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PubMed1991

Differential effects of the immunosuppressive macrolides FK-506 and rapamycin on activation-induced T-cell apoptosis.

Activation of certain T-cell lines induces, besides lymphokine production, a suicide process (apoptosis) mediated by fragmentation of the cell's genome. This also occurs intrathymically during negative selection of the T-cell receptor (TcR) repertoire. Cyclosporin A (CsA) has been shown to block activation-driven T-cell apoptosis, an effect which may account for the perturbations of TcR repertoire selection caused by this agent in vivo. Recently, the macrolide FK-506 was demonstrated to suppress T-cell activation by inhibiting lymphokine production in a manner apparently similar to CsA. Thus, it seemed important to determine whether FK-506 would also prevent T-cell apoptosis. For the purpose of comparison, we also investigated rapamycin (RAP), a macrolide structurally related to FK-506, but that does not block lymphokine production and antagonizes the immunosuppressive action of FK-506. The DO-11.10 T-cell hybridoma stimulated with ionomycin plus PMA was used as a model system. FK-506 (1.2 nM) totally prevented DNA fragmentation detectable by agarose gel electrophoresis at 16 h of culture. FK-506 still inhibited this phenomenon when added 2 h after the initiation of the cultures but not later. In contrast, concentrations of RAP as high as 1 microM failed to block apoptosis. However, RAP (110 nM) reversed the apoptosis-inhibitory effect of FK-506, even if added 1-2 h after the latter to the cultures. Consistent with this antagonism, RAP also reversed the binding of a radiolabeled derivative of FK-506 in DO-11.10 cells. Therefore, FK-506 interferes with an early event of T-cell activation that leads to apoptosis whereas RAP does not.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Multiple binding sites for nuclear factors in the 5'-upstream region of two alpha 2u-globulin genes: implications for hormone-regulated and tissue-specific control.

In order to understand the tissue- and hormone-specific control of alpha 2u-globulin synthesis we isolated the 5'-upstream putative regulatory region of two alpha 2u-globulin genes: RAP 01 and RAO 01. Both clones seem to be expressed in rat liver. DNAseI footprinting analysis after incubation with rat liver nuclear extracts was used to identify regions of potential interest. Particular attention was paid to protected regions located in the neighbourhood of domains which, according to our previous studies, interact specifically with androgen- and glucocorticoid-receptor complexes. Fifteen DNAseI footprints could be mapped in clone RAO 01 (bp -758 up to the cap site). Nineteen footprints were observed in the corresponding region of RAP 01. Differences in the footprinting patterns were mainly observed in the more distal regions. Our data confirm the presence in both clones of two binding sites for the liver enriched factor pseudo-NF1 and one site for C/EBP previously observed in other alpha 2u-globulin genes. In addition we have been able to demonstrate, in RAP 01 only, a binding site for transferrin-liver factor 1. No differences in footprinting patterns could be demonstrated using liver nuclear extracts derived from animals with a high hepatic expression of alpha 2u-globulins (normal male rats) and animals with low to absent expression (prepubertal rats, female rats, rats with the testicular feminization syndrome, diabetic rats and hypophysectomized animals). Transfection experiments indicate that a fragment of RAP 01 (bp -643 up to -617) is able to act as a glucocorticoid and as an androgen response element. Larger fragments of RAP 01 and fragments of RAO 01 are ineffective. It is concluded that the expression of individual alpha 2u-globulin genes is probably the result of combinatorial interactions of several trans-acting factors with appropriate cis-acting elements. Moreover, important sites for tissue-specific and hormone-regulated expression may be situated outside the regions investigated.

Alpha-Globulins↗

PubMed1994

Effects of immunosuppressants FK506 and rapamycin on the heterooligomeric form of the progesterone receptor.

