A French collaborative survey of 272 fetuses with 22q11.2 deletion: ultrasound findings, fetal autopsies and pregnancy outcomes.

OBJECTIVE: The 22q11.2 deletion (del22q11.2) is one of the most common microdeletions. We performed a collaborative, retrospective analysis in France of prenatal diagnoses and outcomes of fetuses carrying the del22q11.2. METHODS: A total of 272 fetuses were included. Data on prenatal diagnosis, ultrasound findings, pathological features, outcomes and inheritance were analyzed. RESULTS: The mean time of prenatal diagnosis was 25.6 ± 6 weeks of gestation. Most of the diagnoses (86.8%) were prompted by abnormal ultrasound findings [heart defects (HDs), in 83.8% of cases]. On fetal autopsy, HDs were again the most common disease feature, but thymus, kidney abnormalities and facial dysmorphism were also described. The deletion was inherited in 27% of cases. Termination of pregnancy (TOP) occurred in 68.9% of cases and did not appear to depend on the inheritance status. However, early diagnosis was associated with a higher TOP rate. CONCLUSION: This is the largest cohort of prenatal del22q11.2 diagnoses. As in postnatally diagnosed cases, HDs were the most frequently observed abnormalities. However, thymus and kidney abnormalities and polyhydramnios should also be screened for in the prenatal diagnosis of del22q11.2. Only the time of diagnosis appeared to be strongly associated with the pregnancy outcome: the earlier the diagnosis, the higher the TOP rate.

Workshop Report: concepts and methods in the economics of nutrition--gateways to better economic evaluation of nutrition interventions.

Improving health through better nutrition of the population may contribute to enhanced efficiency and sustainability of healthcare systems. A recent expert meeting investigated in detail a number of methodological aspects related to the discipline of nutrition economics. The role of nutrition in health maintenance and in the prevention of non-communicable diseases is now generally recognised. However, the main scope of those seeking to contain healthcare expenditures tends to focus on the management of existing chronic diseases. Identifying additional relevant dimensions to measure and the context of use will become increasingly important in selecting and developing outcome measurements for nutrition interventions. The translation of nutrition-related research data into public health guidance raises the challenging issue of carrying out more pragmatic trials in many areas where these would generate the most useful evidence for health policy decision-making. Nutrition exemplifies all the types of interventions and policy which need evaluating across the health field. There is a need to start actively engaging key stakeholders in order to collect data and to widen health technology assessment approaches for achieving a policy shift from evidence-based medicine to evidence-based decision-making in the field of nutrition.

Dietary treatment of cows' milk protein allergy in childhood: a commentary by the Committee on Nutrition of the French Society of Paediatrics.

The diagnosis of cows' milk protein allergy (CMPA) requires first the suspicion of diagnosis based on symptoms described in the medical history, and, second, the elimination of cows' milk proteins (CMP) from the infant's diet. Without such rigorous analysis, the elimination of CMP is unjustified, and sometimes harmful. The elimination diet should be strictly followed, at least until 9-12 months of age. If the child is not breast fed or the mother cannot or no longer wishes to breast feed, the first choice is an extensively hydrolysed formula (eHF) of CMP, the efficacy of which has been demonstrated by scientifically sound studies. If it is not tolerated, an amino acid-based formula is warranted. A rice protein-based eHF can be an alternative to a CMP-based eHF. Soya protein-based infant formulae are also a suitable alternative for infants >6 months, after establishing tolerance to soya protein by clinical challenge. CMPA usually resolves during the first 2-3 years. However, the age of recovery varies depending on the child and the type of CMPA, especially whether it is IgE-mediated or not, with the former being more persistent. Once the child reaches the age of 9-12 months, an oral food challenge is carried out in the hospital ward to assess the development of tolerance and, if possible, to allow for the continued reintroduction of CMP at home. Some children with CMPA will tolerate only a limited daily amount of CMP. The current therapeutic options are designed to accelerate the acquisition of tolerance thereof, which seems to be facilitated by repeated exposure to CMP.

Osteopenia and vitamin D deficiency in children with sickle cell disease.

