Search

Assesses the extent of unrecognized human immunodeficiency virus (HIV) infection in the heterosexual community. The number of seropositives found in an unlinked anonymous testing program was compared with the number of reports of births to women known to be infected.

Cytomegalovirus (CMV) disease is a common complication of advanced human immunodeficiency virus (HIV) infection. Administration of oral valaciclovir, a valine ester of acyclovir, achieves sufficient plasma acyclovir levels to inhibit many clinical isolates. Acyclovir has been associated with enhanced survival in AIDS but not with CMV disease prevention. CMV-seropositive patients (1227) with CD4 cell counts <100/mm3 were enrolled in a randomized, double-blind trial. Valaciclovir, 8 g/day, was compared with acyclovir, 3.2 or 0.8 g/day, for CMV prevention; all three arms were compared for survival. The confirmed CMV disease rate was 11.7% among valaciclovir recipients and 17.5% in the pooled acyclovir arms, a 33% reduction in risk. Time to confirmed CMV disease was significantly longer for the valaciclovir group (P = .03). A trend toward earlier mortality for valaciclovir recipients was seen (P = .06). Toxicity and earlier medication discontinuation were more common in this group. Valaciclovir significantly reduces the risk of CMV disease. Further exploration of a better-tolerated dose is warranted.

The molecular pathogenesis of vestibular schwannoma has been investigated by determining the extent of chromosome 22 loss of heterozygosity in 77 tumors and relating these findings to clinical and immunohistochemical indexes of tumor behavior. Loss of heterozygosity was looked for at eight chromosome 22q loci. Clinical details were obtained in all 77 cases, and a clinical growth index was calculated for each tumor. The proliferative index was estimated in all tumors by using a monoclonal antibody to the proliferating cell nuclear antigen and by calculating the labeling index. Forty percent (31 of 77) of the tumors showed allele loss, and in each case this loss involved the region of the neurofibromatosis type 2 gene. No evidence was found that the presence of chromosome 22 allele loss was associated with the clinical growth index. On the log scale, however, an association was seen between the clinical growth index and the proliferating cell nuclear antigen labeling index p = 0.001). These results suggest that chromsome 22 allele loss is a frequent event in vestibular schwannoma. Tumor behavior, however, appears to be independent of the chromosome 22 mutation. It is proposed that chromosome 22 allele loss and neurofibromatosis type 2 gene inactivation is an early event, possibly involved in the initiation of tumorigenesis in vestibular schwannoma. Tumor growth appears to be independent of this mutation and is likely to be determined by other as yet undefined factors.

Unlinked anonymous HIV-1 testing of neonatal samples routinely collected for metabolic screening is now carried out in many parts of the United Kingdom. The purpose of this study was to assess the completeness of screening coverage in infants born to women known to be infected with HIV-1. Research nurses at family HIV clinics in three London hospitals searched for Guthrie cards from all infants born to known infected residents of North East, North West, and South West Thames regions over a 32 month period. If no card was found initially, mothers were approached for more information. Overall coverage was estimated to be 96.4% (94.6% in infants of African origin and 100% in white infants). These figures are similar to recent general population coverage estimates in inner London. We conclude that the anonymous newborn HIV testing programme is providing sufficiently accurate information on both absolute levels and time trends in maternal seroprevalence.