The non-DNA binding form of the rabbit uterus cytosol progesterone receptor (PR) contains, in addition to the hormone binding unit and heat shock protein M(r) 90kDa (hsp90), a Heat shock protein Binding Immunophilin (p59/HBI) which interacts with hsp90. P59/HBI binds the immunosuppressants FK506 and Rapamycin (RAP) and belongs to the FK506 binding protein family. A recombinant p59/HBI-glutathione-S-transferase fusion protein, purified by Sephadex LH-20 filtration of tritiated drug-p59/HBI complexes, binds FK506 and RAP with apparent Kd values of 75 +/- 40 and 40 +/- 15 nM, respectively. Immunopurification from cytosol of [3H]steroid-labeled tungstate-stabilized PR with anti-PR immunoadsorbent yielded "9S"-PR species in which hsp90, hsp70 and p59/HBI were present. In the absence of tungstate ions, only the 4-6S PR was eluted, and Western blot analysis demonstrated the absence of hsps and p59/HBI. In contrast 30 to 50% of the original 9S-PR species containing hsps and p59/HBI, was eluted in the absence of tungstate ions but after exposure of cytosol to 5 microM FK506 or RAP. Other experiments showed that cytosol fractions incubated for 2 h at 25 degrees C with 0.05 to 10 microM FK506 or RAP, then with [3H]steroids (the agonist [3H]Org 2058 or the anti-progestin [3H]RU486), contains greater amounts of 9S-PR species than that detected in non-immunosuppressant exposed control cytosol. Scatchard analysis showed an up to 2-fold decrease of the Kd value for both hormones following exposure to drugs, without modification of the number of steroid binding sites. Purification of cytosol PR on immobilized FK506 yields a 9S form still containing hsp90, hsp70 and p59/HBI associated to PR units. Altogether, these results suggest that binding of immunosuppressants to p59/HBI does not promote hsps dissociation from the receptor and, as a consequence, that inhibition of peptidyl-prolyl isomerase activity of p59/HBI by immunosuppressants binding does not transform (activate) PR in vitro. However, given the assumption that hsp90 binds to receptor and that p59/HBI binds hsp90 but not directly to receptor, immunosuppressants affect hormone binding by an unknown mechanism involving receptor associated proteins. In addition, we show that the chick oviduct cytosol 9S-PR, not displaced with the EC1 antibody specific for several mammalian p59/HBI, also binds to FK506 columns and can be eluted by exchange with either FK506 or RAP, suggesting that there is an avian HBI homolog.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2006

Rapid auditory processing and learning deficits in rats with P1 versus P7 neonatal hypoxic-ischemic injury.

Hypoxia-ischemia (HI) is associated with premature birth, and injury during term birth. Many infants experiencing HI later show disruptions of language, with research suggesting that rapid auditory processing (RAP) deficits (i.e., impairment in the ability to discriminate rapidly changing acoustic signals), play a causal role in language problems. We recently bridged these lines of research by showing RAP deficits in rats with unilateral-HI injury induced on postnatal days 1, 7, or 10 (P1, P7, or P10. While robust RAP deficits were found in HI animals, it was suggested that our within-age sample size did not provide sufficient power to detect age-at-injury differences within the pooled HI group. The current study sought to examine differences in neuropathology and behavior following unilateral-HI injury on P1 versus P7 in rats. Ages chosen for HI induction reflect differential stages of neurodevelopmental maturity, and subsequent regional differences in vulnerability to reduced blood flow/oxygen (modeling age-related differences in premature/term HI injury). Results showed that during the juvenile period, both P1 and P7 HI groups exhibited significant RAP deficits, but deficits in the P1 HI group resolved with repeated testing (compared to shams), while P7 HI animals showed lasting deficits in RAP and spatial learning/memory through adulthood. The current findings are in accord with evidence that HI injury during different stages of developmental maturity (age-at-injury) leads to differential neuropathologies, and provide the novel observation that in rats, P1 versus P7 induced pathologies are associated with different patterns of auditory processing and learning/memory deficits across the lifespan.

Acoustic Stimulation↗

PubMed2004

Noninvasive assessment of right atrial pressure using Doppler tissue imaging.

