PURPOSE: The aim of this study was to determine long-term results of intestinal transplantation in children with pseudo-obstruction, particularly when stomach and colon are not part of the allograft. METHODS: The authors conducted a case-record review of all children who underwent transplantation at our center for a primary diagnosis of pseudo-obstruction. Supplementary information was obtained from outpatient charts, computerized database, and telephone survey of parents. RESULTS: Six small bowel and 3 liver-small bowel transplants were carried out in 8 patients between 1993 and 1999. Median follow-up is 40 months (range, 13 to 73 months). Median age at transplantation was 2.7 years (range, 0.7 to 12.8 years). Median graft survival in this series is 15 months (range, 1 day to 71 months). Stomach and colon were excluded from all allografts. Two children died 5 and 368 days after transplant and 2 graft losses occurred in 1 patient. Two children had lymphoproliferative disease; both are alive with functioning grafts. Five survivors with functioning grafts receive full enteral feedings at home. Four of the 5 have had ileostomies closed, and 3 have normal bowel movements. CONCLUSIONS: Intestinal transplantation without stomach or colon provides children with chronic intestinal pseudo-obstruction with a good quality of life. The underlying disease poses special challenges in management.

Child↗

PubMed2000

5,6-Dihydropyran-2-ones possessing various sulfonyl functionalities: potent nonpeptidic inhibitors of HIV protease.

On the basis of previous SAR findings and molecular modeling studies, a series of compounds were synthesized which possessed various sulfonyl moieties substituted at the 4-position of the C-3 phenyl ring substituent of the dihydropyran-2-one ring system. The sulfonyl substituents were added in an attempt to fill the additional S(3)' pocket and thereby produce increasingly potent inhibitors of the target enzyme. Racemic and enantiomerically resolved varieties of selected compounds were synthesized. All analogues in the study displayed decent binding affinity to HIV protease, and several compounds were shown to possess very good antiviral efficacy and safety margins. X-ray crystallographic structures confirmed that the sulfonamide and sulfonate moieties were filling the S(3)' pocket of the enzyme. However, the additional substituent did not provide improved enzymatic inhibitory or antiviral activity as compared to the resolved unsubstituted aniline. The addition of the sulfonyl moiety substitution does not appear to provide favorable pharamacokinectic parameters. Selected inhibitors were tested for antiviral activity in clinical isolates and exhibited similar antiviral activity against all of the HIV-1 strains tested as they did against the wild-type HIV-1. In addition, the inhibitors exhibited good antiviral efficacies against HIV-1 strains that displayed resistance to the currently marketed protease inhibitors.

Animals↗

PubMed1999

Nonpeptidic HIV protease inhibitors: 6-alkyl-5,6-dihydropyran-2-ones possessing a novel and achiral 3-(2-t-butyl-5-methyl-4-sulfamate)phenylthio moiety.

Dihydropyran-2-ones possessing a sulfamate moiety at the 4-position of the thiophenyl ring were designed to reach S3' pocket of the HIV protease. Synthetic routes for the preparation of thiotosylates possessing 3-(2-t-butyl-5-methyl-4-sulfamate) phenylthio moiety were established. SAR of various sulfamate analogs including HIV protease binding affinities, antiviral activities and therapeutic indices will be described.

Animals↗

PubMed1999

Nonpeptidic HIV protease inhibitors: 6-alkyl-5,6-dihydropyran-2-ones possessing achiral 3-(4-amino/carboxamide-2-t-butyl,5-methylphenyl thio) moiety: antiviral activities and pharmacokinetic properties.

Dihydropyran-2-ones possessing amino and carboxamide functionalities on 3-SPh (2-tert-butyl, 5-methyl) ring were synthesized and evaluated for their antiviral activities. Both the enantiomers of inhibitor 15 were synthesized. The in vitro resistance profile, inhibitory activities against cytochrome P450 isozymes and pharmacokinetic properties of inhibitor 15S will be discussed.

Animals↗

PubMed1998

The role of phytosterols in the pathogenesis of liver complications of pediatric parenteral nutrition.

Long-term parenteral nutrition of infants who have had major gut resections is associated with a high incidence of cholestatic liver disease. Affected infants have high plasma concentrations of phytosterols--compounds that resemble cholesterol but have an alkylated side chain. The phytosterols that accumulate in patients receiving parenteral nutrition are derived from the soya oil and/or soya lecithin used to make the intravenous lipid emulsion. There is a striking association between phytosterolemia and cholestatic liver disease. This has led us to put forward the hypothesis that phytosterols can cause cholestasis in susceptible infants. Experiments using neonatal piglets indicate that phytosterols (given without any of the other components of parenteral nutrition) can indeed reduce bile flow. We suggest that increasing the content of phytosterols in cell membranes may interfere with the function of important transport proteins involved in the secretion of bile. Other factors that might contribute to cholestasis (such as inhibition of cholesterol 7 alpha-hydroxylase) are discussed.

