Endometriosis and its coexistence with irritable bowel syndrome and pelvic inflammatory disease: findings from a national case-control study--Part 2.

OBJECTIVE: To investigate whether the increased chances of having a diagnosis of irritable bowel syndrome (IBS) and pelvic inflammatory disease (PID) in women with endometriosis is due to misdiagnosis or co-morbidity. DESIGN: A case-control study of women aged 15-55 years with endometriosis and matched controls. SETTING: Data from the UK's General Practice Research Database for the years 1992-2001. SAMPLE: A total of 5540 women aged 15-55 years, diagnosed with endometriosis, each matched to four controls without endometriosis. The index date was defined as the date of diagnosis. METHODS: Data were analysed to determine whether women with endometriosis were more likely to receive a diagnosis of PIDor IBS than women without endometriosis. Odds ratios were calculated for endometriosis associated with IBS and PID before and after the index date. MAIN OUTCOME MEASURES: Diagnosis of IBS or PID before and after the index date. RESULTS: Compared with the controls, women with endometriosis were 3.5 times more likely to have received a diagnosis of IBS (OR 3.5 [95% CI: 3.1-3.9]). Even after women had been diagnosed with endometriosis, they were still two and a half times more likely to receive a new diagnosis of IBS when compared with the controls (OR 2.5 [95% CI: 2.2-2.8]). Similarly, women with endometriosis were more likely than those without endometriosis to have been treated for PID both before (OR 5.9 [95% CI: 5.1-6.9]) and after (OR 3.8 [95% CI: 3.1-4.6]) being diagnosed with endometriosis. CONCLUSIONS: Women with endometriosis are more likely to be diagnosed with IBS and PID than controls, even after a definitive diagnosis of endometriosis has been reached.

Can symptomatology help in the diagnosis of endometriosis? Findings from a national case-control study--Part 1.

OBJECTIVE: To determine the value of patient-reported symptoms in diagnosing endometriosis. DESIGN: A national case-control study. SETTING: Data from the UK General Practice Research Database for years 1992-2001. SAMPLE: A total of 5540 women aged 15-55 years, diagnosed with endometriosis, each matched to four controls without endometriosis. METHODS: Data were analysed to determine whether specific symptoms were highly indicative of endometriosis. Odds ratios for these symptoms were derived by conditional logistic regression analysis. MAIN OUTCOME MEASURES: Symptoms associated with endometriosis. RESULTS: The prevalence of diagnosed endometriosis was 1.5%. A greater proportion of women with endometriosis had abdominopelvic pain, dysmenorrhoea or menorrhagia (73%) compared with controls (20%). Compared with controls, women with endometriosis had increased risks of abdominopelvic pain (OR 5.2 [95% CI: 4.7-5.7]), dysmenorrhoea (OR 8.1 [95% CI: 7.2-9.3]), menorrhagia (OR 4.0 [95% CI: 3.5-4.5]), subfertility (OR 8.2 [95% CI: 6.9-9.9]), dyspareunia and/or postcoital bleeding (OR 6.8 [95% CI: 5.7-8.2]), and ovarian cysts (OR 7.3 [95% CI: 5.7-9.4]), and of being diagnosed with irritable bowel syndrome (IBS) (OR 1.6 [95% CI: 1.3-1.8]) or pelvic inflammatory disease (OR 3.0 [95% CI: 2.5-3.6]). Women with endometriosis were also found to consult the doctor more frequently than the controls and were twice as likely to have time off work. CONCLUSIONS: Specific symptoms and frequent medical consultation are associated with endometriosis and appear useful in the diagnosis. Endometriosis may coexist with or be misdiagnosed as pelvic inflammatory disease or IBS.

"What else is there to do?"--A qualitative study of the barriers to soldiers stopping smoking.