Right atrial pressure (RAP) reflects volume and pressure hemodynamics of right cardiac chambers. Previous attempts for noninvasive assessment of RAP include 2-dimensional and Doppler correlates of RAP, which require the presence of optimal subcostal views that may not be always feasible. In this study we utilized Doppler tissue imaging of the tricuspid annulus in the apical 4-chamber view, for noninvasive assessment of RAP. An inverse relationship was demonstrated between mean RAP and the interval between the end of the systolic annular motion to the onset of the early diastolic filling wave (right ventricular regional isovolumic relaxation time).

Aged↗

PubMedDate not supplied

Surgical treatment of pancreas divisum causing chronic pancreatitis: the outcome benefits of duodenum-preserving pancreatic head resection.

Pancreas divisum (PD) represents a duct anomaly in the pancreatic head ducts, leading frequently leading to recurrent acute pancreatitis (rAP) or chronic pancreatitis (CP). Based on endoscopic retrograde cholangiopancreatography, pancreas divisum can be found in 1% to 6% of patients with pancreatitis. The correlation of this abnormality with pancreatic disease is an issue of continuing controversy. Because of the underlying duct anomalies and major pathomorphological changes in the pancreatic head, duodenum-preserving pancreatic head resection (DPPHR) offers an option for causal treatment. Thirty-six patients with pancreatitis caused by PD were treated surgically. Thirty patients suffered from CP, 6 from rAP. The mean duration of the disease was 47.5 and 49.8 months, respectively. The age at the time of surgery was 39.2 years in the CP group, and 27.6 years in the rAP group. Median hospitalization since diagnosis was 18.8 weeks for CP patients and 24.6 weeks for rAP patients. Previous procedures performed in these patients included endoscopic papillotomy (30%), duct stenting (14%), and surgical treatment (17%). The median preoperative pain score was 8 on a visual analog scale. According to the classification of pancreas divisum, 10 patients demonstrated a complete PD, 25 had a functionally incomplete PD, and 1 had a dorsal duct type. The pain status as well as the endocrine (oral glucose tolerance test) and exocrine (pancreolauryl test) function were evaluated preoperatively and early and late postoperatively with a median follow-up time of 39.3 months. There was no operative-related mortality. The follow-up was 100%; 4 patients died (1 from suicide, 1 from cardiac arrest, and 2 from cancer of the esophagus). Fifty percent of the patients were completely pain-free, 31% had a significant reduction of pain with a median pain score of 2 (P < 0.001). Six patients (5 CP, 1 rAP) had further attacks of acute pancreatitis with a need for hospitalization. DPPHR reduced pain and preserved the endocrine function in the majority of patients with pancreas divisum. Therefore, DPPHR is an alternative to other resective or drainage procedures after failure of interventional treatment.

Adult↗

PubMed2004

Expression and purification of rat recombinant aminopeptidase B secreted from baculovirus-infected insect cells.

Aminopeptidase B (Ap-B) is a ubiquitous enzyme and its physiological function still remains an open question. This Zn2+ -exopeptidase catalyzes the amino-terminal cleavage of basic residues of peptide or protein substrates, indicating a role in precursor processing. In addition, the enzyme exhibits a residual capacity to hydrolyze leukotriene A4 (LTA4) into the pro-inflammatory lipid mediator leukotriene B4 (LTB4) in vitro. This potential bi-functional nature of Ap-B is supported by a close structural relationship with LTA4 hydrolase, which hydrolyzes LTA4 into LTB4, in vivo, and exhibits an aminopeptidase activity, in vitro. Structural studies are necessary for the detailed understanding of the bi-functional enzymatic mechanism of Ap-B. In this study, we report cDNA cloning, baculovirus expression, and purification of the rat Ap-B (rAp-B). The Ap-B cDNA was constructed from extracted rat testes total RNA and introduced into the pBAC1 baculovirus transfer vector to generate recombinant baculoviruses. rAp-B expression, with or without COOH-hexahistidine tag, was tested in two different insect cell hosts (Sf9 and H5). The enzyme is secreted into the insect cell culture medium, which allowed a rapid purification of the protein. The His-tagged rAp-B was purified using metal affinity resin while the native recombinant rAp-B was partially purified using a single step DEAE Trisacryl ion exchange column. Although the recombinant rAp-B exhibits biochemical properties equivalent to those of the rat testes purified protein, the presence of the histidine-tag seems to partially inhibit the exopeptidase activity. However, this report shows that baculovirus-infected cells are a useful system to produce rat Ap-B for use in studying enzymatic mechanisms in vitro and 3D structure.