Objective: To estimate the reduction in the number of children infected with HIV that might be achieved by extending the provision of voluntary antenatal HIV testing. This effect would be mediated by increased numbers of women infected with HIV who receive an intervention to reduce the risk of vertical transmission (for example, zidovudine or caesarean section delivery), who use an alternative to breast feeding, or whose pregnancy is terminated., Setting: London, United Kingdom., Methods: Relevant data were derived from neonatal seroprevalence studies, obstetric and paediatric reporting schemes, and review of external information. Sensitivity analyses were performed for certain parameters., Results: Of 106,000 births annually in London, an estimated 169 are to women infected with HIV whose infection is not currently recognised before pregnancy. An estimated 28-33 children born to these women will be infected. Precise prediction of the number of paediatric HIV infections that could be prevented is difficult because of uncertainty in certain factors, particularly the uptake of antenatal testing and the efficacy and acceptability of interventions to reduce prenatal or perinatal transmission. If a testing programme detected 70% of infected women, none of whom opted for a termination but all of whom exclusively bottle fed and received an intervention which halved the risk of transmission, about 12-16 (42-46%) paediatric HIV infections would be prevented annually., Conclusions: The estimated cost of preventing each paediatric infection is high, but this should be seen in the context of the lifetime health and social care costs for a child infected with HIV. The feasibility of selective testing should be considered when formulating policies on antenatal HIV testing. Programmes that are introduced should be audited to obtain better estimates of costs and benefits.

Gonadotropin-independent precocious puberty presents a challenge in diagnosis and management and in the elucidation of its pathophysiologic basis. Current therapeutic strategies reflect the fact that, irrespective of the underlying mechanism, the clinical and biochemical aspects of the disease process are consequences of gonadal autonomy. In MAS and in testotoxicosis, the most successful therapeutic maneuvers have focused on the local inhibition of steroidogenesis. Despite the positive reports on the use of MPA and cyproterone acetate, long-term experience with these preparations has been generally unsatisfactory, and there is a consensus that testolactone or ketoconazole represent optimal management. Although ketoconazole use, in our experience, has not been associated with any adverse effects either on liver function or on cortisol metabolism, the risk potential is always there. Nevertheless, its effects are dramatic in boys with testotoxicosis, and its mode of action allows for easy monitoring of its efficacy. Testolactone use in MAS, and in combination with spironolactone in testotoxicosis, appears to be relatively safe and reasonably effective. However, because serum testosterone levels are not lowered during treatment, assessment of efficacy depends largely on long-term evaluation of growth rate and of skeletal maturation. The etiology of these disorders remains unclear. The McCune-Albright syndrome is a multisystem disease and sporadic in nature. The organ involvement--ovary, thyroid, adrenal glands, bone, and kidney--is reminiscent of pseudohypoparathyroidism, ironically also bearing Albright's name (Albright's hereditary osteodystrophy, AHO). It is well established that in this syndrome, organ hypofunction associated with the AHO phenotype is caused by deficiency or dysfunction of the G-(or N) regulatory protein essential for production of intracellular cAMP and induction of specific protein kinases. The hypothesis that MAS is caused by abnormal regulation of the membrane receptor/kinase complex would seem logical. Despite its clinical similarity to MAS, the mechanism underlying testostoxicosis is clearly different. This disease is autosomal dominant and is expressed clinically only in boys. Its effects are confined to the production of gonadal autonomy. However, it is difficult to theorize how such autonomy could arise. The enzymatic reactions converting cholesterol to testosterone within the testis or adrenal gland are acquired typically through autosomal recessive inheritance, including the initial rate-limiting step of desmolase side-chain cleavage.(ABSTRACT TRUNCATED AT 400 WORDS)

Background: Patients with transfusion-dependent thalassemia major tend to have abnormal growth and sexual maturation at puberty, presumably as a result of pituitary iron overload. This study was designed to determine whether chelation therapy with deferoxamine before the age of puberty would ameliorate this problem., Methods: We examined 40 patients over 14 years of age with transfusion-dependent thalassemia major. The 19 patients in group A (mean [+/- SD] age at study, 17.0 +/- 1.5 years) had begun nightly treatment with subcutaneous deferoxamine before the age of 10 (mean age at start of treatment, 7.5 +/- 1.8 years). The 21 patients in group B (mean age, 24.1 +/- 3.8 years) had begun treatment after the age of 10 (mean age at start of treatment, 14.4 +/- 4.7 years)., Results: The abnormal findings were essentially confined to sexual development. The final height did not differ between groups or from the mean parental height in each group. Ninety percent of the patients in group A had normal sexual development, as compared with 38 percent of those in group B (P = 0.001). Outcomes were correlated with indexes of iron overload; the patients in group A had lower serum ferritin levels before chelation treatment (P = 0.01) and lower average serum ferritin levels during treatment (P = 0.005)., Conclusions: Beginning chelation treatment with deferoxamine before the age of puberty can help children with transfusion-dependent thalassemia major to attain normal sexual maturation.

