Ibuprofen treatment of patent ductus arteriosus.
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Brain↗
Biomedical subjects
J Patel
Publications and source records attributed to J Patel.
A prodrug approach to increasing the oral potency of a phenolic drug. Part 2. Pharmacodynamics and preliminary bioavailability of an orally administered O-(imidomethyl) derivative of 17 beta-estradiol.
The O-saccharinylmethyl prodrug of 17 beta-estradiol was about nine times as potent, based on 50% effective dose (ED50) values, as 17 beta-estradiol when each was given as an oral dose to ovariectomized rats. Similarly, a significant lowering of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels at 24 h was observed when an ED50 dose of the prodrug was given but not when an equimolar dose of 17 beta-estradiol was given orally. However, when given intravenously, there was no difference in potency between the two drugs. In the bioavailability studies, a significantly longer half-life (approximately 5-7 times) for 17B-estradiol was observed when the prodrug was given orally than when 17 beta-estradiol was given orally or when the prodrug or 17 beta-estradiol were given intravenously. This result was consistent with an observed five-fold enhancement in the oral bioavailability of 17 beta-estradiol when the prodrug was given.
Administration, Oral↗
Expression of interleukin 8 and CD54 by human gastric epithelium after Helicobacter pylori infection in vitro.
BACKGROUND/AIMS: Helicobacter pylori is associated with neutrophil infiltrates, although the mechanism of their recruitment is only partially defined. The aim of the study was to determine if Kato III, a human gastric epithelial cell line, expressed cytokines and the intercellular adhesion molecule 1 (ICAM-1), which could contribute to the initiation of inflammation during infection with H. pylori. METHODS: Kato III cells were stimulated with H. pylori and were examined for evidence of infection, cytokine production, and the expression of ICAM-1. RESULTS: The expression of interleukin 8 messenger RNA and immunoreactive protein by Kato III cells was significantly increased over constitutive levels within 3 hours of infection with H. pylori. Infected Kato III supernatants activated neutrophils as evidenced by increased CD11b/CD18 and decreased L-selectin that could be blocked by anti-interleukin 8. In contrast, Campylobacter jejuni, lipopolysaccharide, killed H. pylori, and supernatants from cultures of H. pylori did not increase interleukin 8. Interleukins 2 and 6; interferons alfa, beta, and gamma; and tumor necrosis factor were not produced by resting or H. pylori-stimulated Kato III cells. In addition to producing interleukin 8, Kato III constitutively expressed surface ICAM-1, which acts as an intercellular adhesion molecule for neutrophils. CONCLUSIONS: Our results indicate that H. pylori stimulates the gastric epithelium to initiate inflammation and neutrophil recruitment and activation.
Base Sequence↗
Biphasic inhibition of stimulated endogenous dopamine release by 7-OH-DPAT in slices of rat nucleus accumbens.
1. Fast cyclic voltammetry was used to investigate the effect of 7-OH-DPAT (7-hydroxy-N,N-di-n-propyl-2-aminotetralin), a putative D3 receptor agonist, on electrically stimulated endogenous dopamine release in slices of rat nucleus accumbens. 2. 7-OH-DPAT inhibited single pulse stimulated dopamine release in a concentration-dependent manner with a maximum inhibition of 95.5%. Analysis of concentration-response curves to 7-OH-DPAT showed that they were biphasic, with the high affinity component contributing 18.0% to the total inhibition and the low affinity component 77.5%. 7-OH-DPAT exhibited a 560 fold selectivity between the high and low affinity components (0.015 nM compared to 8.4 nM). 3. Concentration-response curves to the non-selective D2/D3 agonist, apomorphine, were monophasic. The maximum inhibition was 93.1% and the EC50 value 82 nM. 4. The selective D2 antagonist, haloperidol (30 nM), antagonized the low affinity component of the concentration-response cuve to 7-OH-DPAT whilst the high affinity component was essentially unaffected. The pKB values calculated for the high and low affinity components were 7.89 and 9.45 respectively. 5. In conclusion, these results demonstrate that 7-OH-DPAT inhibits stimulated dopamine release by acting at two different sites. Furthermore, the results are consistent with the hypothesis that the high and low affinity components of the concentration-response curve to 7-OH-DPAT may reflect activation of functional D3 and D2 release-regulating autoreceptors respectively. However, the possibility that the biphasic nature of the curve may reflect different subtypes of the D2 receptor cannot be excluded.