OBJECTIVES: To assess the prevalence in children with sickle cell disease of low bone mineral density (BMD), a feature found in up to 82% of adults but not well known in children. METHODS: In 53 children (45 SS, 4 SC, 4 Sbeta-thalassemia) with a mean age of 12.8 +/- 2.4 years, we assessed height; weight; sexual maturation; number of hospitalizations, painful crises, and transfusions in the last 3 years; calcium intake; steady-state hemoglobin and leukocyte count; calcaemia, phosphataemia, and calciuria/creatinuria; serum 25-(OH)D and PTH concentrations; and osteocalcin, urinary deoxypyridinoline, and the C-terminal component of pro-collagen type I. BMD was assessed using dual X-ray absorptiometry. RESULTS: Mean lumbar spine Z-score was -1.1 +/- 1.3 (-3.9 to +1.8). The Z score was significantly lower in girls than in boys in the prepubertal subgroup (-1.74 +/- 0.27 vs. -0.53 +/- 0.31) (P = 0.0169), but not in the pubertal group (-1.15 +/- 0.41 vs. -1.33 +/- 0.70). BMD was not associated with any of the disease-severity markers in girls but was unexpectedly associated with fewer vaso-occlusive crises and hospitalizations in boys. BMD did not correlate with hemoglobin or leukocyte counts. Vitamin D deficiency [25-(OH)D < 12 ng/mL] was found in 76% of patients and secondary hyperparathyroidism (PTH > 46 pg/mL) in 38%. BMD was not related to calcium intake, vitamin D status, osteocalcin, or bone resorption markers. CONCLUSION: A slight BMD decrease was found in SCD children, starting before puberty and being more marked in females. The decrease was unrelated to disease severity, vitamin D deficiency, or bone hyperresorption, suggesting abnormal bone formation as the underlying mechanism.

[Feeding during the first months of life and prevention of allergy]. / Alimentation des premiers mois de vie et prévention de l'allergie.

Allergy consists in the different manifestations resulting from immune reactions triggered by food or respiratory allergens. Both its frequency and severity are increasing. The easiest intervention process for allergy prevention is the reduction of the allergenic load which, for a major allergen such as peanuts, has to begin in utero. The primary prevention strategy relies first on the detection of at risk newborns, i.e. with allergic first degree relatives. In this targeted population, as well as for the general population, exclusive breastfeeding is recommended until the age of 6 months. The elimination from the mother's diet of major food allergens potentially transmitted via breast milk may be indicated on an individual basis, except for peanut, which is systematically retrieved. In the absence of breastfeeding, prevention consists in feeding at-risk newborns until the age of 6 months with a hypoallergenic formula, provided that its efficiency has been demonstrated by well-designed clinical trials. Soy based formulae are not recommended for allergy prevention. Complementary feeding should not be started before the age of 6 months. Introduction of egg and fish into the diet can be made after 6 months but the introduction of potent food allergens (kiwi, celery, crustaceans, seafood, nuts, especially tree nuts and peanuts) should be delayed after 1 year. This preventive policy seems partially efficacious on early manifestations of allergy but does not restrain the allergic march, especially in its respiratory manifestations. Probiotics, prebiotics as well as n-3 fatty polyunsaturated acids have not yet demonstrated any definitive protective effect.

[Folic acid and prevention of neural tube closure defects: the question is not solved yet]. / Prévention par l'acide folique des défauts de fermeture du tube neural: la question n'est toujours pas réglée.

Between 1981 and 1996, several interventional studies proved the efficacy of periconceptional folic acid supplementation in the prevention of neural tube closure defects (NTCD), first in women at risk (with a previous case of NTCD) and also in women of the general population in age to become pregnant. The poor observance of this supplementation led several countries (USA, Canada, Chile...) to decide mandatory folic acid fortification of cereals, which permitted a 30% (USA) to 46% (Canada) reduction in the incidence of NTCD. Moreover, this benefit was accompanied by a diminished incidence of several other malformations and of stroke and coronary accidents in elderly people. However, several papers drew attention to an increased risk of colorectal and breast cancer in relation with high blood folate levels and the use of folic acid supplements. A controlled interventional study showed a higher rate of recurrence of colic adenomas and a higher percentage of advanced adenomas in subjects receiving 1mg/day of folic acid. A recent study demonstrated an abrupt reversal of the downward trend in colorectal cancer 1 year after the beginning of cereal folic acid fortification in the USA and Canada. Two studies also reported impaired cognitive functions in elder persons with defective vitamin B(12) status. Taken in aggregate, these studies question the wisdom of a nationwide, mandatory, folic acid fortification of cereals. As of today, despite their limited preventive efficacy, a safe approach is to keep our current French recommendations and to increase the awareness of all caregivers, so as to improve the observance of these recommendations.