Bile↗

PubMed1995

Sequence and analysis of the human ABL gene, the BCR gene, and regions involved in the Philadelphia chromosomal translocation.

The complete human BCR gene (152-141 nt) on chromosome 22 and greater than 80% of the human ABL gene (179-512 nt) on chromosome 9 have been sequenced from mapped cosmid and plasmid clones via a shotgun strategy. Because these two chromosomes are translocated with breakpoints within the BCR and ABL genes in Philadelphia chromosome-positive leukemias, knowledge of these sequences also might provide insight into the validity of various theories of chromosomal rearrangements. Comparison of these genes with their cDNA sequences reveal the positions of 23 BCR exons and putative alternative BCR first and second exons, as well as the common ABL exons 2-11, respectively. Additionally, these regions include the alternative ABL first exons 1b and 1a, a new gene 5' to the first ABL exon, and an open reading frame with homology to an EST within the BCR fourth intron. Further analysis reveals an Alu homology of 38.83 and 39.35% for the BCR and ABL genes, respectively, with other repeat elements present to a lesser extent. Four new Philadelphia chromosome translocation breakpoints from chronic myelogenous leukemia patients also were sequenced, and the positions of these and several other previously sequenced breakpoints now have been mapped precisely, although no consistent breakpoint features immediately were apparent. Comparative analysis of genomic sequences encompassing the murine homologues to the human ABL exons 1b and 1a, as well as regions encompassing the ABL exons 2 and 3, reveals that although there is a high degree of homology in their corresponding exons and promoter regions, these two vertebrate species show a striking lack of homology outside these regions.

Animals↗

PubMed1994

The complete nucleotide sequences of the SacBII Kan domain of the P1 pAD10-SacBII cloning vector and three cosmid cloning vectors: pTCF, svPHEP, and LAWRIST16.

The complete nucleotide sequence of the 16,009-bp SacBII Kan domain of the P1 pAD10-SacBII cloning vector and the sequences of three cosmid cloning vectors, pTCF (7941 bp), svPHEP (9201 bp), and LAWRIST16 (5194 bp) have been determined. A modified diatomaceous earth (Prep-A-Gene)-based procedure, which rapidly yields highly supercoiled double-stranded DNA from recombinant P1 and cosmid clones suitable for generating shotgun libraries, also has been developed. The isolated recombinant DNAs were physically sheared to generate 1- to 2-kb fragments that then were blunt-ended and subcloned into double-stranded pUC-based sequencing vectors. The double-stranded sequencing templates were isolated by an alkaline lysis method and subjected to Taq polymerase catalyzed fluorescent end-labeled primer cycle sequencing. After shotgun sequence assembly, contig gaps were closed and ambiguities were resolved via Sequenase catalyzed fluorescent dye-terminator sequencing.

Bacteriophage P1↗

PubMed1990

Ocular atropine induced psychosis--is there a direct access route to the brain?

Explore the source record for details and available documents.

Atropine↗

PubMed1988

Endogenous opioids and TSH secretion in azotemic male rats.

The role of endogenous opioids in the control of thyroid-stimulating hormone (TSH) secretion in uremic male rats was investigated using the narcotic antagonist naloxone. In order to eliminate the effect of weight loss due to uremia-induced anorexia as a cause of altered TSH secretion in uremia, we also studied a group of normal control animals who were pair-fed with the uremic animals, so that their weights were comparable to that of the uremic animals. Naloxone administration produced a significant increase in the basal concentration of TSH response to TRH (5 micrograms i.v.) was significantly blunted in the uremic animals compared to the normal controls and the starved animals. Naloxone administration did not alter the peak thyrotropin-releasing hormone (TRH) stimulated TSH response in any of the experimental groups of rats. Because of the possibility that the effects of naloxone on TSH secretion in the uremic rats were related to impaired clearance of the naloxone in those animals, an additional group of normal rats was given twice the dose of naloxone administered to the uremic animals. The higher dose of naloxone was similarly without effect on the basal or TRH-stimulated TSH secretion in this group. The data suggest that experimental renal failure is associated with diminished sensitivity of the thyrotroph to TRH stimulation and that this blunted sensitivity cannot be abolished by blockade of endogenous opioids by naloxone. Opioid blockade does, however, increase basal TSH secretion in uremic animals, suggesting an increase in endogenous opioidergic tone in uremia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Gonadotropin secretion in azotemic male rats--effect of opioid blockade.

