During the past decade, possible advancement in timing of puberty has been reported in the United States. In addition, early pubertal development and an increased incidence of sexual precocity have been noticed in children, primarily girls, migrating for foreign adoption in several Western European countries. These observations are raising the issues of current differences and secular trends in timing of puberty in relation to ethnic, geographical, and socioeconomic background. None of these factors provide an unequivocal explanation for the earlier onset of puberty seen in the United States. In the formerly deprived migrating children, refeeding and catch-up growth may prime maturation. However, precocious puberty is seen also in some nondeprived migrating children. Attention has been paid to the changing milieu after migration, and recently, the possible role of endocrine- disrupting chemicals from the environment has been considered. These observations urge further study of the onset of puberty as a possible sensitive and early marker of the interactions between environmental conditions and genetic susceptibility that can influence physiological and pathological processes.

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The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration

We studied the acquisition and transmission of Clostridium difficile infection prospectively on a general medical ward by serially culturing rectal-swab specimens from 428 patients admitted over an 11-month period. Immunoblot typing was used to differentiate individual strains of C. difficile. Seven percent of the patients (29) had positive cultures at admission. Eighty-three (21 percent) of the 399 patients with negative cultures acquired C. difficile during their hospitalizations. Of these patients, 52 (63 percent) remained asymptomatic and 31 (37 percent) had diarrhea; none had colitis. Patient-to-patient transmission of C. difficile was evidenced by time-space clustering of incident cases with identical immunoblot types and by significantly more frequent and earlier acquisition of C. difficile among patients exposed to roommates with positive cultures. Of the hospital personnel caring for patients with positive cultures, 59 percent (20) had positive cultures for C. difficile from their hands. The hospital rooms occupied by symptomatic patients (49 percent) as well as those occupied by asymptomatic patients (29 percent) were frequently contaminated. Eighty-two percent of the infected cohort still had positive cultures at hospital discharge, and such patients were significantly more likely to be discharged to a long-term care facility. We conclude that nosocomial C. difficile infection, which was associated with diarrhea in about one third of cases, is frequently transmitted among hospitalized patients and that the organism is often present on the hands of hospital personnel caring for such patients. Effective preventive measures are needed to reduce nosocomial acquisition of C. difficile.

Nosocomial acquisition of Clostridium difficile infection

We have examined factors concerned with the maintenance of uterine quiescence during pregnancy and the onset of uterine activity at term in an animal model, the sheep, and in primate species. We suggest that in both species the fetus exerts a critical role in the processes leading to birth, and that activation of the fetal hypothalamic-pituitary-adrenal axis is a central mechanism by which the fetal influence on gestation length is exerted. Increased cortisol output from the fetal adrenal gland is a common characteristic across animal species. In primates, there is, in addition, increased output of estrogen precursor from the adrenal in late gestation. The end result, however, in primates and in sheep is similar: an increase in estrogen production from the placenta and intrauterine tissues. We have revised the pathway by which endocrine events associated with parturition in the sheep come about and suggest that fetal cortisol directly affects placental PGHS expression. In human pregnancy we suggest that cortisol increases PGHS expression, activity, and PG output in human fetal membranes in a similar manner. Simultaneously, cortisol contributes to decreases in PG metabolism and to a feed-forward loop involving elevation of CRH production from intrauterine tissues. In human pregnancy, there is no systemic withdrawal of progesterone in late gestation. We have argued that high circulating progesterone concentrations are required to effect regionalization of uterine activity, with predominantly relaxation in the lower uterine segment, allowing contractions in the fundal region to precipitate delivery. This new information, arising from basic and clinical studies, should further the development of new methods of diagnosing the patient at risk of preterm labor, and the use of scientifically based strategies specifically for the management of this condition, which will improve the health of the newborn.

/pdf/endocrine-and-paracrine-regulation-of-birth-at-term-and-4igz1kdkru.pdf

Endocrine and paracrine regulation of birth at term and preterm

Molecular cloning, expression, and gene localization of a fourth melanocortin receptor

THIS REVIEW will deal with the biosynthesis of many of the members of the ACTH/lipotropin (LPH) family of peptides (Fig. 1). Peptides in this family fall into two groups: peptides related to ACTH include α-melanotropin (αMSH) and corticotropin-like intermediate lobe peptide (CLIP); peptides related to βLPH include γLPH, βMSH, and β-endorphin. In several species ACTH and βLPH each contain an identical heptapeptide segment located in the region of the molecule that is responsible for melanotropic bioactivity (1, 2). In this review we have taken a somewhat historical approach, and will therefore begin with a discussion of the biosynthesis of ACTH and the characterization of biosynthetic precursors to ACTH. When this work began, βLPH, γLPH, and βMSH were well-characterized pituitary peptides, but the opioid peptides (and β-endorphin in particular) had not yet been identified (3–5). Studies on the biosynthesis of ACTH were heavily influenced by prior work defining the biosynthetic pathways for insulin and para...

