Variable expression of 5 alpha-reductase deficiency: presentation with male phenotype in a child of Greek origin

A male infant with perineal hypospadias and a small phallus bound in chordee is described. Biochemical investigation at age 9 months after hCG stimulation revealed a testosterone to dihydrotestosterone (DHT) ratio of 40, a markedly elevated value suggestive of deficient steroid 5 alpha-reductase activity. The diagnosis of 5 alpha-reductase deficiency was confirmed by elevated urinary 5 beta/5 alpha-steroid metabolite ratios and demonstration of defective 5 alpha-reductase activity in cultured fibroblasts from the patient's scrotum and foreskin. Application of DHT cream to the patient's abdomen raised circulating levels of DHT to the adult male range. Two courses of DHT given nightly for 3 and 4 months resulted in phallic enlargement. Surgical release of the chordee and hypospadias repair have resulted in normal male appearance of the genitalia. This case illustrates the heterogeneity of the 5 alpha-reductase deficiency phenotype.     

Evaluation of the interrupter technique for measuring change in airway resistance in 5-year-old asthmatic children

The interrupter technique is a noninvasive method for measuring airway resistance during quiet breathing which requires minimal subject cooperation. It, therefore, has enormous potential for use in young children unable to cooperate with conventional lung function tests. We evaluated the interrupter technique during bronchial challenge with methacholine administered by the tidal breathing method in 10 5-year-old asthmatic children. The mouth pressure/time [P_mo(t)] curve obtained following brief airflow interruption during the expiratory phase of quiet breathing was analyzed to determine the interrupter resistance R,_int using four different methods: R_intC, a smooth curve fit with back-extrapolation; R_intEO, calculated from the pressure change after the postinterruption oscillations had decayed (end-oscillation); R_intL two-point linear fit with back-extrapolation; and R_intEL, calculated from the pressure change at the end of the period of interruption. The four R_int methods were compared for repeatability and sensitivity with the direct measurement of resistance by the forced oscillation technique (R_rs) and with an independent method of measuring the response to challenge, utilizing the change in transcutaneous oxygen tension (P_tcO2). The sensitivity of the methods was defined by a sensitivity index (SI), the change after challenge expressed in multiples of the baseline standard deviation. The P_tCo2 method had the lowest variability and was by far the most sensitive method (geometric mean SI 18.9), at least 1 doubling concentration more sensitive than the other techniques in every subject (P < 0.05). R_intL was more sensitive than the other interrupter methods (geometric mean SI: R_intL 4.2; R_intC 1.O; R_intEO 2.7; R_intEL 3.1; P < 0.05) and similar in sensitivity to R_rs (geometric mean SI 4.6) in 7 out of 10 children in which this could be measured. We conclude that the interrupter method provides a simpler method than the oscillation technique for assessing airway obstruction in this age group. Pediatr Pulmonol. 1995; 20:387–395 . © 1995 Wiley-Liss, Inc.     

Use of the day 6 bone marrow to alter remission induction therapy in patients with acute myeloid leukaemia: a leukemia intergroup study

Patients with acute myeloid leukaemia who fail to show substantial bone marrow cytoreduction by day 6 of induction therapy enter complete remission (CR) less frequently than patients with good bone marrow leukaemic cytoreduction. The objective of the current study was to determine whether an increase in the intensity of therapy on days 8, 9 and 10 ('augmentation' of remission induction therapy) for patients with poor bone marrow cytoreduction detected in the day 6 bone marrow could improve the complete remission rate without increasing the number of toxic deaths. Patients from six centres were entered and treated with standard dose ara-C for 7 or 10 d and an anthracycline for the first 3 d. Patients aged less than 60 years and with greater than 30% bone marrow biopsy cellularity or greater than 10% abnormal cells on the aspirate obtained 6 d after the start of therapy were augmented with cytosine arabinoside 3 g/m2 every 12 h on days 8, 9 and 10. Therapy was augmented in 116 of the 252 patients less than 60 years. There was a highly statistically significant difference between augmented and nonaugmented patients (P less than 0.001) for the per cent biopsy cellularity and per cent abnormal cells in the day 6 marrow. The CR rate for augmented patients was 69% and for nonaugmented patients 60% suggesting that augmentation therapy abrogated the prognostic significance of more extensive residual leukaemia in the day 6 bone marrow. The results suggest that augmentation of remission induction for patients with poor bone marrow cytoreduction detected 6 d after initiation of therapy, may salvage patients who are destined to fail remission induction because of resistant disease without producing excessive toxicity.     