Relationship between gamma-glutamyltransferase and fat mass in a general population of 8-17 years old children. The FLVS II study.

AIM: Elevated gamma-glutamyltransferase (GGT) is positively associated with severity of obesity in obese children and with increased BMI and waist circumference in general populations of adults. We aimed to study the relationships between GGT and anthropometric parameters in a general population of children. METHODS: This cross-sectional study was conducted in 219 boys and 214 girls included in the Fleurbaix Laventie Ville Santé II study. Weight, height, four skinfolds and waist circumference were measured. We compared the means of GGT activity according to gender and Tanner stage, and according to overweight status (IOTF definition) and quartiles of anthropometric parameters. We then calculated partial Pearson correlations by gender between GGT and anthropometric parameters taking age and Tanner stage into account. RESULTS: GGT activity was higher in boys than in girls as soon as puberty started (P<0.001). The higher difference was observed for Tanner stage III (GGT=10.2 UI/L, CI95% of mean (9.5, 11.1) vs. 7.8 UI/L (7.2, 8.4)). Anthropometric parameters were significantly associated with GGT, particularly waist circumference (r=0.28 in boys; r=0.24 in girls). After an additional adjustment for sum of skinfolds, this correlation disappeared in boys (r=0.06), and was still significant in girls (r=0.19). CONCLUSION: In a general population of children, overweight and abdominal fat distribution were associated with increased GGT. As some studies have shown that GGT could predict the metabolic syndrome in children and type 2 diabetes in adults, the modest elevation of GGT observed in overweight children may be of pathophysiological importance in the long term.

Luteinizing hormone pulsatility in patients with major ovarian hyperandrogenism.

Hyperandrogenism and ovulatory dysfunction are common in women with either polycystic ovary (PCOS) or ovarian virilizing tumor. However, contrasting with the numerous studies that have extensively described gonadotropin secretory abnormalities, principally increased LH pulse amplitude and frequency, few studies have concerned gonadotropin secretion in patients with ovarian virilizing tumors; low gonadotropin levels have occasionally been reported, but never extensively studied. The goal of the present study was to further evaluate the pulsatility of LH secretion in women with ovarian virilizing tumor compared with that of PCOS patients. Eighteen women with major hyperandrogenism (plasma testosterone level >1.2 ng/ml) were studied (5 women with ovarian virilizing tumor, 13 women with PCOS, and 10 control women). Mean plasma LH level, LH pulse number and amplitude were dramatically low in patients with ovarian tumors when compared to both PCOS (p<0.001) and controls (p<0.001). In case of major hyperandrogenism, LH pulse pattern differs markedly between women with ovarian virilizing tumor or PCOS, suggesting different mechanisms of hypothalamic or pituitary feedback.

Development of the gastrointestinal mucosal barrier. Evidence for structural differences in microvillus membranes from newborn and adult rabbits.

Electron spin resonance (ESR) and spin label methods with 5-doxylstearic acid as a probe were used to investigate the structure of microvillus membrane from the small intestine of adult and newborn rabbits. The spin label in microvillus membrane of newborns appeared to be in a more disordered environment than spin label in microvillus membrane of adult animals in the temperature range from 4 to 56 degrees C. In addition, a temperature transition at 39.6 +/- 0.3 degrees C was observed in the temperature dependence of the hyperfine splitting parameter for microvillus membrane from adult animals whereas a linear temperature dependence of the hyperfine splitting parameter was found for microvillus membrane from newborns. Cholera toxin was used as an external stimulus to test for the structural response in these two membrane preparations. Cholera toxin at 6 pM caused a decrease in the hyperfine splitting parameter at temperatures below 40 degrees C and a shift in the temperature break from 39.6 degrees C to 30.7 degrees C in microvillus membrane from adults. Using microvillus membrane from newborns, the temperature dependence of the hyperfine splitting parameter remained linear with a cholera toxin stimulus and the disordering effect of cholera toxin was only observed below 30 degrees C. These studies suggested that microvillus membrane from newborns were inherently more disordered than microvillus membrane from adult animals and that this difference in membrane organization might in part account for the increased attachment and penetration of macromolecules noted during the perinatal period.

Segregation of chromosomes in sperm of Robertsonian translocation carriers.