Animals↗
Elevation of maternal alpha-fetoprotein in systemic lupus erythematosus: a controlled study.
OBJECTIVE: To determine if maternal alpha fetoprotein (AFP) is elevated in lupus pregnancy and, if so, whether it is associated with treatment or outcome. METHODS: Maternal serum AFP values were obtained once during Weeks 16.3 to 31.7 in 54 pregnancies followed prospectively. AFP was measured by the Maryland State Health Department, who reported the AFP level and a corrected value, multiple of the median (AFP MOM), adjusted for weight, gestational age, and insulin dependent diabetes. Controls were 1001 consecutive samples measured by the same laboratory. RESULTS: AFP MOM was higher in lupus pregnancies (1.425 +/- 0.73 vs 1.169 +/- 0.50, p = 0.001), as were the unadjusted AFP levels (lupus 68.26 +/- 42.2, control 52.49 +/- 27.25, p = 0.001). Of lupus pregnancies 7.4 vs 2.6% of control pregnancies had an abnormal AFP MOM (p = 0.06). The 4 patients with abnormal AFP-MOM, using the 2.3 cutoff, were taking more prednisone (27.25 +/- 18.54 mg vs 10.85 +/- 12.29 mg, p = 0.02), were more likely to have delivered preterm (31.50 +/- 36.31 weeks, p = 0.02), and were more likely to have a high anticardiolipin (aCL) antibody during the pregnancy (p = 0.03). CONCLUSION: AFP is higher in lupus than in control pregnancies, without any increase in neural tube or other birth defects. An abnormal maternal serum AFP level is associated with higher prednisone dose, preterm delivery and aCL. Patients and obstetricians need to be aware that an elevated maternal AFP in lupus pregnancy is not necessarily due to a birth defect, and may be predictive of preterm delivery.
Adult↗
Deletions within the DNA recognition subunit of M.EcoR124I that identify a region involved in protein-protein interactions between HsdS and HsdM.
The DNA recognition subunit (HsdS) of type I restriction endonucleases can be divided into domains by means of amino acid identity between subunits from the same family. It has been proposed that DNA-protein interactions occur within the variable domains of the subunit and that protein-protein interactions involve the conserved domains. We have constructed a number of deletion mutants of HsdS that have allowed us to investigate protein-protein interactions. Using a combination of a "competitive" complementation assay and the ability of HsdM to "solubilize" HsdS, we have defined a region within the central conserved domain of HsdS that is responsible for HsdS-HsdM interaction. Computer analysis of amino acid identity between the N-terminal half and the C-terminal half of HsdS identifies a region (repeated in both conserved domains), one copy of which overlaps the region we have identified as essential for HsdS-HsdM interactions, which may be responsible for such protein-protein interactions.
Amino Acid Sequence↗
Mechanism of inhibition of FaDu hypopharyngeal carcinoma cell growth by tetraphenylphosphonium chloride.