Glucose kinetics in rats infused with endotoxin-induced monokines or tumor necrosis factor

This study was conducted to determine if macrophage elaborated monokines in general, and human recombinant tumor necrosis factor (hrTNF alpha) in particular alter glucose metabolism in a manner analogous to that observed in endotoxin-treated animals. Endotoxin-tolerant rats were infused for 3 hr with saline, E. coli endotoxin (100 micrograms/l weight) or monokines contained in conditioned media from endotoxin-stimulated RAW 264.7 cells (1 microgram/ml). Compared to saline- and endotoxin-infused rats, animals receiving the monokine mixture had no change in mean arterial blood pressure or heart rate but exhibited overt signs of morbidity including stupor and diarrhea. Monokine-infused rats remained euglycemic but had elevated lactate concentrations and a 15-30% increase in glucose rate of appearance (Ra). Nontolerant rats received a 3 hr infusion of saline, hrTNF alpha (15 micrograms/100 g), or heat-treated hrTNF alpha. HrTNF alpha infusion increased glucose Ra about 25% compared to the two control groups but did so without producing signs of morbidity seen in the monokine infused animals. Serum TNF levels were 6-fold higher in rats infused with the monokine mixture compared to animals infused with hrTNF alpha, and this reflected the different levels of TNF contained in the monokine mixture and hrTNF alpha infusates. Plasma insulin, glucagon, and catecholamine concentrations were increased in rats infused with either the monokine mixture or hrTNF alpha, but the increases were more pronounced in rats receiving the monokine mixture. The results demonstrate that monokines and hrTNF alpha increase glucose production in vivo, and that the effect may be mediated by endocrine changes known to influence glucose homeostasis.     

Dicarbonyl Electrophiles Mediate Inflammation-Induced Gastrointestinal Carcinogenesis

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Phosphorylative respiratory activity of mitochondria isolated from the left and right ventricles of rabbit hearts following partial pulmonary trunk occlusion

Right ventricular hypertrophy was produced by placing a spiral Monel metal clip around the pulmonary trunks of rabbits causing a sustained 67% occlusion of the vessel. The operation produced a doubling of right ventricular weight, by 13 days post-surgery, which persisted throughout the post-operative period studied (13 to 84 days); only a slight increase in left ventricular free wall weight was observed. Isolated mitochondria exhibited region-specific changes with time in state 3 Qo₂. Thirteen days after operation, the state 3 Qo₂ of right ventricular mitochondria was depressed to about 85% of controls. Thereafter, respiration increased fairly sharply, peaking at just above control values by 40 days post-operation. Finally, it declined abruptly to about 70% of controls by 84 days. A very different pattern of change was observed when left ventricular mitochondrial respiratory activities were examined. Thirteen days after the operation, state 3 Qo₂ was elevated somewhat above controls. Thereafter, it declined linearly and gradually, dropping to about 85% of controls by 84 days.     

On control of spontaneous testicular regression in tree sparrows (Spizella arborea)