The role of endogenous opioids in the control of gonadotropin secretion in uremic male rats was investigated using the narcotic antagonist, naloxone. In order to eliminate the effect of weight loss due to uremia-induced anorexia as a cause of previously described altered gonadotropin secretion in uremia, we also studied a group of normal pair-fed control animals who exhibited a weight loss comparable to that of the uremic animals. Naloxone administration had no effect on the basal or LRH-stimulated peak concentrations of LH and FSH in the normal or the uremic rats. Basal and LRH-stimulated gonadotropin responses in the pair-fed rats were comparable to those seen in the normal rats. Similarly, opioid blockade produced no change in the basal or LRH-stimulated gonadotropin responses in the pair-fed animals. Testosterone concentrations were significantly lower in the uremic and pair-fed animals compared to the normal rats. The data suggest that experimental renal failure is not associated with altered opioidergic tone, as it relates to gonadotropin secretion, or to diminished sensitivity of the gonadotroph to LRH stimulation. The decreased testosterone concentration seen in the uremic and pair-fed rats may reflect abnormalities in gonadal hormone secretion due to primary pathology occurring at the level of the gonad. These abnormalities may be reflected as diminished Leydig cell sensitivity to LH. The inappropriately low concentrations of LH in the presence of low testosterone together with normal gonadotropin response to exogenous LRH also suggest an abnormal secretion of endogenous LRH. It is not clear whether this presumed abnormality in LRH secretion is a primary event or is related to decreased testosterone production by the testes in the uremic and pair-fed rats.

Animals↗

PubMed1987

Pluripotent steroidogenesis and ultrastructure in adrenocortical adenomas causing Cushing's syndrome.

Adrenal vein catheterization data from 2 patients with adrenocortical adenomas causing Cushing's syndrome are presented and the electron-microscopic features of one of the tumors are described. Based on the catheterization data both tumors produced all three classes of adrenal steroids (mineralocorticoids, glucocorticoids and sex steroids). Electron-microscopic examination of the tumor cells suggested an origin from the zona fasciculata. If one accepts the theory of a common cellular origin of adrenal tumors, then the pattern of steroidogenesis would indicate that the postulated original 'stem' cell retains the potential of secreting all classes of adrenocortical steroids. The clinical presentation of such tumors would thus reflect the hypersecretion of one of the steroid classes relative to the others.

Adenoma↗

PubMed1987

Dopamine and TSH secretion in uremic male rats.

The role of dopamine in the dysregulation of TSH secretion in uremic male rats was investigated using the dopamine antagonist, pimozide. In order to obviate the effect of weight loss due to uremia-induced anorexia as a cause of altered TSH secretion in uremia, we also studied a group of normal animals whose food intake was restricted and who demonstrated weight loss comparable to that of the uremic animals. Baseline TSH concentrations were not significantly different in the normal, uremic or starved animals. Pimozide administration produced no change in the baseline TSH concentrations in any of the groups of rats. The peak TSH response to TRH (5 micrograms IV) was significantly blunted in the uremic animals compared to the normal controls and the starved animals. Pimozide administration did not alter the peak TRH-stimulated TSH response in either the normal animals or the starved animals. However, the peak TRH-stimulated TSH response was significantly increased in the uremic animals and was comparable to the peak TSH response seen in the pimozide-untreated control animals. The data suggest that experimental renal failure in rats is associated with diminished sensitivity of the thyrotroph to TRH stimulation, and that this blunted sensitivity may be dopamine-dependent since it can be abolished by pharmacologic dopamine blockade.

Animals↗

PubMed1987

Gamma-aminobutyric acid and dysregulation of TSH secretion in uremic male rats.

The role of gamma-aminobutyric acid (GABA) in the abnormal secretion of thyrotropic hormone (TSH) in uremia was studied in male Sprague-Dawley rats rendered renally insufficient by subtotal nephrectomy. Baseline TSH concentrations in normal control animals and in the uremic animals were similar. The peak TSH response to thyrotropin-releasing hormone (TRH; 5 micrograms i.v.) was significantly blunted in the uremic animals compared to the controls. Pretreatment of the uremic animals with the specific GABA antagonist, bicuculline (1.5 mumol i.v.) resulted in normalization of the peak TSH response to TRH. Bicuculline pretreatment, however, did not alter the basal secretion of TSH in either the normal or the uremic animals, and it also did not augment the TRH-stimulated TSH response in the normal animals. Sham-operated animals demonstrated basal and TRH-stimulated TSH responses comparable to the control group. In order to assess whether the weight loss associated with uremia could have accounted for the blunted TRH-stimulated TSH secretion in the uremic animals, a group of rats were starved so that their weights were comparable to those of the uremic animals. Basal and TRH-stimulated TSH responses in this group were not significantly different from the controls. Bicuculline pretreatment of the starved animals also failed to alter the basal and TRH-stimulated TSH responses. These data indicate that an increase in central gabaergic tone may be partly responsible for the blunted TSH response to TRH seen in uremia, but that GABA is not an important modulator of TSH secretion in the normal rat.

Animals↗