OBJECTIVES: To investigate the impact of Army life on soldiers' motivation for stopping smoking. METHOD: A two stage study using a questionnaire to identify smokers in a British Army infantry battalion of 560 soldiers based in the United Kingdom with either a low or high intention to quit smoking, followed by semi-structured interviews of a purposive sample of 18 respondents. RESULTS: 31.3% of soldiers were current smokers. In addition to recognised barriers to stopping smoking, the interview data revealed structural and cultural barriers, some of which are unique to the Army. Structural barriers included an increased opportunity to smoke in terms of time, place, and cost. Cultural barriers included peer pressure, the smoking norm, and a lack of discouragement from the 'regimental family'. These barriers to stopping smoking often arise from established British Army values and standards. For example, the need for punctuality requires early arrival at destinations, which in turn, provides an increased time opportunity to smoke. Other attitudes that the Army wishes to encourage, such as building teamwork and interdependence, can also be enhanced through smoking. CONCLUSION: Whilst the numerous, previously identified barriers to stopping smoking exist within and outside the armed forces, specific additional barriers arise from the structure and culture of the Army. Changes in the structure of daily life within the Army may reduce the barriers to stop smoking. Army clinicians also play an important part in soldiers' stopping smoking and an increased understanding of the specific barriers to stopping smoking may help them to support soldiers more effectively.

Sustained hemodynamic effects of the selective dopamine-1 agonist, fenoldopam, during 48-hour infusions in hypertensive patients: a dose-tolerability study.

Eight patients with stage I-II hypertension received a continuous IV infusion of the selective dopamine-1 agonist, fenoldopam, for up to 48 hours at rates from 0.4 to 1.9 micrograms/kg/min. Hemodynamics and clinical symptoms during infusion were compared to the same parameters in the 24-hour periods before and after infusion. Fenoldopam lowered blood pressure and increased heart rate. Greatest changes occurred during the first 12 hours of infusion and gradually returned toward preinfusion values throughout the remaining 36 hours in the six patients who completed 48 hours of infusion. Fenoldopam was discontinued within 2 hours of starting the infusion in two patients who received drug rates of 0.9 microgram/kg/min and 1.9 micrograms/kg/min because of precipitous bradycardia. Clinical symptoms noted at fenoldopam doses higher than 0.8 microgram/kg/min were headache, dizziness, diaphoresis, nausea and vomiting, and restlessness. In this pilot study, fenoldopam effectively reduced blood pressure in patients with stage I-II hypertension for up to 48 hours, but fixed-dose infusion rates above 0.8 microgram/kg/min were associated with a high frequency of clinically significant and often intolerable adverse effects.

Metabolism of leukotriene C4 in gamma-glutamyl transpeptidase-deficient mice.

We have investigated the metabolism of leukotriene C4 (LTC4) in gamma-glutamyl transpeptidase (GGT)-deficient mice (Lieberman, M. W., Wiseman, A. L., Shi, Z-Z., Carter, B. Z., Barrios, R., Ou, C-N., Chevez-Barrios, P., Wang, Y., Habib, G. M., Goodman, J. C., Huang, S. L., Lebovitz, R. M., and Matzuk, M. M. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 7923-7926) and have found substantial conversion of LTC4 to leukotriene D4 by high performance liquid chromatography and continuous flow fast atom bombardment-tandem mass spectrometric analyses. LTC4-converting activity has a tissue distribution different from GGT with highest activity in spleen followed by small intestine, kidney, and pancreas and lower activity in liver and lung. The activity is membrane-bound and is inhibited by acivicin, a known inhibitor of GGT. The enzyme was partially purified from the small intestine of GGT-deficient mice by papain treatment and gel filtration chromatography. The partially purified fragment released by papain has an apparent molecular mass of 65-70 kDa and the same substrate specificity as the tissue homogenate. In addition to LTC4, S-decyl-GSH is also cleaved. GSH itself, oxidized GSH, and the synthetic substrates used to analyze GGT activity (gamma-glutamyl-p-nitroanilide and gamma-glutamyl-4-methoxy-2-naphthylamide) are not substrates for this newly discovered enzyme. These data demonstrate that in addition to GGT at least one other enzyme cleaves LTC4 in mice. To reflect this enzyme's preferred substrate, we suggest that it be named gamma-glutamyl leukotrienase.

A 21-kDa C-terminal fragment of protein-disulfide isomerase has isomerase, chaperone, and anti-chaperone activities.