Cationic phosphonium salts are interesting because they inhibit the proliferation of carcinoma cells more than untransformed epithelial cells in vitro. This differential anti-proliferative effect has been used to identify phosphonium salts and other lipophilic cations that later demonstrated effects in animals. Using 6 carcinoma-derived and 2 untransformed epithelial cell lines, tetraphenylphosphonium chloride (TPP) and other cationic aryl phosphonium salts (CAPS) demonstrated a growth inhibition pattern similar to that of cation rhodamine 123, suggesting that CAPS may inhibit mitochondrial function. We tested this hypothesis for the effect of phosphonium salt TPP on FaDu human hypopharyngeal carcinoma cells. TPP inhibited the proliferation of FaDu carcinoma cells at submicromolar concentrations. Uptake of 3H-TPP by FaDu cells was partially inhibited in medium containing high K+ and fully inhibited by valinomycin in this medium, indicating that TPP accumulates preferentially in mitochondria, and to a lesser extent in the cytoplasm. FaDu cells exposed to TPP exhibited damage to mitochondrial inner membranes, reduced ATP/ADP ratios, decreased oxygen uptake rates and decreased mitochondrial membrane potentials. The treated cells secreted lactate more rapidly than untreated controls and exhibited hypersensitivity to 2-deoxyglucose, an inhibitor of glycolysis. TPP's antimitochondrial effects apparently enhance cytoplasmic glycolysis. In conclusion, TPP inhibits FaDu carcinoma cell growth by inhibiting mitochondrial respiration and ATP synthesis. Cationic phosphonium salts that inhibit carcinoma cell growth through antimitochondrial effects might be used to treat solid tumors without the risk of secondary tumors associated with agents affecting nuclear DNA.
Animals↗
Results of radical cystectomy for transitional cell carcinoma of the bladder and the effect of chemotherapy.
BACKGROUND: Radical cystectomy continues to be one of the primary modalities of treatment for locally advanced bladder cancer. However, long-term survival after cystectomy has improved only marginally in the last decade, and still, nearly half of the patients die from the disease within 5 years. Adjuvant treatments such as radiation therapy and chemotherapy have been used, but a clear advantage has not been demonstrated. METHODS: The authors reviewed 130 patients who underwent radical cystectomy by the same surgeon as treatment for transitional cell carcinoma of the bladder. Morbidity, postoperative mortality, overall survival time, and accuracy of clinical staging as well as the effect of perioperative chemotherapy were evaluated. RESULTS: The overall actuarial survival rate at 2, 5, and 10 years was 80%, 53%, and 45%, respectively. The survival rate based on T-classification at 5 years was 82%, 65%, and 28% for less than pT2, pT2, and greater than pT2, respectively. Regional lymph node status had a significant effect on survival. The 5-year survival rate for all patients with negative nodes was 65%, whereas patients with positive nodes had a 18% 5-year survival rate. The overall clinical staging error was 61.5%, with 41.5% of the cancers understaged. Of the patients with cTis, 60% were found to be of greater extent than pT1 tumors. No apparent survival advantage was noted for those patients who received perioperative chemotherapy when compared with patients who were followed conservatively or received chemotherapy upon relapse. These results, however, are not conclusive because this was an observation study and the number of patients was limited. CONCLUSIONS: Only a modest improvement in survival time after radical cystectomy has been observed in the last decade, despite the use of adjuvant treatments such as radiation and chemotherapy. The pathologic (pT) classification is the most accurate prognostic indicator. Clinical errors in classification are common and impair the evaluation of neoadjuvant treatments. A high incidence of invasive tumors of greater extent than pT1 was found among patients with clinical cTis; this supports an aggressive approach when these patients do not respond promptly to intravesical chemotherapy. Prospective randomized studies are needed to evaluate objectively the benefit of perioperative adjuvant treatment in locally advanced transitional cell carcinoma of the bladder.
Aged↗
Electrocardiographic and segmental wall motion abnormalities in pancreatitis mimicking myocardial infarction.
Transient electrocardiographic changes in patients with acute cholecystitis, pancreatitis, and pneumonia have been reported in the past. These changes usually are in the form of T-wave inversion, ST-segment depression, and rarely ST-segment elevation in the absence of coronary artery disease. To the authors' knowledge, this is the first report documenting both left ventricular segmental wall motion abnormality and electrocardiographic changes of myocardial injury in the presence of acute pancreatitis.
Acute Disease↗
Evaluation of long-term central venous patency in children with chronic venous catheters using image-directed Doppler ultrasonography.
All children in the Oncology Unit in the Royal Hospital for Sick Children, Edinburgh who had had long-term central venous catheters removed between 1987 and 1991 underwent central venous assessment by image-directed Doppler ultrasound scanning techniques. In this study, the implant vein remained patent after decannulation, and we believe should be re-accessed rather than moving to another site.