Robertsonian translocations are the most frequent structural chromosomal abnormalities in humans and can affect fertility, with various degrees of sperm alterations in men; or the pregnancy outcome of the carriers. The studies on meiotic segregation of chromosomes in sperm of Robertsonian translocation males find a majority of normal or balanced spermatozoa for the chromosomes related to the translocation (mean 85.42%; range 60-96.60%). Furthermore, recent studies suggest an interchromosomal effect. Studies on spermatozoa from translocation carriers, and in mouse models help the comprehension of the meiotic segregation mechanisms. Results of meiotic segregation analysis in man could be integrated in genetic counselling especially when assisted reproductive technology is required.

Growth hormone (GH) and prolactin receptors in human peripheral blood mononuclear cells: relation with age and GH-binding protein.

GH receptors (GHRs) and PRL receptors (PRLRs) were studied in human peripheral blood mononuclear cells (PBMC) using flow cytometry, biotinylated anti-GH receptor monoclonal antibody 10B8, and biotinylated human PRL. Variations of GHR and PRLR expression and the relationship of plasma GHBP and GH receptor in PBMC subsets were examined as a function of age and sex. By double immunofluorescence staining, we show that about 30% of total cells express GH receptors, with a low expression in T cells, whereas almost all B cells and monocytes are GH receptor positive. Four age groups were defined among the 64 normal volunteers, aged 12 to 85 yr, who were included in the study. The percentage of PBMC expressing GH receptors is significantly lower in group 2 (20-40 yr) than in group 1 (12-20 yr) and group 4 (>60 yr). In T cells, monocytes and B cells, no significant changes are detected in either the percentage of GH receptor positive cells or in the GH receptor level per cell. The level of PRLRs expressed in PBMC is significantly higher in age group 2 than in age group 4. A negative correlation is observed between plasma GHBP and the percentage of PBMC expressing GH receptors. These results suggest that regulation of GH receptors in lymphocytes and in other target cells could be different.

Glucose-induced insulin hypersecretion in lipid-infused healthy subjects is associated with a decrease in plasma norepinephrine concentration and urinary excretion.

We investigated the effect of a 48 h triglyceride infusion on the subsequent insulin secretion in response to glucose in healthy men. We measured the variations in plasma concentration and urinary excretion of catecholamines as an indirect estimation of sympathetic tone. For 48 h, 20 volunteers received a triglyceride/heparin or a saline solution, separated by a 1-month interval. At time 48 h, insulin secretion in response to glucose was investigated by a single iv glucose injection (0.5 g/kg(-1)) followed by an hyperglycemic clamp (10 mg.kg(-1).min(-1), during 50 min). The triglyceride infusion resulted in a 3-fold elevation in plasma free fatty acids and an increase in insulin and C-peptide plasma concentrations (1.5- and 2.5-fold, respectively, P < 0.05), compared with saline. At time 48 h of lipid infusion, plasma norepinephrine (NE) concentration and urinary excretion levels were lowered compared with saline (plasma NE: 0.65 +/- 0.08 vs. 0.42 +/- 0.06 ng/ml, P < 0.05; urinary excretion: 800 +/- 70 vs. 620 +/- 25 nmol/24 h, P < 0.05). In response to glucose loading, insulin and C-peptide plasma concentrations were higher in lipid compared with saline infusion (plasma insulin: 600 +/- 98 vs. 310 +/- 45 pM, P < 0.05; plasma C-peptide 3.5 +/- 0.2 vs. 1.7 +/- 0.2 nM, P < 0.05). In conclusion, in healthy subjects, a 48-h lipid infusion induces basal hyperinsulinemia and exaggerated insulin secretion in response to glucose which may be partly related to a decrease in sympathetic tone.

Protein-metabolism kinetics and energy-substrate utilization in infants fed parenteral solutions with different glucose-fat ratios.

The relative effect of glucose and lipids on whole-body protein-metabolism kinetics was assessed in seven infants undergoing parenteral feeding. Protein intake was kept constant and nonprotein energy was either provided as glucose alone or as an isoenergetic glucose-lipid mixture according to a randomized crossover trial. Protein metabolism and energy-substrate utilization were assessed by a primed, constant L-[13C]leucine infusion, combined with indirect calorimetry. There was a significant difference in the pattern of energy-substrate utilization according to regime. Protein turnover (11.3 +/- 0.7 vs 9.8 +/- 0.4 g.kg-1.d-1; P less than 0.05), protein breakdown (8.4 +/- 0.6 vs 7.1 +/- 0.4 g.kg-1.d-1; P less than 0.05), and amino acid oxidation rates (2.7 +/- 0.4 vs 1.4 +/- 0.5 g.kg-1.d-1; P less than 0.05) were higher for the glucose than the glucose-lipid treatment, whereas protein-synthesis rates did not significantly differ. These results suggest that the nature of energy substrates delivered to parenterally fed infants may affect protein metabolism.