Aminopeptidases↗

PubMed2006

Performance of subjects with and without severe mental illness on a clinical test of problem solving.

Severe mental illness is associated with impairments in executive functions, such as conceptual reasoning, planning, and strategic thinking all of which impact problem solving. The present study examined the utility of a novel assessment tool for problem solving, the Rapid Assessment of Problem Solving Test (RAPS) in persons with severe mental illness. Subjects were 47 outpatients with severe mental illness and an equal number healthy controls matched for age and gender. Results confirmed all hypotheses with respect to how subjects with severe mental illness would perform on the RAPS. Specifically, the severely mentally ill subjects (1) solved fewer problems on the RAPS, (2) when they did solve problems on the test, they did so far less efficiently than their healthy counterparts, and (3) the two groups differed markedly in the types of questions asked on the RAPS. The healthy control subjects tended to take a systematic, organized, but not always optimal approach to solving problems on the RAPS. The subjects with severe mental illness used some of the problem solving strategies of the healthy controls, but their performance was less consistent and tended to deteriorate when the complexity of the problem solving task increased. This was reflected by a high degree of guessing in lieu of asking constraint questions, particularly if a category-limited question was insufficient to continue the problem solving effort.

Adult↗

PubMed1999

Evolutionary conservation of circulating soluble low density lipoprotein receptor-related protein-like ("LRP-like") molecules.

Low density lipoprotein receptor family members characteristically bind 39-kDa receptor associated protein (RAP). Soluble forms of these receptors have been described in humans including the 515/85-kDa dimeric receptor, low density lipoprotein receptor-related protein (LRP/alpha2MR), which is involved in multiple processes including lipoprotein and protease metabolism. Here we demonstrate evolutionary conservation in the generation of these soluble RAP-binding proteins of high molecular weight, by identifying their presence in mammalian, avian, and reptilian sera as well as in the circulating haemolymph of a mollusc. Sera extracted on immobilized RAP, produced bands at approximately 500 kDa in radiolabeled ligand blots by using the LRP/alpha2MR-specific ligand, Pseudomonas exotoxin A (PEA). These findings suggest that circulating RAP-binding proteins with high molecular weight in vertebrates share features of LRP/alpha2MR (LRP-like molecules). RAP-binding molecules in the mammalian serum extracts were further characterized as LRP/alpha2MR homologues in Western blots by using antibodies against the 515-kDa alpha-chain of LRP/alpha2MR. Western blots of mammalian serum extracts using two monoclonal antibodies recognizing the 85-kDa transmembrane beta-chain suggested that a portion of the beta-chain's ectodomain remains associated with the alpha-chain, but the beta-chain's intracellular carboxy terminus is absent. These results are consistent with evolutionary conservation in the generation, composition, and ligand-binding ability of soluble LRP-like receptors and suggest that their presence is a necessary aspect of the receptor's function.

Animal Population Groups↗

PubMed2003

Renal artery pseudoaneurysm after partial nephrectomy: three case reports and a literature review.

