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Pallister-Hall syndrome (PHS) is a rare malformative disorder that is due to truncating functional repressor mutations in GLI3. Since the seminal publication in 1980, hypothalamic tumors have been recognized to be a cardinal feature of PHS. In their original description of the neuropathologic features of PHS, Clarren et al. coined the term “hamartoblastoma” to characterize what they deemed to be a dual malformative and neoplastic mass of the hypothalamus. In subsequent published cases/series of PHS, the term “hamartoma” was often substituted for hamartoblastoma given what appeared to be a benign natural history of this lesion. Additional confusion in the literature has ensued since most hypothalamic hamartomas (HH) encountered on the clinical neuropathology service are “isolated” in nature (ie, no other congenital malformations) and present in a very different and stereotypical fashion with gelastic seizures and/or precocious puberty. While genomic investigations of isolated HH have begun to uncover a mutational profile of these cases, GLI3 mutations have only been recognized in a small subset of isolated HH. Herein, we describe the autopsy findings from a 21-week gestational age fetus with features of PHS. Moreover, we provide a detailed description of the hypothalamic tumor affecting this fetus and propose a novel subclassification of HH, distinguishing syndromic from isolated forms based upon the presence or absence of neocortical-like areas. [ABSTRACT FROM AUTHOR]

Objective:To examine whether early inflammation is related to cortisol levels at 18 months corrected age (CA) in children born very preterm.Study Design:Infants born 32 weeks of gestational age were recruited in the neonatal intensive care unit (NICU), and placental histopathology, magnetic resonance imaging (MRI) and chart review were obtained. At 18 months CA, developmental assessment and collection of three salivary cortisol samples were carried out. Generalized least squares was used to analyze data from 85 infants providing 222 cortisol samples.Result:Infants exposed to chorioamnionitis with funisitis had a significantly different pattern of cortisol across the samples compared with infants with chorioamnionitis alone or no prenatal inflammation (F(4, 139)=7.3996, P<0.0001). Postnatal infections, necrotizing enterocolitis and chronic lung disease were not significantly associated with the cortisol pattern at 18 months CA.Conclusion:In children born very preterm, prenatal inflammatory stress may contribute to altered programming of the hypothalamic-pituitary-adrenal (HPA) axis. [ABSTRACT FROM AUTHOR]

Bourque DK, Peñaherrera MS, Yuen RKC, Van Allen MI, McFadden DE, Robinson WP. The utility of quantitative methylation assays at imprinted genes for the diagnosis of fetal and placental disorders. An imbalance of imprinted gene expression within 11p15.5 is observed in Beckwith-Wiedemann syndrome (BWS), as well as in a variety of placental abnormalities including complete hydatidiform mole (CHM), placental mesenchymal dysplasia (PMD) and triploidy. To facilitate the diagnosis of epigenetic errors and chromosomal imbalance of 11p15.5, we validated a pyrosequencing assay to measure methylation at KvDMR1 using blood samples from 13 BWS cases, 8 of which showed reduced methylation as compared to control blood. An imbalance between maternal and paternal genomes as is found in triploidy, CHM or PMD was also associated with altered KvDMR1 methylation. A reciprocal pattern of methylation was obtained in the triploid cases by assaying the proximal 11p15.5 ICR associated with H19. To distinguish chromosome 11 specific alterations from whole genome imbalance, other imprinted differentially methylated regions (DMRs) can be utilized. Thus, pyrosequencing assays for DMRs associated with SGCE, SNRPN, and MEST were also compared for their utility in diagnosing parental imbalance in placental samples. While each of these assays could successfully distinguish parental origin of triploidy, SGCE showed the clearest separation between groups. The combined use of a chromosome 11p15.5 assay (e.g. KvDMR1 or H19-ICR) and non-chromosome 11 assay (e.g. SGCE) provides a potentially valuable diagnostic tool in the rapid screening of methylation errors in placental disorders. These results also show the maintenance of imprinting status at these loci in the human placenta, even in the presence of abnormal pathology. [ABSTRACT FROM AUTHOR]