Blood Flow Velocity↗
Molecular genetic changes associated with ovarian cancer.
Multiple specific chromosomal deletions can be found in human epithelial ovarian cancer by cytogenetic analysis or molecular techniques. Somatic allelic deletion or loss of heterozygosity (LOH) in a tumor is considered circumstantial evidence for the location of tumor suppressor genes. We have examined 27 primary epithelial ovarian tumors for the presence of LOH at 19 polymorphic markers on chromosomes 1, 5, 6, 9, 11, 13, and 17. Markers near the adenomatous polyposis coli (APC) gene at 5q21 showed LOH in 50% (10/20) of informative cases. LOH was seen in 53% (8/15) at the IFNA locus on 9p, another region implicated in other tumors, but not previously associated with ovarian cancer. We observed LOH for markers on 11p15 in 50% (12/24) of ovarian cancer DNAs from informative cases, while only 25% (4/16) at 11q13 and 29% (5/17) at 11q24 showed LOH. Only a portion of distal 11p was deleted in six cases. The incidence of LOH (50%) at HGH (17q22-q24) was greater than that at D17S579 (39%; 17q21), a locus tightly linked to BRCA1. Sixty-four percent (7/11) showed allelic loss at 17p11. LOH was infrequently observed at markers on chromosomes 1, 6, and 13q. Most cases showing LOH were stage III or IV, and most showed LOH at more than one locus. These studies support the concept that multiple genetic loci are involved in ovarian tumorigenesis. Two additional regions thought to harbor genes important in other cancers, 5q21 and 9p21, can now be added to the growing spectrum of molecular alterations seen in ovarian cancer.
Adult↗
A single P1 clone bearing three genes from human chromosome 11p15.5: HRC1, HRAS1, and RNH.
Molecular genetic alterations of chromosome 11p15.5 are a common finding in human cancer. We previously reported the characterization of two cosmids representing a 55-kilobase (kb) region of DNA surrounding the protooncogene HRAS1. A cluster of genes was identified adjacent to this locus, and one of these genes, HRC1, was divergently transcribed 30 kb upstream from HRAS1. A recent report placed the gene for placental ribonuclease inhibitor (RNH, ribonuclease-angiogenin inhibitor) within 90 kb of HRAS1 by pulsed-field gel electrophoresis (PFGE) mapping. We used recombinant P1 bacteriophage clones for physical mapping to determine the position of RNH relative to the HRAS1 transcription unit and HRC1 on chromosome 11p15.5. PFGE and Southern analysis of genomic DNA suggested the order of the genes (HRC1-HRAS1-RNH). P1 clones confirmed this assignment, and placed RNH within 30-50 kb of the 3' end of HRAS1. Furthermore, a single 80-kb P1 clone that bears all three genes was isolated and clarified the Not I restriction map for the HRAS1-RNH interval. Their close physical association was predicted by simple screening of an arrayed P1 library; the clone containing all three genes was selected from multiple positive signals obtained for each HRC1 and RNH because it mapped to the same library-well address.
Bacteriophage P1↗
Anti-arrhythmic efficacy of beta-adrenergic blockade during acute ischemia in myocardium with scar.
Ventricular arrhythmia production in the ischemic heart is considered to be influenced by prior infarction. Although beta-adrenergic blockade is known to have beneficial effects during acute ischemia, its anti-arrhythmic efficacy during post-infarction ischemia is not known. To explore this question, we have used a model with a relatively high incidence of ischemic arrhythmias. Mongrel dogs 2 to 3 years of age were studied intact under anesthesia. An irreversible injury of the infero-posterior myocardium was produced with an electrode catheter 1 week earlier. The arrhythmic response to acute ischemia was assessed using serial, transient 15-minute occlusions of the left-anterior descending coronary artery with a balloon catheter. During ischemia alone, the incidence of ventricular fibrillation in animals who underwent all phases of the study was 6 of 9; with atenolol (0.2 mg/kg intravenously) and ischemia, 1 of 9 (p < 0.05). To assess the role of the bradycardic response, the latter was repeated 1 week subsequently during atrial pacing at the heart rate that existed before ischemia. Fibrillation occurred in 8 of 9, a significant reversal of the therapeutic effect. To exclude the potential artifact of a fixed intervention protocol, a study was undertaken with the short-acting esmolol, in which three ischemic periods were alternated at 1-hour intervals: (A) ischemia without treatment, (B) ischemia with continuous infusion of 150 micrograms/kg/min esmolol, and (C) same as B except that heart rate was maintained by atrial pacing.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic beta-Antagonists↗
Pulmonary infiltrates following bone marrow transplantation.