The chronic administration of the long-acting LHRH agonist analog D-Ser(TBU)6-LHRH-EA10 (HOE 766, Buserelin) suppresses pituitary gonadotropin secretion. Since a similar analog was shown to be effective in the short term parenteral treatment of idiopathic precocious puberty in girls (10), we used Buserelin both intranasally and sc to treat patients of both sexes with idiopathic and secondary central precocious puberty to test its efficacy, safety, and potential for long term use. Six girls and two boys presented with advanced skeletal maturity, accelerated growth velocity, Tanner stage II-IV pubertal development, and pubertal levels of sex steroids and gonadotropins. Patients were treated for 6 months sc and up to 5 months intranasally. Optimal doses ranged from 10-20 micrograms/kg X day in girls and 30 micrograms/kg X day in boys, with marked individual variation. During sc therapy, there was significant suppression of growth velocity (P less than 0.001), serum gonadotropins (P less than 0.001), 17 beta-estradiol (P less than 0.005), and testosterone as well as clinical and behavioral improvement. The rate of bone maturation was reduced. All effects were reversed after discontinuation of therapy for 1 month in one girl. No reduction in efficacy was seen after changing four girls and one boy to intranasal therapy, but improved acceptability and compliance were reported by parents. Apart from withdrawal bleeding in one girl and transient acceleration of puberty in two patients during the initial phase of treatment, no serious unwanted effects occurred. Antibodies to native LHRH were not detected after 6 months of therapy. These results confirm the efficacy and safety of Buserelin by intranasal and sc routes in patients with sexual precocity and indicate a need for long term studies.

The "empty sella" (ES), a common entity in adults, is so named because a cerebrospinal fluid-filled arachnoid hernia fills the pituitary fossa and compresses the pituitary gland, creating the illusion of an "empty" sella. We report our experience of ES in childhood. Our four cases represent associations with ES that have not been previously described in childhood: case 1 was associated with central precocious puberty; case 2 with secondary ES resulting from shrinkage of a prolactinoma during bromocriptine therapy; case 3 with pseudotumor cerebri; and case 4 with no significant pathology. Together, they account for approximately 1 percent of cases of radiographically enlarged sella tursica investigated here. This brings the number of cases of ES reported in children to 27. Review of these 27 cases reveals seven with local skull dysplasia and/or a familial inheritance. The remainder lacked clinical homogeneity or similarity to the common adult variety of ES. Children with ES did not exhibit the higher female preponderance reported in adults with ES. They showed a higher frequency of secondary cases (4/27), and of associated endocrine (10/15) and visual (8/17) abnormalities than is seen in adults with the "empty sella."

The effects of electrical stimulation of the brain stem on ACTH and GH secretion were studied in pentobarbital-anesthetized dogs. Stimulations in or near the subcoeruleus area or ventral ascending noradrenergic pathway inhibited the stress-induced increase in ACTH secretion, while stimulations in other areas of the brain stem did not. No significant changes in GH secretion occurred following stimulation of the subcoeruleus area, ventral ascending noradrenergic pathway or adjacent regions of the canine brain stem. These results are consistent with the hypothesis that there is central noradrenergic input to the hypothalamus which can inhibit ACTH secretion. This input appears to be separate from the postulated noradrenergic input that may increase the secretion of GH.