Structure and Biosynthesis of Pro-Adrenocorticotropin/Endorphin and Related Peptides*

Animal experiments have suggested that the pineal gland produces an anti-gonadotropic hormone. The hamster, for example, undergoes reproductive collapse when kept in short-day periods, an effect which is abolished by pinealectomy. Although there is little direct evidence about the endocrine role of the pineal gland in man, it has been noted that tumours of the pineal gland in young boys are associated with precocious puberty and the human pineal gland has been suggested to produce a substance that holds sexual maturation in check. This observation has been extended by Kitay, who has shown that destructive tumours are associated with precocious puberty whereas hyperactive tumours are associated with delayed puberty. However, no studies have described any change of pineal function with normal puberty. Because two pineal indoles, melatonin and methoxytryptophol, have been shown to be antigonadotropic when administered to animals, we have now measured them in schoolchildren. Our findings show that in young boys there is an abrupt fall in the concentration of melatonin with advancing development suggesting that it may play an important physiological role in the control of human puberty.

Melatonin, the pineal gland and human puberty

THE pituitary gland produces a family of related peptide hormones (Fig. 1). Adrenocorticotrophic hormone (ACTH), β-lipotropic hormone (β-LPH) and possibly γ-lipotropic hormone (γ-LPH) are produced by the pars distalis. α-Melanocyte stimulating hormone (α-MSH), β-melanocyte stimulating hormone (β-MSH) and corticotropin-like intermediate lobe peptide (CLIP)1, however, are thought to be formed in the pars intermedia2, their being found only in those species in which this structure can be distinguished. They have not been identified in man3. The human foetus, however, does develop a rudimentary pars intermedia which involutes shortly after birth4. We present, for the first time, evidence for the occurrence of peptides resembling α-MSH and CLIP in the human foetal pituitary in the second half of pregnancy, and we suggest that these peptides are the dominant hormones of foetal life, only replaced by ACTH before parturition.

Human foetal pituitary peptides and parturition.

Typing scheme for Clostridium difficile: its application in clinical and epidemiological studies.

To investigate whether melatonin (aMT) can be metabolized to N-acetyl serotonin (NAS), a low dose of deuterated aMT was administered to four normal subjects, and their urine samples were analyzed for the presence of deuterated NAS and deuterated 6-hydroxymelatonin (6-HaMT). In one set of experiments, the urine samples were subjected to column chromatography to separate the glucuronide and sulfate conjugates for independent analysis. In another, an internal standard (NAS-sulfate) was used for quantification and total conjugate analysis. Measurement was by gas chromatography-mass spectrometry, and the molecular ions of deuterated and nondeuterated NAS and 6-HaMT were monitored. Deuterated aMT was metabolized to deuterated NAS and deuterated 6-HaMT. The proportion of NAS was less in the sulfate than in the glucuronide conjugates and, overall, represented 15% of the total. Since demethylation is not a pathway that occurs with other pineal methoxyindoles, even at a much larger dose, it seems to be a significant finding with regard to aMT. Thus, it may be important to elucidate the differential metabolism of aMT at different time points and in different age groups.

Melatonin is metabolized to N-acetyl serotonin and 6-hydroxymelatonin in man.

The direct involvement of the pituitary–adrenal axis in birth has been well established, at least in sheep, and its removal prolongs pregnancy1,2. As part of the process the fetal sheep adrenal grows rapidly during the 10–15 d prepartum and is associates with a large rise in the plasma corticosteroid concentration3,4. This does not seem to result from an increased ACTH secretion5,6. The fetal adrenal in vivo seems refractory to circulating ACTH and shows poor response to elevation of plasma concentration1,2,7–9. Thus the signal for the adrenal hypertrophy and the initiation of parturition remains unclear. The responsiveness of the fetal adrenal to ACTH has been re-examined using isolated adrenal cells. The study shows that in the fetal sheep these are not inherently unresponsive to ACTH, but that high-molecular-weight forms of ACTH block the action of ACTH1–39. These peptides may be responsible for controlling the activity of the adrenal in situ.

R.E. Silman

Papers

Melatonin, the pineal gland and human puberty

Human foetal pituitary peptides and parturition.

Typing scheme for Clostridium difficile: its application in clinical and epidemiological studies.

Melatonin is metabolized to N-acetyl serotonin and 6-hydroxymelatonin in man.

In vitro effects of high molecular weight forms of ACTH on the fetal sheep adrenal