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Bone Marrow Transplantation↗
Lack of involvement of nitric oxide in NMDA-induced neuronal cell death in cortical culture.
In primary cultures of rat cerebral cortex, N-methyl-D-aspartate causes widespread neurotoxicity. Inhibitors of the nitric oxide generating the enzyme nitric oxide synthase has been shown to attenuate the effects of N-methyl-D-aspartate in a number of neuronal systems both in vivo and in vitro. In our experiments, the nitric oxide synthase inhibitor N-nitroarginine was ineffective at blocking neurotoxicity induced by N-methyl-D-aspartate. Cyclic guanine monophosphate, known to be synthesized in response to nitric oxide was demonstrably inhibited by identical treatments with N-nitroarginine in sister cultures. We conclude that although nitric oxide is produced in response to N-methyl-D-aspartate, it is neither necessary nor sufficient for neurotoxicity.
Amino Acid Oxidoreductases↗
A deletion mutant of the type IC restriction endonuclease EcoR1241 expressing a novel DNA specificity.
We have developed a complementation assay which allows us to distinguish between mutations affecting subunit assembly and mutations affecting DNA binding in the DNA recognition subunit (HsdS) of the multimeric restriction endonuclease EcoR1241. A number of random point mutations were constructed to test the validity of this assay. Two of the mutants produced were found to be truncated polypeptides that were still capable of complementation with the EcoR1241 Hsd subunits to give an active restriction enzyme of novel DNA specificity. The N-terminal variable domain (responsible for recognition of GAA from the EcoR1241 recognition sequence GAAnnnnnnRTCG) and the spacer region (central conserved region) is intact in both of these mutants. One of these mutant genes (hsdS(delta 50) has been cloned as an active Mtase. Purification of the Mtase proved to be difficult because the complex is weak. However, Mtase activity was obtained from a soluble cell extract, and this allowed us to determine the DNA recognition sequence of the Mtase to be GAAnnnnnnnTTC. This recognition sequence is an inverted repeat of 5'-end of the EcoR1241 recognition sequence. This suggests that the mutant Mtase is assembled from two inverted HsdS(D50) subunits, possibly held together by the HsdM subunits.
Amino Acid Sequence↗
Electrically stimulated gracilis sphincter for bladder incontinence.
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Adult↗
Physiological and histochemical adaptation of the electrically stimulated gracilis muscle to neoanal sphincter function.
The physiological and histochemical characteristics of the gracilis muscle were studied in 19 patients undergoing electrically stimulated gracilis neosphincter construction. Indications for surgery were faecal incontinence (n = 11) and reconstruction following sphincter excision or congenital absence (n = 8). Transposition of the gracilis muscle around the anal canal followed by chronic low-frequency electrical stimulation was associated with a shift in the frequency-response curve and a prolongation of the time-course of individual muscle twitches suggestive of transformation to a slow-twitch fatigue-resistant type. Temporary cessation of electrical stimulation resulted in a reversal of the frequency-response changes. Muscle biopsies taken before and a median of 80 (range 49-137) days after transposition and low-frequency electrical stimulation indicated a significant increase in the proportion of type 1 fibres and a significant decrease in their diameter. These results show that the human gracilis muscle is capable of physiological and histochemical adaptation to long-term neosphincter function.
Adaptation, Physiological↗