Apoptosis and gastrointestinal disease.
Explore the source record for details and available documents.
Apoptosis↗
Biomedical subjects
S Freier
Publications and source records attributed to S Freier.
Pharmacokinetic properties of 2'-O-(2-methoxyethyl)-modified oligonucleotide analogs in rats.
Plasma pharmacokinetics, biodistribution, excretion, and metabolism of four modified 20-mer antisense oligonucleotides targeted to human intercellular adhesion molecule-1 mRNA have been characterized in rats and compared with a first-generation phosphorothioate oligodeoxynucleotide (PS ODN), ISIS 2302. The modified oligonucleotides contained 2'-O-(2-methoxyethyl) (2'-O-MOE) ribose sugar modifications on all or a portion of the nucleotides in the antisense sequence. The 2'-O-MOE-modified oligonucleotides were resistant to nuclease metabolism in both plasma and tissue. In general, plasma pharmacokinetics was not substantially altered by addition of the 2'-O-MOE modification to PS ODN. Thus, plasma clearance was dominated by distribution to tissues, broadly, with less than 10% of the administered dose excreted in urine or feces over 24 h. However, the 2'-O-MOE modification combined with the phosphodiester (PO) backbone exhibited 10-fold more rapid plasma clearance, with approximately 50% of the dose excreted in urine as intact oligonucleotide. Consistent with its rapid and extensive excretion, the PO 2'-O-MOE modification distributed to very few organs in any substantial amount with the exception of the kidney. Oligonucleotides that contained phosphorothioate backbones were highly bound to plasma proteins. Indeed, the primary characteristic that resulted in the most marked alterations in pharmacokinetics appeared to be the affinity and capacity of these compounds to bind plasma proteins. A balance of greater stability supplied by the 2'-O-MOE modification together with maintenance of plasma protein binding appears to be necessary to ensure favorable pharmacokinetics of this new generation of antisense oligonucleotides.
Animals↗
Patterns of variant polyadenylation signal usage in human genes.
The formation of mature mRNAs in vertebrates involves the cleavage and polyadenylation of the pre-mRNA, 10-30 nt downstream of an AAUAAA or AUUAAA signal sequence. The extensive cDNA data now available shows that these hexamers are not strictly conserved. In order to identify variant polyadenylation signals on a large scale, we compared over 8700 human 3' untranslated sequences to 157,775 polyadenylated expressed sequence tags (ESTs), used as markers of actual mRNA 3' ends. About 5600 EST-supported putative mRNA 3' ends were collected and analyzed for significant hexameric sequences. Known polyadenylation signals were found in only 73% of the 3' fragments. Ten single-base variants of the AAUAAA sequence were identified with a highly significant occurrence rate, potentially representing 14.9% of the actual polyadenylation signals. Of the mRNAs, 28.6% displayed two or more polyadenylation sites. In these mRNAs, the poly(A) sites proximal to the coding sequence tend to use variant signals more often, while the 3'-most site tends to use a canonical signal. The average number of ESTs associated with each signal type suggests that variant signals (including the common AUUAAA) are processed less efficiently than the canonical signal and could therefore be selected for regulatory purposes. However, the position of the site in the untranslated region may also play a role in polyadenylation rate.
3' Untranslated Regions↗
Increased spontaneous chromosomal breakage in Shwachman syndrome.
Explore the source record for details and available documents.
Amylases↗
Expression of the insulin-like growth factors and their receptors in adenocarcinoma of the colon.
AIMS: To study changes in the expression of insulin-like growth factors (IGFs) and their receptors, as well as production of the IGF-I and IGF-II polypeptides, in adenocarcinoma of the colon. METHODS: Malignant tissue obtained at operation was used. Total RNA was extracted and specific IGF-I and IGF-II and their receptor mRNAs were measured by a solution hybridisation RNase protection assay. IGF-I and IGF-II polypeptides were measured by specific immunoassays. RESULTS: All normal tissues expressed IGF-II, IGF-I receptor, and IGF-II/mannose-6-phosphate (Man-6-P) receptor. IGF-I mRNA could not be detected but the polypeptide was present in small but equal amounts in normal and malignant tissue. IGF-II was expressed 40 times more abundantly in colonic tumours than in adjacent normal tissue and the concentration of the corresponding polypeptide was twice as high in the malignant tissue. IGF-I receptor expression was increased by a factor of 2.5 and IGF-II/Man-6-P receptor by a factor of 4. CONCLUSIONS: This study confirms that in adenocarcinoma of the human colon there is increased expression of IGF-I receptor and IGF-II. Furthermore, IGF-II/Man-6-P receptor message is increased and the increase in IGF-II message is accompanied by a doubling of the IGF-II protein in the tumour tissue compared with the adjacent normal tissue. These findings suggest that the IGF-II/Man-6-P receptor may also be involved in development of adenocarcinoma of the colon. There is rapidly accumulating evidence implicating the IGF system in the development of malignancy of the large bowel.
