Treatment of familial dysautonomia with bethanecol.
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Biomedical subjects
Publications and source records attributed to Z Hochberg.
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Handedness, immunologic disorders, language lateralization, reading fluency, and visual-motor achievements were assessed in 25 patients with congenital adrenal hyperplasia and age-matched right- and left-handed normal controls. An increased rate of left-handedness in the congenital adrenal hyperplasia group was evident. The prevalence of immunologic disorders, dichotic listening patterns, and visual-motor/reading achievement ratio were more similar to left-handed and significantly different from right-handed controls. Females appeared to be more affected than males in some of the functions. These results partly support the hypothesis of intrauterine androgenic effects on hemispheric function, but not to the extent of a complete lateralization shift.
Following the demonstration of inhibin activity in the ovary, a search was conducted for such activity in the rabbit placenta. A bioassay was utilized that consisted of 16 hours' incubation of the test substance with cultured rat anterior pituitary cells and determination of gonadotrophins in the recovered media. A crude extract of rabbit placenta had no effect on luteinizing hormone (LH) but a slight and insignificant inhibiting effect on follicle-stimulating hormone (FSH) secretion. Ethanol-extracted low steroid preparation of the rabbit placenta significantly inhibited FSH, but had no effect on LH secretion. On Sephadex G100 chromatography a fraction was identified which had inhibin activity. In a parallel chromatography of human seminal fluid inhibin activity was identified in the same elution volume as that of the rabbit placenta extract. It is suggested that rabbit placenta extract contains a non-steroidal substance that interferes with pituitary secretion of FSH, and that this substance may be inhibin.
In humans, oxoreducing 11beta-HSD-1 activity appears to be related to body fat distribution in male-type central obesity, but not in female-type peripheral obesity. We postulated that inhibition of 11beta-HSD-1 might have clinical therapeutic significance in oxoreducing mostly visceral fat and its metabolic activity. Our current study investigated the consequence at the cellular level of such inhibition. As an inhibitor of 11beta-HSD-1 activity, we used the licorice derivative carbenoxolone. Carbenoxolone has an inhibitory effect on the activity of both oxidizing 11beta-HSD-2, which converts cortisol to cortisone, and oxoreducing 11beta-HSD-1; yet, preadipocytes and adipocytes only express the latter. Preadipocytes were retrieved from omental and subcutaneous fat from healthy non-obese individuals and differentiated in vitro to mature adipocytes. Activity of 11beta-HSD-1 was assayed by measuring conversion of added 500 nM cortisone to cortisol. Expression of 11beta-HSD-1 mRNA was determined by real-time PCR, while lipolytic effects were determined by measuring glycerol and triglyceride concentration in the culture medium. Carbenoxolone decreased 11beta-HSD-1 activity in a dose-dependent manner with an IC-50 of 5X10 -6 M, but did not affect the expression of 11beta-HSD-1 mRNA. Cortisone stimulated subcutaneous, but not omental preadipocytes proliferation, an effect that was not abolished by carbenoxolone. Dexamethasone had a stimulatory effect on the maturation of both omental and subcutaneous preadipocytes. Carbenoxolone per se, either with or without cortisone, had a negative effect on preadipocyte maturation. Inhibiting 11beta-HSD-1 activity by carbenoxolone had no impact on leptin secretion. Thus, carbenoxolone has no effect on preadipocyte proliferation, but a dramatic inhibitory effect on preadipocyte differentiation into mature adipocytes. The mechanism is only partly related to its inhibitory effect on 11beta-HSD-1 activity. The present observations lend support to the presence of an intracrine loop of a hormone that is both produced from a precursor and active within the preadipocyte and adipocyte.
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The growth retardation of children with thalassemia major is multifactorial. Along the endocrine axis of growth hormone (GH), serum somatomedin has been shown to be deficient and GH response to GH-releasing hormone impaired, while GH response to provocative stimuli is normal. We studied the spontaneous secretion of GH in seven patients with thalassemia major and growth retardation. Three of the patients were hypothyroid, and the other four were euthyroid. Spontaneous secretion of GH in all seven patients was subnormal: the number of pulses, the mean pulse amplitude, and the integrated concentration of GH were all lower than in 14 age- and sex-matched (10 pubertal and 4 prepubertal) control subjects. GH response to provocative stimuli was normal in the euthyroid patients. This pattern of response corresponds with the definition of neurosecretory dysfunction of GH secretion. It is concluded that the growth retardation of patients with thalassemia major is partly due to neurosecretory dysfunction of GH secretion.