Contribution of odd-chain fatty acid oxidation to propionate production in disorders of propionate metabolism.

Whole-body propionate and protein kinetics and energy substrate metabolism were studied in five metronidazole-treated patients with propionic or methylmalonic acidemias by the use of a primed, 4-h constant infusion of [1-13C]propionate and L-[O-2H5]phenylalanine combined with indirect calorimetry. Measurements were performed during fasting and carbohydrate feeding, successively, to assess the contribution of odd-chain fatty acid oxidation to total propionate production. Fat oxidation decreased from 490 +/- 179 to 57 +/- 49 mumol.kg-1.h-1 (P < 0.05) as a result of feeding. Propionate appearance rate was 38.6 +/- 8 mumol.kg-1.h-1 during fasting and decreased to 22.6 +/- 5 mumol.kg-1.h-1 (P < 0.05) on the carbohydrate diet. Precursor amino acid catabolism did not change significantly (22 +/- 5 vs 21.2 +/- 5 mumol.kg-1.h-1), suggesting that the 41% reduction in propionate production observed in response to feeding was related to the suppression of fatty acid oxidation. Therefore, significant therapeutic gains may be expected from the use of diets aimed at reducing lipid oxidation.

Anatomical and ontogenetic studies of the human paraventriculo-infundibular corticoliberin system.

In human fetus, newborn, infant and adult hypothalami, antibodies to ovine corticoliberin-41 stain a paraventriculo-infundibular neuroglandular pathway. The perikarya are located in the paraventricular nucleus, they mainly project to the ventral and lateral areas of the median eminence. Eminential corticoliberin-positive fibres appear during the 16th week of fetal life, and increase in number during the following weeks. Perikarya were first revealed in the 19th week. In some areas of the median eminence, corticoliberin-, vasopressin- or [Met]enkephalin-immunoreactive terminals are similarly distributed. Sequential stainings or staining comparison of contiguous semi-thin sections failed to prove the coexpression of corticoliberin and [Met]enkephalin immunoreactivities in fibres, but indicated that corticoliberin and vasopressin immunoreactivities may be coexpressed in a few fibres. Those methods enabled us to observe, in the paraventricular nucleus, perikarya revealed by corticoliberin and vasopressin antisera. Our results suggest a possible release of corticoliberin in portal vessels of the median eminence beginning in the 16th week of fetal life, i.e. 8 weeks later than appearance of the corticotrophs in the pituitary. Establishment of a corticoliberin hypothalamic control of pituitary corticotrophs at mid gestation agrees with previous physiological and teratological studies. Abundance, as well as immunostaining intensity of the corticoliberin processes, in the infant and adult median eminence attest to the physiological importance of this system. Close vicinity of corticoliberin, vasopressin and [Met]enkephalin fibres, in some eminential areas and coexpression of corticoliberin and vasopressin immunoreactivities in some neurons, are morphological correlates of functional relations which were reported.

Sources of propionate in inborn errors of propionate metabolism.

Amino acids are widely regarded as the most important sources of propionate in disorders of propionate metabolism. Propionate production was measured in the fasting state by continuous infusion of sodium [1-13C]propionate in three children with methylmalonic acidemia (MMA) and three with propionic acidemia (PA). The contribution of isoleucine, valine, threonine, and methionine catabolism to total propionate production was estimated by extrapolation from the hydroxylation of phenylalanine determined by a continuous-infusion [2H5]phenylalanine technique. The contribution of gut bacterial propionate production was determined by measuring total propionate production before and after treatment with oral metronidazole (10 to 20 mg/kg/d for 1 week). Amino acid catabolism accounted for a mean of 51.7% (range, 24.5% to 66.4%) of total propionate production. The mean decrease in propionate production after metronidazole was 22.2% +/- 8.5 (P less than .02); this percentage is likely to represent the minimum propionate production attributable to gut bacteria. Approximately 30% of total propionate production was unaccounted for, and is likely to arise primarily from odd-chain fatty acid catabolism in the fasting state. These results indicate that sources of propionate other than from protein catabolism are important in disorders of propionate metabolism, and explain the generally disappointing response to dietary protein restriction.

