candidiasis and thymic tumors are reviewed. This form of chronic candidiasis is unique in that the infections do not occur until after the third decade and, in contrast to patients in whom candidiasis develops during infancy or childhood, it is not accompanied by failure of endocrine organs. Instead, the patients have the disorders that often accompany thymoma, such as myasthenia gravis, hypogammaglobulinemia, and abnormalities of the bone marrow and circulating blood elements. Evidence of impaired cell-mediated immunity was found in 16 of the 21 patients in whom studies were made. The pathogenesis of the immunodeficiency in these patients is unknown. Immunosuppressive activities in the plasma of four patients were found, but none of the five patients in whom the appropriate studies were made was found to have suppressor cells. The features of this disorder are unique enough that it should be considered a syndrome, and patients in whom candidiasis develops during their adult years should be studied for the presence of thymoma.

Frequency of mitral valve dysfunction from mitral anular calcium as detected by Doppler echocardiography.

Doppler echocardiography is useful for detecting and quantifying mitral regurgitation (MR) and mitral stenosis (MS). To determine the prevalence of these abnormalities in patients with mitral anular calcium (MAC), 51 consecutive patients who had an echocardiographic diagnosis of MAC were examined by Doppler ultrasound. Transmitral flow was evaluated to determine the presence of MR or left ventricular inflow obstruction (MS) by continuous and pulsed-wave Doppler echocardiography. The severity of these hemodynamic abnormalities was quantitated by previously described techniques. Eleven patients (22%) had mild MR, 17 (33%) had moderate to severe MR and 4 (8%) had significant MS. Clinical findings such as a systolic murmur, evidence of congestive heart failure, and dyspnea on exertion were not helpful in distinguishing patients with no or mild MR from those who had moderate to severe MR. M-mode measured left atrial size was significantly larger (p less than 0.05) in patients with moderate to severe MR. This study suggests that MR is often associated with MAC, that MS is not a rare finding with MAC, and that Doppler echocardiography can quantitate these lesions in the elderly when symptoms are not specific and physical findings are inconclusive or absent.

Photopromotion of sister chromatid exchanges by psoralen derivatives.

Several derivatives of 8-methoxypsoralen and 4,5'8-trimethylpsoralen were compared with respect to their photopromotion of sister chromatid exchanges. Peripheral blood leukocytes from heparinized blood of human volunteers were cultivated for 24 h. Selected flasks received psoralens (6.5 X 10(-8) M) and/or were irradiated (UV-A, 365 nm, 0.9 J/cm2). Bromodeoxyuridine (20 micrograms/ml) was added and flasks were further incubated for 48 h when colchicine was added. Spreads of mitotic chromosomes were prepared, stained with Hoechst 33258 and Giemsa, and scored for the number of sister chromatid exchanges (SCEs) per 100 chromosomes. Results were: Control (16.5); 8-methoxypsoralen (23.9); 5'-methyl-8-methoxypsoralen (25.7); 4-methyl-8-methoxypsoralen (27.8); 4,5'-dimethyl-8-methoxypsoralen (31.9); 4'-methoxymethyl, 4,5'8-trimethylpsoralen (42.9); 4'aminomethyl, 4,5'8-trimethylpsoralen-hydrochloride (59.1); 4'hydroxymethyl,4,5'8-trimethylpsoralen (75). In general, the psoralens with strong affinity for DNA as determined by KD values promoted more SCEs than did those with lower affinity. Trimethylpsoralen and its derivatives promoted more SCEs than did 8-methoxypsoralen and its derivatives, which may be indicative of relative DNA cross-linking potential.

Data on drugs and adverse experiences: moving from the specific to the general.

Summary displays of data should illustrate narrative points made about the clinical experiment. Documentation of the source of the information selected for the critical displays should be assembled based on the data reduction steps that have occurred. Understanding and systematizing the presentation of the data reduction steps will facilitate the review of complex adverse experience data bases and allow well-informed decisions about the safety information.

Vitamin A analogs in skin disease.

Although large doses of oral retinoids produce marked toxic effects in some circumstances, it appears there may be a potential for the use of synthetic retinoids in cancer prevention and therapy in addition to the profoundly important benefits shown thus far in a variety of dermatological conditions. Furthermore, the wide diversity of retinoid effects on cell systems suggests that other, nondermatological, diseases may eventually be found to respond to this new class of therapeutic agents. This is to be expected particularly if newer retinoids show new tissue specificities. As was true of steroids in 1950, the potential of retinoids in 1982 is only partly visible, but very exciting.