OBJECTIVES: To report 3 cases of renal artery pseudoaneurysm (RAP) after partial nephrectomy and review the literature to discuss their unique presentation, clinical course, and management. RAPs are a rare clinical entity. They are a well-documented source of hemorrhage in association with renal biopsy, renal trauma, renal transplant, and percutaneous procedures; however, little is known about their presentation, pathophysiology, and management after nephron-sparing surgery. METHODS: Between 2000 and 2002, 698 partial nephrectomies were performed at our institution for treatment of suspected localized renal malignancy. A retrospective review of these cases revealed that 3 patients developed a postoperative RAP. These cases were reviewed along with the current medical literature available from the MEDLINE database to characterize this clinical entity further. RESULTS: Three patients developed RAP after 698 uncomplicated partial nephrectomies were performed (0.43% incidence). Illustrating a classic presentation, the patient in case 1 was successfully treated with selective embolization after presenting with symptoms 3 weeks postoperatively. The patient in case 2 was treated with elective partial selective embolization for an asymptomatic lesion that later resolved spontaneously. In case 3, the patient presented early during the hospital course and required urgent selective embolization. CONCLUSIONS: RAP after nephron-sparing surgery is a rare, but potentially life-threatening, condition that is often difficult to diagnose and requires a high index of suspicion. Treatment should be tailored to each patient's clinical presentation to minimize morbidity and maximize renal conservation. All urologists should be aware of this potential postoperative complication and prepare accordingly.

Aged↗

PubMed1997

Recurrent abdominal pain in children: a review of psychological factors and treatment.

This paper reviews current knowledge regarding recurrent abdominal pain (RAP) and the physiological, dietary, and psychological variables that may have some influence in pain episodes. Emphasis is placed on psychological factors and studies that have investigated psychological treatment modalities. There is some limited evidence of physiological dysfunction in RAP patients, and while some researchers have asserted that RAP may be a dietary disorder, results of several studies do not support this assertion. Studies examining psychological variables in RAP patients show elevated anxiety levels; however, elevated anxiety is also associated with organic abdominal pain. Psychological treatments focusing on cognitive-behavioral methods have demonstrated success in treating RAP. Follow-up studies are needed to determine the long-term success of these treatments, and continued research examining which children benefit from treatment would also be beneficial.

Abdominal Pain↗

PubMed2003

Structural organization of the receptor associated protein.

The receptor associated protein (RAP) is a 38 kDa ER-resident protein that binds tightly to the low density lipoprotein receptor-related protein (LRP), and other members of the LDL receptor family of receptors, and competes with all known LRP ligands for binding to LRP. To better understand the domain structure and organization of RAP, we have expressed RAP subfragments and examined them by two-dimensional HSQC NMR and fluorescence spectroscopies, by differential scanning calorimetry, and by both equilibrium and velocity sedimentation measurements. We found that the protein is organized into three domains located in the first third (1D), middle third (2D), and last third (3D) of the protein. All three domains adopt stable tertiary structure as isolated domains and are monomers. Whereas domains 1D and 2D do not interact with one another, 3D interacts with 2D, both in a 2D-3D construct and in intact RAP. Sedimentation measurements also indicated that intact RAP, although monomeric, is significantly elongated.

Calorimetry, Differential Scanning↗

PubMed2005

Independent and cooperative roles of N-glycans and molecular chaperones in the folding and disulfide bond formation of the low-density lipoprotein (LDL) receptor-related protein.

The low-density lipoprotein receptor-related protein (LRP) is a large receptor that contains extensive glycosylation sites and disulfide bonds. Here we analyzed how N-linked glycosylation and molecular chaperones function during LRP folding. Treatment of cells with a glycosylation inhibitor tunicamycin significantly impaired LRP folding, although binding to receptor-associated protein (RAP), a specialized chaperone for LRP, was not affected. The effects of tunicamycin on LRP folding were not due to an inhibition of RAP glycosylation since a mutant RAP that harbors a mutation at its sole glycosylation site was still capable of promoting LRP folding. The roles of N-linked glycosylation and the lectin chaperone, calnexin, in LRP folding were further dissected using LRP minireceptors that carry mutations at individual glycosylation sites. Interestingly, we found that RAP interacts with oxidoreductase ERp57 and mediates its interaction with LRP. Since previous studies have shown that N-glycan-bound calnexin/calreticulin are also capable of recruiting ERp57, our results suggest that N-linked glycosylation and RAP can independently and cooperatively recruit oxidoreductases to facilitate protein folding and proper disulfide bond formation.

Animals↗

PubMed2003

1H, 13C and 15N resonance assignments of domain 1 of receptor associated protein.