Adenocarcinoma↗
Histologic evaluation of endoscopic versus suction biopsies of small intestinal mucosae in children with and without celiac disease.
BACKGROUND: Concern over the adequacy of histologic diagnosis of endoscopic duodenal biopsies in children prompted this comparative study on the histologic quality of endoscopic versus capsule biopsies. We found this problem addressed in only six previous reports. METHODS: Blind examinations of the histologic sections of 48 duodenal biopsies obtained by gastrointestinal endoscopy in children aged 2-18 years were compared to 52 biopsies obtained by the small bowel suction method (from children aged 1-16 years). RESULTS: Although 87.5% of endoscopic biopsies and 94.2% of capsule biopsies were adequate for histologic diagnosis, fragmentation or squashing was seen in 83.3% of endoscopic biopsies and only in 25% of capsule biopsies. CONCLUSIONS: Biopsies obtained by suction are of better quality than those obtained by endoscopy. If endoscopy is preferred for technical reasons, the following conditions should be observed: the patients should be aged over 2 years, and a minimum of four biopsies should be obtained with forceps of a diameter greater than 2 mm. Adequate histologic criteria for diagnosis should include at least one full-thickness mucosal specimen more than 3 mm in length, vertically oriented, and not fragmented. In children under age 2, duodenal or jejunal capsule biopsies are preferred, since the specimens are usually larger and less fragmented. Endoscopy is technically more difficult in the very young patient.
Adolescent↗
Are intraepithelial lymphocytes in celiac mucosa responsible for inducing programmed cell death (apoptosis) in enterocytes? Histochemical demonstration of perforins in cytoplasmic granules of intraepithelial lymphocytes.
BACKGROUND: Programmed cell death refers to the genetically determined processes by which cells die in response to physiologic extracellular and intracellular signals, morphologically described as apoptosis. In physiologic and pathologic circumstances this process may involve effector and target cells. METHODS: To identify serine esterase granules in intraepithelial lymphocytes, fresh-frozen human small intestine mucosal sections from normal and celiac-affected mucosa were incubated with substrate-specific N-alpha-benzyloxy-carbonyl-L-lysine thiobenzyl (BLT) and a chromogen (4 Benzoylamino-2,5-diethoxybenzene-dazonium chloride hemi [zinc chloride] salt as capture agent and were examined by light microscopy. RESULTS: Normal mucosa showed an occasional intraepithelial lymphocyte with BLT-positive intracytoplasmic granules. Some large mononuclear cells of the lamina propria were similarly stained. Many more intraepithelial lymphocytes were BLT-positive among the surface enterocytes of untreated celiac mucosa. Lamina propria mononuclear cells close to the basal layer of crypt cells also appeared to be increased. CONCLUSIONS: The histochemical identification of BLT-positive esters within intraepithelial lymphocytes suggests their involvement in enterocyte death under physiologic conditions. The increased BLT-positive intraepithelial lymphocytes found in the celiac mucosa may be related to the known increase in cytotoxic intraepithelial lymphocytes in untreated celiac disease.
Apoptosis↗
Hereditary CD4+ T lymphocytopenia.
Two siblings suffering from mental retardation, progressive bronchiectasis, extensive warts, and persistent hepatitis B are described. The propositus also had an unusual physiognomy and non-specific colitis. Both patients had a marked decrease in the population of CD4+ helper T cells.
Adolescent↗
Complex FISH probes for the subtelomeric regions of all human chromosomes: comparative hybridization of CEPH YACs to chromosomes of the Old World monkey Presbytis cristata and great apes.
We have generated a human subtelomere probe panel, utilizing well characterized CEPH YACs, for the investigation of human chromosome pathology and evolution through fluorescent in situ hybridization (FISH). Region-specific FISH probes will be extremely valuable for detecting cytogenetically cryptic telomere abnormalities. Here, we present the first comparative mapping study (with 29 subtelomere probes and 6 chromosome paints) to the Old World monkey Presbytis cristata, followed by hybridizations to the great apes, gorilla and orangutan, when rearrangements were detected. We observed that the position of telomere-associated genomic sequences has been only moderately conserved during primate evolution. YAC 364f9, specific for the subtelomeric long arm of human chromosome 3, contains an evolutionary inversion breakpoint that was involved in independent chromosome rearrangements in P. cristata and gorilla.
