Structure-activity studies on high affinity NOP-active hexapeptides.

Nociceptin/orphanin FQ (N/OFQ) is a 17 amino acid peptide that is the endogenous ligand for the G-protein coupled receptor ORL1 (NOP), a member of the opioid receptor family. Although it is clear that this receptor system is involved in a variety of physiologic functions, including analgesia, the precise actions of N/OFQ remain largely uncharacterized. One reason for this has been limited number of high-affinity ligands to NOP, and particularly the lack of availability of useful specific antagonists. Herein, we describe the pharmacologic activity of a series of modified amino acid containing modifications of the hexapeptide Ac-RYYRWR-NH2, with high affinity for NOP. These compounds were tested for binding affinity using [3H]N/OFQ binding to human NOP in CHO cells, and functional activity by measuring stimulation of [35S]GTPgammaS-binding in CHO cell membranes. These studies suggest that each Arg of the hexapeptide is required to maintain high-binding affinity. The peptide maintains high affinity if the Tyr2 or Tyr3 are modified, but at least one of these residues must maintain its hydroxyl group or there is a large decrease in intrinsic activity of the peptide.

N-terminal modifications leading to peptide ORL1 partial agonists and antagonists.

Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide that is the endogenous ligand for the G protein-coupled receptor (opioid receptor like 1, ORL1), a member of the opioid receptor family. Although it is clear that this receptor system is involved in a variety of physiological functions, including analgesia, the precise actions of N/OFQ remain largely uncharacterized. One reason for this has been limited high affinity ligands to ORL1, and particularly the lack of availability of useful specific antagonists. Herein we describe the pharmacological activity of a series of N-terminally modified hexapeptides with high affinity for ORL1. These compounds were tested for binding affinity using [3H]N/OFQ binding to human ORL1 in CHO cells, and functional activity by measuring stimulation of [35S]GTPgammaS binding in CHO cell membranes. The N-terminal modifications have produced compounds that maintained very high receptor affinity, but led to significant changes in intrinsic activity. One compound, pentanoyl-RYYRWR-NH2, with barely measurable agonist activity was tested in vivo. It was found to possess modest analgesic activity, but it was unable to block the morphine modulatory activity of N/OFQ.

Preeclampsia does not increase the risk for culture proven sepsis in very low birth weight infants.

The risk of sepsis associated with neutropenia in infants born to mothers with preeclampsia remains controversial. The objective of this study is to investigate the incidence of culture-proven sepsis along with changes in the complete blood count in very-low-birth-weight infants born to mothers with preeclampsia. We conducted a retrospective cohort study of infants cared for at a single tertiary care neonatal intensive care unit during a 4-year period. Infants born to mothers with preeclampsia (n = 88) were compared to infants born to mothers without preeclampsia (n = 416) by univariate and multivariate analysis. Although infants born to mothers with preeclampsia had lower absolute neutrophil and platelet counts throughout the first week of life, they were no more likely to have a platelet count <100,000 /mm3, and only more likely to be neutropenic at 24 and 72 hr of life compared to infants born to mothers without preeclampsia. After controlling for potential confounding variables, there was no increase in the odds of culture proven sepsis in infants born to mothers with preeclampsia (odds ratio 1.6, 95% confidence intervals 0.7-3.6, p = 0.3) compared to those infants born to mothers without preeclampsia. We conclude that very-low-birth-weight infants born to mothers with preeclampsia are not at increased risk of culture proven sepsis despite a reduction in absolute neutrophils.

Interstitial deletion of the short arm of chromosome 1 (46XY, del(1)(p13p22.3))

A male patient with a de novo proximal interstitial deletion of the short arm of chromosome 1 (46XY, del(1)(p13p22.3) is described with multiple anomalies and developmental delay. This patient's clinical manifestations are compared to previously reported patients with deletions of chromosome 1p.

Major congenital neurologic malformations. A 17-year survey.

We present characteristics of four major congenital neurologic malformations--anencephaly, spina bifida, encephaloceles, and hydrocephalus--from a population of 763, 364 live-born and still-born infants born from 1971 through 1987. During the 17-year study period, 275 infants had anencephaly (0.36 per 1000 total births), 526 had spina bifida (0.69 per 1000 total births), 112 had encephaloceles (0.15 per 1000 total births), and 370 had hydrocephalus (0.48 per 1000 total births). There was a female preponderance of infants with anencephaly, spina bifida, and encephaloceles, while males predominated among those with hydrocephalus. We found declining incidences of anencephaly, spina bifida, and encephaloceles only among white females. Black infants were significantly less likely than white infants or infants of other races to have spina bifida. Twenty percent of infants with anencephaly had congenital anomalies unrelated to the primary defect, as did 40% with encephaloceles, 37% with hydrocephalus, and 22% with spina bifida. Because the racial background of the patient population closely resembles that of the United States as a whole, the features of the malformations described may reflect those of the country.

Necrotizing enterocolitis in full-term infants. A case-control study.

We performed a case-control investigation of 43 full-term infants with necrotizing enterocolitis (NEC) to identify possible risk factors and unique features of the disorder in the more mature infant. Two control groups were used. The first consisted of "healthy" term infants. The second was a group of "sick" term infants who did not develop NEC. The 43 term infants with NEC represented 12.7% of all 338 neonates with NEC. The median age at onset of symptoms was 2 days, and 18 infants developed NEC on the first day of life. Two (4.7%) of the 43 affected term infants died, while 35 (11.9%) of 295 preterm infants with the disorder died. Only three of the full-term infants who subsequently developed NEC had entirely unremarkable courses prior to the onset of symptoms. Sick infants, in particular those who are small for gestational age or require exchange transfusions, are at risk for NEC. Several other features that may be associated with the subsequent development of NEC include the following: perinatal asphyxia, presence of umbilical catheters, antecedent respiratory distress, polycythemia, and maternal preeclampsia. Full-term infants with these features should be treated with cautious observation and aggressive management early in the neonatal period should they develop signs and symptoms suggestive of NEC.