The CRF neuron: immunocytochemical study.

In the central nervous systems of several species belonging to different vertebrate classes, immunocytochemical stainings with an antiserum to ovine CRF 41 show multiple location of CRF perikarya and various areas containing CRF fibres and terminals. These stainings reflect species and interspecies functional adaptations of the CRF neurones which constitute a prominent hypothalamo-infundibular system involved in pituitary gland control, and also interneurone systems as attested to by extrahypothalamic perikarya and by CRF perisomatal endings in several brain areas. Perikarya of the hypothalamo-infundibular system are mainly packed in the paraventricular nucleus (mammals, birds) or in homologous areas, e.g.: paraventricular organ (turtle) where they are CSF-contacting neurones and preoptic nucleus (amphibians, fishes). In all species but fish, CRF fibres end in the median eminence (ME) against portal vessels. In fish, CRF processes terminate in the peripheral areas of proadenohypophyseal neurodigitations, close to corticotrophs. In all species these stainings are abolished by preabsorption of the serum by CRF. In fishes, reptiles and amphibians they are also suppressed by urotensin I, which is thought to be the teleost's CRF. Adrenalectomy experiments in the rat provided evidence for a corticosteroid regulation of ME CRF: short term (12-24 hr) adrenalectomy induces a complete depletion of CRF immunoreactivity followed by a secondary accumulation (5-20 days). This biphasic evolution is prevented by a dexamethasone replacement therapy. Inhibitory role of catecholamines on CRF release was indicated by: disappearance of ME CRF, induced by a single reserpine injection and suppression of this effect by monoamineoxidase inhibitor (pargyline or tranylcypromine) pretreatment. CRF fibres were first observed in the ME at the 16th week of fetal development in the human, and at the 18th day in the rat fetus. Thus, immunoreactive CRF system develops later than pituitary corticotrophs.

Pattern of chromosomal imbalances in non-B virus related hepatocellular carcinoma detected by comparative genomic hybridization.

Only limited data are available on comparative genomic hybridization (CGH) in hepatocellular carcinoma (HCC). They concern mainly B virus related HCC. Therefore, we used CGH to detect chromosomal imbalances in 16 non-B virus related HCC in alcoholic cirrhosis in 7 cases (HA1 to HA7), in C virus cirrhosis in 7 cases (HC1 to HC7), in non-cirrhotic liver in 2 cases (NC1, NC2), and in 9 non-malignant cirrhotic tissues. The most frequent imbalances in HCC were gains of whole chromosomes or chromosomal regions 7 or 7q (10/16, 62%), 1q (9/16, 56%), 5 or 5q (9/16, 56%), 8q (8/16, 50%), 6p (6/16, 37%), 15q (5/16, 31%), 20 or 20q (5/16, 31%), and losses of 17p (6/16, 37%), and 8p (5/16, 31%). High-level gains were identified in HCC on 1q (2/16), 3q (1/16), 7q (1/16), and 8q (3/16). No chromosomal imbalances were detected in any of the cirrhotic tissues. Most of the gains, losses, and amplifications detected in this CGH study corresponded well to those identified in previous studies, except for gains of whole chromosome 5 or 7 and/or of chromosome arms 5q or 7q and losses on 4q. Our results suggest that other chromosomal regions are involved in hepatocarcinogenesis.

Human corticoliberin hypothalamic neuroglandular system: comparative immunocytochemical study with anti-rat and anti-ovine corticotropin-releasing factor sera in the early stages of development.

Development of the paraventriculo-infundibular corticoliberin system was studied by immunocytochemical analysis of human hypothalamic sections using antisera raised against rat or ovine corticotropin-releasing factor (CRF). This comparative study confirms the presence of a significant number of CRF-immunoreactive fibers in the median eminence during the 16th week of fetal development and suggests they may appear as early as the 14th week. Some hypothalamic peri- and paraventricular neurons, observed from the 12th week, are rat-CRF-immunoreactive but not ovine CRF-immunoreactive. There appears to be chronological differences concerning the ability of the two antisera to recognize hypothalamic structures during the early stage of development.