Animals↗
2'-O-aminopropyl ribonucleotides: a zwitterionic modification that enhances the exonuclease resistance and biological activity of antisense oligonucleotides.
Oligonucleotides containing 2'-O-aminopropyl-substituted RNA have been synthesized. The 2'-O-(aminopropyl)adenosine (APA), 2'-O-(aminopropyl)cytidine (APC), 2'-O-(aminopropyl)-guanosine (APG), and 2'-O-(aminopropyl)uridine (APU) have been prepared in high yield from the ribonucleoside, protected, and incorporated into an oligonucleotide using conventional phosphoramidite chemistry. Molecular dynamics studies of a dinucleotide in water demonstrates that a short alkylamine located off the 2'-oxygen of ribonucleotides alters the sugar pucker of the nucleoside but does not form a tight ion pair with the proximate phosphate. A 5-mer with the sequence ACTUC has been characterized using NMR. As predicted from the modeling results, the sugar pucker of the APU moiety is shifted toward a C3'-endo geometry. In addition, the primary amine rotates freely and is not bound electrostatically to any phosphate group, as evidenced by the different sign of the NOE between sugar proton resonances and the signals from the propylamine chain. Incorporation of aminopropyl nucleoside residues into point-substituted and fully modified oligomers does not decrease the affinity for complementary RNA compared to 2'-O-alkyl substituents of the same length. However, two APU residues placed at the 3'-terminus of an oligomer gives a 100-fold increase in resistance to exonuclease degradation, which is greater than observed for phosphorothioate oligomers. These structural and biophysical characteristics make the 2'-O-aminopropyl group a leading choice for incorporation into antisense therapeutics. A 20-mer phosphorothioate oligonucleotide capped with two phosphodiester aminopropyl nucleotides targeted against C-raf mRNA has been transfected into cells via electroporation. This oligonucleotide has 5-10-fold greater activity than the control phosphorothioate for reducing the abundance of C-raf mRNA and protein.
Exonucleases↗
[New infant formula based on soy milk and corn flour].
In recent years the use of infant feeding formulas based on soy bean has been increasing. We report a trial of a new, soy bean-based formula to which starch was added. A control group was given a cow milk-based formula widely used in this country ("Materna" with cornflour, Ma'abaroth Products Ltd.). Healthy infants, between 3-6 months of age and of normal length and weight were enrolled at random at Infant Welfare Centers in Jerusalem. 25 received the soy formula, and 21 the cow milk-based formula. During the 2-month trial the infants did not receive any other foods. They were examined by the senior author every 2 weeks and weight, length and head circumference were measured at their Infant Welfare Clinic visits. The mothers filled questionnaires concerning the amount of formula ingested, the nature and number of stools, and complaints, such as crying. Both groups gained weight at the normal rate during the trial. In each group, the mothers were satisfied with the product and wanted to continue with it after the trial. We conclude that a soy-based formula containing starch is comparable to a cow milk formula containing star.
Body Height↗
Cholecystokinin-octapeptide (CCK-OP) and substance P (SP) influence immune response to cholera toxin in live animals.
Explore the source record for details and available documents.
Administration, Oral↗
Substance P accelerates secretory component-mediated transcytosis of IgA in the rat intestine.
Explore the source record for details and available documents.
Albumins↗
Shigella lipopolysaccharide antibodies in pediatric populations.
Shigellosis is the most common cause of bacterial dysentery. To study the specific immunity to the two major groups causing shigellosis, we assayed antibodies to lipopolysaccharide (LPS) by enzyme-linked immunoadsorbent assay to both Shigella sonnei and Shigella flexneri 2a serotypes in the following populations: (1) women immediately after delivery and their infants to assess the transfer of passive immunity by placenta and the presence of secretory antibodies in breast milk; (2) children of different ages; and (3) the kinetics of antibody production in pediatric patients, who had culture-proved shigellosis. The sera of these women showed variable concentrations of antibodies of all three isotypes to LPS of S. sonnei and S. flexneri 2a. These serotype-specific antibodies were not cross-reactive. Transfer of IgG anti-LPS across the placenta was significantly correlated with concentration of the specific antibody in the mother (S. sonnei, r = 0.96; S. flexneri, r = 0.84). Varying concentrations of anti-LPS IgA were present in colostrum, which was correlated with serum anti-LPS IgA titers in the case of S. sonnei (r = 0.44; P < 0.05) but not S. flexneri (r = 0.17). Healthy children between the ages of 6 months and 4 years in our population had undetectable or relatively low titers of anti-S. sonnei IgG. More children had detectable antibody titers to S. flexneri 2a than to S. sonnei. The relatively high concentrations of these natural antibodies are particularly noteworthy because there is a far lower incidence (< 10% of patients) with S. flexneri than with S. sonnei disease in this population.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
[Breast milk banks--are they really necessary?].