The phenotypes of triploid fetuses and placentae are now well established and known to correlate with parental origin of the extra haploid set of chromosomes. In fetuses, it is not clear whether there is a direct parent of origin effect on the fetus itself or if the phenotypes are the result of growth differences influenced by abnormalities in growth and function of the placenta. Examining the phenotype of triploid embryos at an earlier stage in gestation, when the placenta effects may be less pronounced, could help clarify this question. A phenotype characteristic of triploidy in the embryonic period has been described; however, parental origin was not determined in these embryonic cases. In the present study, a population of triploid embryos is assessed to determine if there is a correlation between parental origin and phenotype. Parental origin was determined in 27 first trimester miscarriages. Digyny accounted for 19 cases and diandry for eight cases. Assessment of embryonic phenotype with parental origin showed no correlation between the phenotype of the embryo and parental origin of the extra haploid set. While there may be subtle effects of imprinting on embryonic development, they are not as obvious as they are in the mouse, consistent with the general trend of fewer imprinted genes in human beings compared with the mouse. [ABSTRACT FROM AUTHOR]

Objectives [ABSTRACT FROM AUTHOR]

Background: Placental mesenchymal dysplasia (PMD) is a distinct syndrome of unknown aetiology that is associated with significant fetal morbidity and mortality. Intrauterine growth restriction is common, yet, paradoxically, many of the associated fetuses/newborns have been diagnosed with Beckwith-Wiedemann syndrome (BWS). Methods: We report two cases of PMD with high levels of androgenetic (complete paternal uniparental isodisomy) cells in the placenta and document, in one case, a likely androgenetic contribution to the fetus as well. Results: The same haploid paternal complement found in the androgenetic cells was present in coexisting biparental cells, suggesting origin from a single fertilisation event. Conclusions: Preferential allocation of the normal cells into the trophoblast explains the absence of trophoblast overgrowth, a key feature of this syndrome. Interestingly, the distribution of androgenetic cells appears to differ from that reported for artificially created androgenetic mouse chimeras. Androgenetic mosaicism for the first time provides an aetiology for PMD, and may be a novel mechanism for BWS and unexplained intrauterine growth restriction. [ABSTRACT FROM AUTHOR]

Growth factor-stimulated intestinal absorption has recently been described, but the cellular transport mechanisms mediating this response are unknown. The purposes of this study were to examine the effect that intraluminal and systemic EGF and TGF have in intestinal absorption, elucidate a possible mechanism through which they exert their activity, and compare this response to that of a mixed meal only. Jejunal and ileal Thiry-Vella intestinal segments were constructed in six dogs. Absorption was measured by infusing the loops with a physiological electrolyte solution containing either 10 mmol or 50 mmol glucose and [14C]PEG as the impermeant marker. In vivo studies show that the addition of either EGF or TGF resulted in increased absorption of Na+, Cl-, H2O, and glucose in the intestine. This response was significantly greater than that seen when giving a mixed meal alone. Luminal phloridzin, an inhibitor of the SGLT-1 transporter, inhibited intestinal absorption observed in response to EGF and TGF. In conclusion, these results suggest that growth factors are capable of up-regulating intestinal absorption of electrolytes and nutrients and, these effects are mediated, at least in part, by SGLT-1 pathways. [ABSTRACT FROM AUTHOR]

Atlas Human cDNA Expression Array, which includes 588 genes divided into functional classes, was used to study gene expression profiles in KYSE 410 human esophageal cancer cells irradiated in doses of 6 and 18 Gy. Considerable changes in the expression of a number of genes was found, including down-regulation of 3 cell cycle regulators and up-regulation of an apoptosis-related gene. Comparison of the expression profiles and identification of genes were performed with Atlas Vision 3.0 software. [ABSTRACT FROM AUTHOR]

Atlas Human cDNA Expression Array, which includes 588 genes divided into functional classes, was used to study gene expression profiles in KYSE 410 human esophageal cancer cells irradiated in doses of 6 and 18 Gy. Considerable changes in the expression of a number of genes was found, including down-regulation of 3 cell cycle regulators and up-regulation of an apoptosis-related gene. Comparison of the expression profiles and identification of genes were performed with Atlas Vision 3.0 software. [ABSTRACT FROM AUTHOR]