The 39 kDa receptor associated protein (RAP) is a modular protein consisting of multiple domains. There has been no x-ray crystal structure of RAP available and the full-length protein does not behave well in a NMR tube. To elucidate the 3D structure of the RAP, we undertook structure determination of individual domains of the RAP. As the first step, here we report the nearly complete assignments of the (1)H, (13)C and (15)N chemical shift signals of domain 1 of the RAP.

Amino Acid Sequence↗

PubMed2002

A similar high level of immunoglobulin A and immunoglobulin G class milk antibodies and increment of local lymphoid tissue on the duodenal mucosa in subjects with cow's milk allergy and recurrent abdominal pains.

In previous studies, we have reported endoscopic and histological alterations locally on the gastrointestinal (GI) tract associated with a gastrointestinal type of cow's milk allergy. In this study, we sought to further characterize endoscopic, and immunological findings in these children. We also hypothesized that the same type of immune responses might also be found in children with unexplained and recurrent abdominal pains. We did a gastroduodenoscopy for persistent GI symptoms, examined the mucosal histology of the small intestine and measured the antibodies to whole cow's milk and its fractions with an enzyme-linked immunosorbent assay (ELISA) in a consecutive series of 22 subjects with untreated and 14 with treated cow's milk allergy (CMA) and 44 with recurrent abdominal pains (RAP). The immunological findings of the study subjects were compared with 54 controls. Lymphonodular hyperplasia (LNH) of the duodenum was the main endoscopic finding in 11 subjects (50%) with untreated and 5 (36%) with treated CMA. It was also found in 6 of 44 subjects with RAP. Compared with the controls, the patients with CMA showed significantly higher levels of IgA class antibodies to whole milk (p = 0.003) and betaLG (p < 0.0001). Of the IgG class antibodies to betaLG (p = 0.032), BSA (p < 0.0001) and alphaCAS (p < 0.0001) were significantly higher. The patients with LNH of the duodenal bulb as the main endoscopic finding showed significantly higher values of IgG class antibodies to betaLG (p = 0.01) and alphaCAS (p = 0.005). Interestingly, the patients examined for RAP showed a similar increment in the pattern of whole milk and specific milk protein antibodies as the CMA children. In conclusion this study showed that gastrointestinal CMA beyond infancy is significantly associated with high levels of IgG and IgA class antibodies to milk and its fractions. As high levels of these antibodies and LNH of the duodenal bulb were also found in subjects with RAP, the study further suggests that gastrointestinal CMA might be one major reason for RAP.

Abdominal Pain↗

PubMed2005

Profiling estrogen-regulated gene expression changes in normal and malignant human ovarian surface epithelial cells.

Estrogens regulate normal ovarian surface epithelium (OSE) cell functions but also affect epithelial ovarian cancer (OCa) development. Little is known about how estrogens play such opposing roles. Transcriptional profiling using a cDNA microarray containing 2400 named genes identified 155 genes whose expression was altered by estradiol-17beta (E2) in three immortalized normal human ovarian surface epithelial (HOSE) cell lines and 315 genes whose expression was affected by the hormone in three established OCa (OVCA) cell lines. All but 19 of the genes in these two sets were different. Among the 19 overlapping genes, five were found to show discordant responses between HOSE and OVCA cell lines. The five genes are those that encode clone 5.1 RNA-binding protein (RNPS1), erythrocyte adducin alpha subunit (ADD1), plexin A3 (PLXNA3 or the SEX gene), nuclear protein SkiP (SKIIP), and Rap-2 (rap-2). RNPS1, ADD1, rap-2, and SKIIP were upregulated by E2 in HOSE cells but downregulated by estrogen in OVCA cells, whereas PLXNA3 showed the reverse pattern of regulation. The estrogen effects was observed within 6-18 h of treatment. In silicon analyses revealed presence of estrogen response elements in the proximal promoters of all five genes. RNPS1, ADD1, and PLXNA3 were underexpressed in OVCA cell lines compared to HOSE cell lines, while the opposite was true for rap-2 and SKIIP. Functional studies showed that RNPS1 and ADD1 exerted multiple antitumor actions in OVCA cells, while PLXNA3 only inhibited cell invasiveness. In contrast, rap-2 was found to cause significant oncogenic effects in OVCA cells, while SKIIP promotes only anchorage-independent growth. In sum, gene profiling data reveal that (1) E2 exerts different actions on HOSE cells than on OVCA cells by affecting two distinct transcriptomes with few overlapping genes and (2) among the overlapping genes, a set of putative oncogenes/tumor suppressors have been identified due to their differential responses to E2 between the two cell types. These findings may explain the paradoxical roles of estrogens in regulating normal and malignant OSE cell functions.