A heterologous radioimmunoassay for canine prolactin was developed and used to study the role of catecholamines and indoleamines in the regulation of prolactin secretion in dogs. Females dogs were found to have a higher plasma prolactin concentration than male dogs. Thyrotropin-releasing hormone (TRH) increased plasma prolactin in male and female trained conscious dogs. L-Dopa blocked the increase produced by TRH, but this effect could be reversed by pretreatment with carbidopa, an inhibitor of the conversion of L-dopa to catecholamines outside the blood-brain barrier. The intravenous administration of the immediate precursor of serotonin, L-5-hydroxytryptophan (5HTP), caused an increase in plasma prolactin and growth hormone. The administration of the serotonin receptor blocker, metergoline, 18 and 3 h before 5HTP, significantly augmented the growth hormone response to 5HTP. In contrast, metergoline diminished the prolactin response to 5HTP. Pretreatment with carbidopa did not change the prolactin or growth hormone responses to 5HTP. These observations indicate that the dog is similar to other mammals in that females have greater plasma prolactin concentrations than males and TRH increases plasma prolactin. L-Dopa appears to act at a site outside the blood-brain barrier to prevent the prolactin response to TRH. The data suggest that 5HTP increases plasma prolactin via a serotonergic mechanism, whereas it increases plasma growth hormone via a different, nonserotonergic mechanism.

A female infant, younger than any other case in the literature, with ACTH-producing microadenoma of the pituitary is reported. She had full-blown symptoms and signs as well as laboratory evidence of Cushing's disease. The tumor was investigated by histology, immunocytology (avidin-biotin-peroxidase complex technique), and electron microscopy. The possibility that the tumor was derived from the fetal intermediate lobe is discussed.

Thyroid function was systematically evaluated in 15 consecutive children (mean age 13.7 years, range 0.5 to 19.5 years) before and serially during treatment with amiodarone (Cordarone), a potent antiarrhythmic agent. Amiodarone is known to affect thyroid homeostasis by competitive inhibition of 5'-monodeiodinase, which converts L-thyroxine (T4) to triiodothyronine (T3) and reverse T3 (rT3) to 3,3'-diodothyronine (T2), and also by the direct effects of its high iodine content (37% by weight). Clinical and/or biochemical evidence of hypothyroidism occurred in three patients, two of whom required treatment with L-thyroxine. An additional patient had persistent hyperthyroxinemia but no clinical evidence of hyperthyroidism. Results from the patients who remained euthyroid showed characteristic alterations in serum thyroid function tests. These included significant increases in serum T4, rT3, basal thyroid-stimulating hormone and thyroid-stimulating hormone response to thyrotropin-releasing hormone testing. These changes were considered to be compensatory adjustments by the pituitary-thyroid axis to competitive inhibition of 5'-monodeiodinase by the amiodarone. Routine screening of thyroid function is needed to allow early detection of hypothyroidism when these compensations fail to occur.

Three boys 3.3 to 3.9 years old, who had precocious puberty that was unresponsive to an analogue of gonadotropin-releasing hormone, were treated with the antifungal agent ketoconazole for up to 12 months. Within 48 hours the serum testosterone concentration fell to normal in two boys and was significantly reduced in the third, paralleling major improvements in behavior. Reciprocal changes in serum levels of 17-hydroxyprogesterone suggested that C17-20 lyase was the principal site of drug action. Although there was evidence of a blunted cortisol reserve during the first week of treatment, the cortisol response to ACTH1-24 had returned to normal by one month of continuous treatment, and normal diurnal cortisol rhythm was preserved. No adverse clinical or biochemical side effects were noted during 9 to 12 months of continuing treatment. During that time, growth velocity was significantly reduced in all three boys, from a mean rate of 1.5 +/- 2.0 cm per year before treatment to 5.9 +/- 0.6 cm per year after ketoconazole therapy. There was a simultaneous retardation of the rate of skeletal maturation. The striking improvements in behavior were sustained for the duration of treatment. These preliminary data suggest that administration of ketoconazole may be a satisfactory treatment for precocious puberty in boys and possibly for other conditions characterized by androgen excess.