Explore the source record for details and available documents.
Humans↗
Anderson's disease: no linkage to the apo B locus.
We describe three patients with Anderson's disease who are members of one family; the father and mother are close relatives and three of seven children show symptoms of the disease. All patients suffered from diarrhea, failure to thrive, and recurrent infections during infancy. Although these symptoms disappeared later in life, biochemical disorders (such as low plasma levels of apolipoproteins A1 and B and cholesterol, resulting in avitaminosis E, plus failure to secrete chylomicrons after a fat meal) persisted. Electron microscopy of enterocytes of one of the patients showed accumulation of lipid vacuoles with no significant aberration of the Golgi apparatus itself. It is possible, therefore, that the disease reflects a defect in chylomicron assembly. We found that low levels of apolipoprotein (apo) B48 were present in the patients' plasma. This suggests that the processing of the B100 message resulting in apo B48 functions normally. The possibility that a mutation in the apo B gene results in an abnormal apo B48 protein is very unlikely since a variable number tandem repeat (VNTR) polymorphism probe mapped to chromosome 2 failed to show correspondence of the parent alleles with the disease. These observations confirm the suggestion that Anderson's disease is not linked to the apo B locus.
Apolipoprotein B-48↗
Lethal toxic encephalopathy due to childhood shigellosis in a developed country.
Shigellosis results in considerable morbidity in endemic areas, but mortality is rare in developed countries. All pediatric deaths (n = 15) in Israel following shigellosis in the past 10 years were reviewed. The patients' ages ranged from 5 months to 11 years; there were eight boys and seven girls. Three were institutionalized mentally retarded patients, 11 were healthy children. Twelve had definite clinical signs of brain death within 48 hours of onset of disease. Cause of death in all patients was consistent with toxic encephalopathy. No other systemic complication was implicated as the cause of death except for one case consistent with a "Reye-like" syndrome. Shigella species were as follows: 8 flexneri, 4 sonnei, 1 dysenteriae, and 2 were not identified. Case-control study of these patients vs surviving, hospitalized patients with shigellosis showed similar severity of fever, diarrhea, vomiting, and dehydration and similar incidence of convulsions. Headache was a prominent feature of patients who died; 5 of 7 verbal patients complained of this symptom as opposed to 2 of 20 in the control group (P less than .01). There were no significant differences in the hematological and biochemical profile (except for an increased incidence of hyponatremia in the study group), pattern of shigella species, or antibiotic sensitivity. These findings indicate that mortality from shigellosis in a developed country is due primarily to the toxic encephalopathy syndrome.
Brain Diseases↗
[Familial hypobetalipoproteinemia with steatorrhea and malabsorption].
In a family in which the father was the mother's uncle, 3 of the 7 children were affected by a syndrome of malabsorption with various clinical symptoms. Diarrhea appeared in 2 of the children at birth, and in the third child at six months. The diarrhea led to failure-to-thrive, muscular wasting and abdominal swelling. However, the children improved spontaneously over the years. During childhood all 3 had manifest steatorrhea. Serum cholesterol was between 39 and 100 mg/dl, while triglycerides were normal to high. Reevaluation during the past year revealed areflexia, deficiency of vitamins A and E and of apoproteins A and B, and prolonged PT time in 2 of the children. Electron and light microscopy of small intestinal biopsies revealed vacuoles in the enterocytes. Electrophysiological tests revealed major disturbances in sensory conduction and brain-stem function. These cases differ from those described in the literature. Although in hypobetalipoproteinemia, 1 of the parents would be expected to be heterozygous and have low serum levels of APO B, in this family the parents had normal levels. Their children had low levels of serum APO A, while in patients with hypobetalipoproteinemia the levels are normal. There is a report of a case of deficiencies of both apolipoproteins, but the patient was asymptomatic, had chylomicronemia after a prolonged fast, and lower cholesterol levels than our patients. 8 other cases of apolipoprotein deficiency have been reported with biochemical characteristics similar to those of our patients, but with retention of chylomicrons in the small intestine.
Apoproteins↗