Cell Line↗

PubMed2001

Systemic levels of glyceryl trinitrate following topical application to the anoderm do not correlate with the measured reduction in anal pressure.

BACKGROUND: Topical 0.2 per cent glyceryl trinitrate (GTN) lowers resting anal pressure (RAP) and heals two-thirds of chronic anal fissures. Over 50 per cent of patients experience headache, presumably through systemic absorption, but the pharmacokinetics of GTN ointment are unknown. This study evaluated the systemic absorption profile of GTN, and correlation between plasma GTN levels, RAP, haemodynamic variables and side-effects. METHODS: Thirty healthy volunteers were recruited with local medical school ethics committee approval. Continuous static anal manometry was performed for 10 min before and 2 h after application of 0.2 per cent GTN (0.5 g) to the anoderm. Blood samples were taken from an intravenous cannula, and pulse and blood pressure were measured before application of GTN, and 10, 20, 30, 40, 50, 60, 90, 120 and 180 min thereafter. Details of side-effects were recorded. RESULTS: GTN was detected in the plasma 10 min to 3 h after topical application. RAP was significantly reduced after 10 min, but had returned to pretreatment values by 120 min. Pulse was statistically unchanged during the study; systolic blood pressure was significantly lower 20-90 min after GTN application, and diastolic pressure was decreased throughout the study. Headaches were experienced by 14 of 30 volunteers after a median (range) of 41 (4-120) min, persisting for 74 (30-176) min, with an intensity score of 19 (5-30) mm represented on a 100-mm linear visual analogue scale. There was no correlation between plasma GTN concentration, RAP, and the onset, duration or intensity of headaches. CONCLUSION: Topical GTN acts locally on the internal anal sphincter; systemic levels do not contribute significantly to the reduction in RAP. There is marked interindividual variation in plasma GTN levels, and no correlation with haemodynamic variables and side-effects.

Absorption↗

PubMed2000

The prevalence of recurrent abdominal pain in 11- to 16-year-old Malaysian schoolchildren.

OBJECTIVE: To determine the prevalence of recurrent abdominal pain (RAP) among Malaysian school children aged from 11 to 16 years. METHODOLOGY: A preliminary cross-sectional survey in which three urban schools and three rural schools were selected randomly. Two classes were selected randomly from each year. A questionnaire was given to each child asking him or her about whether they had experienced abdominal pain occurring at least three times over a period of at least 3 months, interfering with normal daily activity. 1 Interfering with normal daily activity was defined as missing school and/or having to stop doing a routine daily activity on account of the pain. Girls whose pains were related to periods were excluded. After the forms had been completed, each child was again interviewed to ensure that Apley's criteria1 was fulfilled in cases of RAP. RESULTS: The overall prevalence of RAP among 1549 schoolchildren (764 boys; 785 girls) was 10.2% (95% confidence interval (CI), 8.8-11.8). There appeared to be a higher prevalence in rural schoolchildren (P = 0.008; odds ratio (OR) 1.58), in those with a lower family income (P < 0.001; OR 2.02) and in children whose fathers have a lower educational attainment (P = 0.002; OR 1. 92). There were no significant differences in the prevalence of RAP among children of different sex, age, ethnic group and family size. CONCLUSION: : In spite of differences in time and culture, the overall prevalence of 10.2% found in this study is similar to that determined by Apley.1 There are significant differences in the prevalence of RAP between children from rural and urban schools, among children with different family incomes and among children whose parents have different educational backgrounds.

Abdominal Pain↗