To clarify whether androgen plays a role in the mechanism of spontaneous testicular regression in chronically photostimulated tree sparrows (Spizella arborea), microgram quantities of testosterone propionate (TP) or the free alcohol of cyproterone, a specific and potent antagonist of androgen, were implanted intracerebrally in separate experiments. Steroids, including cholesterol implanted in controls, were mixed homogeneously with cocoa butter. TP implants in the basal infundibular nucleus of the hypothalamus induced in photostimulated birds regressive changes that frequently culminated in testicular dysfunction and collapse; cholesterol implants in or near the basal infundibular nucleus were ineffective. Contrarily, cyproterone implants terminating in a central portion of the TP-sensitive basal infundibular nucleus inhibited spontaneous testicular regression in birds held 17 wk on 20-hr daily photoperiods. Magnitude of inhibition-assessed by both weight and histological criteria-ranged from complete to partial. Cyproterone implants elsewhere in the basal infundibular nucleus, as well as cholesterol or cocoa-butter implants, did not impede regression. Taken together, our results suggest that androgen-sensitive receptors in or near the basal infundibular nucleus are capable of detecting local concentrations of androgen and of altering pituitary gonadotropin secretion, presumably by varying the rate of neurohormone synthesis and/or release. Confirmation of Wilson's (1970) observation that cyproterone can prevent initiation of spontaneous testicular regression strengthens the notion that androgen plays an important role in the mechanism that terminates testicular function in chronically photostimulated tree sparrows.     

Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings

Activation of presynatic histamine H(3) receptors (H(3)R) down-regulates norepinephrine exocytosis from cardiac sympathetic nerve terminals, in both normal and ischemic conditions. Analogous to the effects of alpha(2)-adrenoceptors, which also act prejunctionally to inhibit norepinephrine release, H(3)R-mediated antiexocytotic effects could result from a decreased Ca(2+) influx into nerve endings. We tested this hypothesis in sympathetic nerve terminals isolated from guinea pig heart (cardiac synaptosomes) and in a model human neuronal cell line (SH-SY5Y), which we stably transfected with human H(3)R cDNA (SH-SY5Y-H(3)). We found that reducing Ca(2+) influx in response to membrane depolarization by inhibiting N-type Ca(2+) channels with omega-conotoxin (omega-CTX) greatly attenuated the exocytosis of [(3)H]norepinephrine from both SH-SY5Y and SH-SY5Y-H(3) cells, as well as the exocytosis of endogenous norepinephrine from cardiac synaptosomes. Similar to omega-CTX, activation of H(3)R with the selective H(3)R-agonist imetit also reduced both the rise in intracellular Ca(2+) concentration (Ca(i)) and norepinephrine exocytosis in response to membrane depolarization. The selective H(3)R antagonist thioperamide prevented this effect of imetit. In the parent SH-SY5Y cells lacking H(3)R, imetit affected neither the rise in Ca(i) nor [(3)H]norepinephrine exocytosis, demonstrating that the presence of H(3)R is a prerequisite for a decrease in Ca(i) in response to imetit and that H(3)R activation modulates norepinephrine exocytosis by limiting the magnitude of the increase in Ca(i). Inasmuch as excessive norepinephrine exocytosis is a leading cause of cardiac dysfunction and arrhythmias during acute myocardial ischemia, attenuation of norepinephrine release by H(3)R agonists may offer a novel therapeutic approach to this condition.     

Evidence for secondary 5 alpha-reductase deficiency in genital and supra-pubic skin of subjects with androgen insensitivity syndrome

The activity of 5 alpha-reductase in genital and supra-pubic skin (homogenate or fibroblasts) from subjects with complete or incomplete androgen insensitivity syndrome was low compared with mean activity in samples from normally differentiated male controls. Also, in two subjects with incomplete androgen insensitivity syndrome the ratio of the concentration of testosterone to that of 5 alpha-dihydrotestosterone in plasma was raised after hCG stimulation but normal under basal conditions. In three subjects with complete androgen insensitivity syndrome there was no evidence of raised ratios of testosterone to 5 alpha-dihydrotestosterone in plasma under basal or hCG-stimulated conditions. The activities of other steroid metabolizing enzymes, e.g. 17 beta-hydroxysteroid dehydrogenase, 3 alpha/beta-hydroxysteroid dehydrogenase, were not decreased. The low 5 alpha-reductase activity of androgen insensitive subjects reported here, and by others, may imply that this enzyme in genital skin is in some way androgen dependent, or responsive to other factors associated with androgen insensitivity syndrome.