In awake dogs, meal ingestion stimulates the absorption of water and electrolytes from neurovascularly intact jejunal Thiry-Vella loops, even though these loops are isolated from the remainder of the gut. This study was designed to investigate the role of Na+-glucose cotransport in mediating this event. Meal ingestion enhanced absorption when the jejunal lumen was perfused with an isotonic solution containing D-glucose, D-galactose, or 3-O-methylglucose. This response was absent when the perfusate contained mannitol or when phlorizin was added to the D-glucose solution. Mucosa from the jejunal loops was serially biopsied and assayed for brush-border Na+-glucose cotransporter (SGLT1) mRNA and protein expression. Although no changes in SGLT1 mRNA levels were observed, protein levels significantly increased within 30 min following meal ingestion. The time course of SGLT1 protein expression corresponded with that of increased Na+ and water absorption. These results suggest that meal-stimulated jejunal absorption may be mediated through an induction of mucosal SGLT1. [ABSTRACT FROM AUTHOR]

This study was initiated to determine if raised (carcinoid) plasma concentrations of substance P induced jejunal secretion of water and electrolytes. Five dogs had isolated and cannulated 25 cm jejunal segments perfused at 2 ml/min with a neutral, isotonic perfusate. Saline, 1.0 ml, was infused intravenously during basal and recovery periods, while substance P was administered intravenously at 75 ng/kg/min (55 pmol/kg/min) during the four 15 minute experimental periods. Infusion increased plasma SP concentrations from basal (5.8 +/- 1.3 pg/ml) to a mean plateau level of 121.2 +/- 25.2 pg/ml (mean +/- SEM). During SP infusion, intestinal secretion of water, Na+, and Cl- were documented (H2O basal +102 +/- 60 to SP -275 +/- 60; microliter/min; Na+ basal +19.8 +/- 7.2 to SP -23.2 +/- 7.5 microEq/min; Cl- basal 21.7 +/- 7.5 to SP -16.5 +/- 5.6 microEq/min). Under basal conditions, there was minimal secretion of potassium (-0.264 +/- 0.282 microEq/min); during SP infusion, K+ flux was altered to significant secretion (-1.784 +/- 0.271 microEq/min). Serum concentrations of Na and Cl were unchanged during SP infusion, but serum potassium concentrations fell from 4.64 +/- 0.12 to 3.85 +/- 0.40 mEq/l. The data demonstrate that substance P at levels noted in the carcinoid syndrome induces significant jejunal secretion of water and electrolytes in the dog. [ABSTRACT FROM PUBLISHER]

Presents a retrospective review of clinical experience with the diagnosis of acute otitis media (AOM) in children. Age-specific patterns of diagnosis; Variation in the rates of diagnosis; Implications of the study's findings on clinical practice, health planning and pediatric research.

Peptide YY (PYY) is a potent regulator of intestinal secretion. These studies investigated the role of Y1 and Y2 receptor subtypes in mediating the antisecretory effects of PYY on mucosa-submucosa preparations of rat distal colon. Addition of vasoactive intestinal peptide (VIP) to these tissues resulted in a 140 +/- 18% increase in basal short-circuit current (Isc) and the induction of Cl- secretion. VIP-stimulated increases in Isc were abolished by the addition of each of PYY, (Pro34)-PYY, a Y1 receptor-selective agonist, and PYY-(3-36), an endogenous Y2 receptor-selective ligand. However, when tissue neural transmission was blocked with tetrodotoxin, neither PYY nor its receptor subtype-selective analogs were able to inhibit VIP-stimulated increases in Isc. These results suggest that in the rat distal colon, the antisecretory actions of PYY are mediated through a combination of Y1 and Y2 receptor subtypes or through a novel receptor subtype that is unable to discriminate between (Pro34)-PYY and PYY-(3-36). [ABSTRACT FROM AUTHOR]

Background: Although laparoscopy reveals undetected metastases in many patients with pancreatic cancer, most surgeons have chosen to proceed directly with laparotomy in an attempt at resection or for palliation of biliary and gastric outlet obstruction. In an effort to overcome this limitation, this study attempted to determine the feasibility of laparoscopic cholecystojejunostomy and gastrojejunostomy.Methods: Under general anesthesia, seven pigs underwent laparoscopic cholecystojejunostomy and gastrojejunostomy using either a hand-sutured or the stapled/sutured technique.Results: Mean operating time was less with the stapled/sutured vs hand-sutured technique (150 +/- 21 vs 230 +/- 13 min, P < 0.05). All animals recovered completely and there was no change in their weight or liver function tests as a result of the procedure. At sacrifice, all anastomoses were patent, although some were significantly narrowed in these unobstructed animals.Conclusions: These results suggest that simultaneous laparoscopic palliation of biliary and gastric outlet obstruction is feasible. We believe these results warrant further study in the clinical setting. [ABSTRACT FROM AUTHOR]

