Clinical and molecular characterization of a Brazilian patient with Pit-1 deficiency.

We studied a 14 year-old girl with extreme short stature (-9.5 SDS), normal psychomotor development and signs of progressive hypothyroidism. Basal IGF-I and T4 were low. Serum GH was low after insulin-induced hypoglycemia and GH-releasing hormone administration. Both TSH and prolactin were low and did not rise after TRH administration. Gonadotropins were normal and cortisol levels were elevated. In contrast, DHEA-S levels were low and she did not develop pubic hair until 26 years of age, compatible with deficiency of a putative pituitary adrenal androgen stimulating hormone. Pituitary size was reduced on magnetic resonance imaging. Sequencing of the Pit-1 gene revealed a heterozygous C to T transition in codon 271 resulting in substitution of tryptophane for a highly conserved arginine. Her parents were homozygous normal for this locus indicating a de novo mutation with dominant expression. Genetic and phenotypic heterogeneity of patients with Pit-1 gene mutations, particularly the R271W mutation, may reveal further information about the nature of genetic silencing, imprinting, and epigenetic inheritance. The relationship of Pit-1 deficiency to abnormal adrenal secretion remains to be elucidated.

Central hypothyroidism reveals compound heterozygous mutations in the Pit-1 gene.

Mutations in the gene encoding the Pit-1 transcriptional activator interfere with the embryologic determination and ultimate functions of anterior pituitary cells that produce growth hormone (GH), prolactin (Prl) and thyroid-stimulating hormone (TSH). Central hypothyroidism is often the presenting feature of combined pituitary hormone deficiency (CPHD), but it is not detected in screening programs that rely upon elevation of TSH. We report a child whose hypothyroidism was recognized clinically at age 6 weeks, and subsequently found to have GH and Prl as well as TSH deficiency. With thyroxine and GH replacement he has reached the 70th percentile for height and has normal intelligence. Molecular analysis of genomic DNA for Pit-1 revealed the presence of compound heterozygous recessive mutations: a nonsense mutation in codon 172 and a novel missense mutation substituting glycine for glutamate at codon 174. This case is the first demonstration of CPHD due to compound heterozygous Pit-1 point mutations, as most reported cases of the CPHD phenotype involve either the dominant negative R271W allele or homozygosity for recessive Pit-1 mutations. Therefore, in cases of CPHD, the possibilities of compound heterozygosity for two different Pit-1 mutations, or homozygosity for mutations in the epigenetic gene, Prop-1, should be considered.

Genes regulating hypothalamic and pituitary development.

Several pituitary transcription factors have been identified in the last 3 years. They offer new insights into the processes that direct organogenesis, cell commitment, proliferation and differentiated function. All are DNA-binding proteins, but they have ties to different families of homeodomain proteins. They differ in their distribution and in the timing of their appearance and extinction. The Rathke's pouch homeobox protein (Rpx) has a paired-like homeodomain. In mice, it appears on embryonic day 8.5 (day e8.5) and is gone by day e14.5. Its targets for activation are unknown. Pituitary OTX has a tryptophan--phenylalanine--lysine motif in its homeodomain. It appears early and persists. It shows independent activation of the alpha-glycoprotein subunit (alpha-GSU) and pro-opiomelanocortin genes and co-operates with Pit-1 in activation of the growth hormone and prolactin genes. Pituitary Lim (P-Lim) protein also acts independently on the alpha-GSU gene, and acts in concert with Pit-1 to activate other genes. A fourth protein, termed the 'Prophet of Pit-1', or Prop-1, is the recently discovered cause of Ames dwarfism in mice. This paired-like protein is necessary for the subsequent expression of Pit-1 in somatotrophs, lactotrophs and thyrotrophs. Any or all of the newly discovered pituitary genes are candidates for mutations causing hypopituitarism in humans. As several are expressed transiently in tissues other than the pituitary during organogenesis, the phenotypes produced by mutations in these genes may prove to be complex.

Use of sentinel health events (occupational) in computer assisted occupational health surveillance.

The U.S. Coast Guard has developed a Coast Guard-wide comprehensive system for surveillance of workplace diseases. The American Medical Association's fifth edition of the Current Medical Information and Terminology (CMIT) was used as a reference to expand the basic list of 50 Sentinel Health Events (Occupational) [SHE(O)] published by the National Institute of Occupational Health and Safety (NIOSH), September, 1983. The expanded list of 107 sentinel events serves as a framework for the development of a computerized system of occupational health surveillance in the U.S. Coast Guard. This application of SHE(O) surveillance can have application in the early detection and prevention of environmental diseases.

Capillaria hepatica (Bancroft) in select rat populations of Hartford, Connecticut, with possible public health implications.

Capillaria hepatica was found in 82% of 86 Norway rats (Rattus norvegicus) trapped in Hartford, Connecticut between February and November 1975. Adults were parasitized more frequently than juveniles and infection rate did not differ between sexes. Rats demonstrated a low intensity of infection, with 9% having extensive liver involvement. A seasonal variation in infection rate may have been a manifestation of environmental factors, cannibalism, and predation.

Epidemiologic aspects of nosocomial infections.

In a currently ongoing surveillance of hospital-associated infections in two metropolitan hospitals in Oklahoma, the results over a four-month period suggest at least tentative principles of host-agent relationships in hospital-associated infections. Within the urinary tract, the site with the highest number of total isolations, Escherichia coli and Klebsiella pneumoniae were the most common pathogens. By age, the under 5 and over 60 year age groups had the highest number of isolations. Staphylococcus aureus and E coli were isolated more frequently in the younger group, while K pneumoniae, Serratia marcescens, and Proteus mirabilis occurred more frequently in infections among the older group. A higher frequency of Enterobacter sp and S aureus were isolated among male patients, while Candida albicans and E coli apparently had a greater affinity for females; however, none of these differences by sex were statistically significant. Over 50% of the infections were manifest within the first ten days of hospitalization.

Seroepidemiological investigation of Brucella canis antibodies in different human population groups.

A study was conducted to determine the prevalence of Brucella canis antibodies in specified groups based on their exposure to dogs. The method used was a microtiter technique, and the presence of antibodies at a 1:12 or greater dilution of serum was considered a positive test. Eleven (5.7%) of the newborn infants had evidence of maternal antibodies, and 67.8% of the persons with an average exposure to dogs had B. canis antibodies, with a 62.1% prevalence in males and a 72.4% prevalence in females (P less than or equal to 0.001). Veterinarians had a much higher rate of infection (72.6%) than male blood donors (56.9%) (P less than or equal to 0.01). Patients with fevers of undetermined origin had significantly higher antibody titers to B. canis than all other patients (P less than or equal to 0.001). This study presents evidence that the prevalence of B. canis antibodies in humans is high, and that the incidence of brucellosis may increase when physicians consider B. canis as a possible etiological agent in febrile illnesses.