Background: Although laparoscopy reveals undetected metastases in many patients with pancreatic cancer, most surgeons have chosen to proceed directly with laparotomy in an attempt at resection or for palliation of biliary and gastric outlet obstruction. In an effort to overcome this limitation, this study attempted to determine the feasibility of laparoscopic cholecystojejunostomy and gastrojejunostomy. Methods: Under general anesthesia, seven pigs underwent laparoscopic cholecystojejunostomy and gastrojejunostomy using either a hand-sutured or the stapled/sutured technique. Results: Mean operating time was less with the stapled/sutured vs hand-sutured technique (150±21 vs 230±13 min, P<0.05). All animals recovered completely and there was no change in their weight or liver function tests as a result of the procedure. At sacrifice, all anastomoses were patent, although some were significantly narrowed in these unobstructed animals. Conclusions: These results suggest that simultaneous laparoscopic palliation of biliary and gastric outlet obstruction is feasible. We believe these results warrant further study in the clinical setting. [ABSTRACT FROM AUTHOR]

In patients with the 3p-syndrome, hemizygous deletion of 3p25-pter is associated with profound growth failure, characteristic facial features, and mental retardation. We performed a molecular genetic analysis of 3p25 breakpoints in four patients with the 3p- syndrome, and a fifth patient with a more complex abnormality, 46,XY,der(3)t(3;?)(p25.3;?). EBV transformed lymphoblasts from each of the patients were initially characterised using fluorescent in situ hybridisation (FISH) and polymorphic microsatellite analyses. The 3p-chromosome from each patient was isolated from the normal chromosome 3 in somatic cell hybrid lines and subsequently analysed with polymorphic and monomorphic PCR amplifiable markers from 3p25. The analysis clearly shows that all five breakpoints are distinct. Furthermore, we have identified yeast artificial chromosomes that cross the 3p25 breakpoints of all four 3p-patients. Two of the patients were deleted for the von Hippel-Lindau (VHL) tumour suppressor gene, although neither has yet developed evidence of VHL disease. The patient with the most centromeric breakpoint, between D3S1585 and D3S1263, had the most severe clinical phenotype including an endocardial cushion defect that was not observed in any of the four patients who had more telomeric breakpoints. This study should provide useful insights into critical regions within 3p25 that are involved in normal human growth and development. [ABSTRACT FROM PUBLISHER]

This paper examines the criteria used to rank infinite-horizon development programmes. Koopmans [17] and Diamond [6] have shown that a planner's preference pre-ordering of all consumption programmes cannot simultaneously satisfy axioms requiring sensitivity to all increases in consumption and equal treatment of generations. However, there do exist partial pre-ordering criteria which satisfy these axioms and which are consistent with some complete planner's preference pre-ordering. A natural partial pre-ordering of this form is the Ramsey-Weizsäcker "overtaking" criterion, which states, roughly, that one program is considered by the planner to be better than a second if all sufficiently large numbers of cohorts (i.e. generations) taken together poll a majority vote for the first program. (The weighting of votes is specified by the planner. [ABSTRACT FROM AUTHOR]

We report two cases of renal tubular dysgenesis (RTD) with calvarial hypoplasia and review the originally reported cases of RTD that came from our institution and published reports regarding the association of RTD and skull abnormalities. Although previously reported in association with RTD, calvarial hypoplasia is probably under-recognised. The cases reported here support the idea that the skull abnormalities observed in the inherited form of renal tubular dysgenesis are a common component of the disorder, as they are in the acquired form of RTD associated with maternal use of ACE inhibitors. Renewed attention to this clinical manifestation of RTD may be important in suggesting the diagnosis before death, providing more complete information to parents and physicians facing important management decisions and ensuring appropriate pathological examination postmortem. [ABSTRACT FROM PUBLISHER]