A catalyst of disulfide formation and isomerization during protein folding, protein-disulfide isomerase (PDI) has two catalytic sites housed in two domains homologous to thioredoxin, one near the N terminus and the other near the C terminus. The thioredoxin domains, by themselves, can catalyze disulfide formation, but they are unable to catalyze disulfide isomerizations (Darby, N. J. and Creighton, T. E. (1995) Biochemistry 34, 11725-11735). A 21-kDa, C-terminal fragment of PDI (amino acids 308-491), termed weePDI, comprises the C-terminal third of the molecule. The kcat for ribonuclease oxidative folding by weePDI is 0.26 +/- 0.02 min-1, 3-fold lower than the wild-type enzyme but indistinguishable from the activity of a full-length mutant of PDI in which both active site cysteines of the N-terminal thioredoxin domain have been mutated to serine. Eliminating the ability of weePDI to escape easily from covalent complexes with substrate by mutating the active site cysteine nearer the C terminus to serine has a large effect on the isomerase activity of weePDI compared with its effect on the full-length enzyme. weePDI also displays chaperone and anti-chaperone activity characteristic of the full-length molecule. As isolated, weePDI is a disulfide-linked dimer in which the single cysteine (Cys-326) outside active site cross-links two weePDI monomers. The presence of the intermolecular disulfide decreases the activity by more than 2-fold. The results imply that the functions of the core thioredoxin domains of PDI and other members of the thioredoxin superfamily might be modified quite easily by the addition of relatively small accessory domains.

Species-dependent post-translational modification and position 2 allelism: effects on streptococcal superantigen SSA structure and V beta specificity.

Epidemiologic and molecular population genetic analyses support a role for superantigens (SAg) in the pathogenesis of severe staphylococcal and streptococcal infections. To investigate how variations in SAg structure influence immunomodulatory activity, we examined the biochemical and functional properties of two allelic variants of streptococcal SAg SSA that differ at position 2. Mass spectrometry revealed both recombinant (Escherichia coli) and native (Streptococcus pyogenes) SSA allelic variants to have significantly larger molecular masses than predicted by primary sequence alone and provided evidence that the proteins were modified by the addition of biochemical moieties, a phenomenon that has not been described for related SAg. Furthermore, the molecular masses of native and recombinant SSA were not the same; SSA was differentially post-translationally modified by the two bacterial genera. The substitution of E. coli-dependent processing for that of S. pyogenes altered both protease digestion and V beta specificity, suggesting that recombinant SAg from E. coli may not accurately represent the native toxin. In addition, the observation that SSA allelic variants differed in V beta specificity supports a role for position 2 in SSA-TCR interactions. That SSA position 2 contributes to V beta specificity could not have been predicted from functional or crystallographic studies of other SAg and suggests that SSA may adopt unique interactions with TCR and/or MHC class II molecules. Determining the structural basis for these differences should offer additional clues to the manner in which SAg exert their effects on the immune system during infection and may allow the designing of SAg mutants with specific quantitative and qualitative immunomodulatory properties.

Fathers of children with disabilities comment on health services.

AIM: A study to investigate the experiences of fathers of children with disabilities generated comments about hospital-based services received around the time of diagnosis. METHODS: Fifteen fathers were interviewed in-depth using an inductive qualitative methodology. Interview transcripts were subjected to computer-assisted analysis in order to identify patterns, themes and categories. RESULTS: Analysis of the data produced a dimension identified and labelled by the authors as negative service evaluation. The components of this dimension were related to poor interpersonal skills by medical staff while breaking bad news, and different expectations of physicians of and fathers over the practical implications of diagnosis. CONCLUSIONS: These results support previous findings and indicate that physicians must take more responsibility for breaking bad news in a way that parents find acceptable.

Dehydration of peptide [M + H](+) ions in the gas phase.

The loss of water from protonated peptides was studied using [(18)O]-labeling of the C-terminal carboxyl group. The structures (including the location of the isotopic label) of first-generation product ions were examined by sequential product ion scanning (MS(3) and MS(4)) using a hybrid sector/quadrupole mass spectrometer. Water loss may involve carboxylic acid groups, side-chain hydroxyls, or peptide backbone oxygens. Although one of these three pathways often predominates, more than one dehydration route can be operative for a single peptide structure. When peptide backbone oxygen is lost, the dehydration can occur at one or two primary sites along the backbone, with the location of the site(s) varying among peptides. When water loss involves the C-terminal carboxyl group, the resulting ion may undergo extensive intraionic oxygen isotope exchange. This evidence for complex intraionic interactions further emphasizes the significance of gas-phase conformation in determining the fragmentations of peptide ions.

Charge promotion of low-energy fragmentations of peptide ions.

We have examined the hypothesis that structural features which predispose to localization of charge at a strongly favored site are not conducive to the low-energy fragmentation of peptide ions via a multiplicity of pathways. Consistent with this proposal, it is demonstrated that the formation of N- or C-terminal pre-charged derivatives is detrimental to the formation of sequence-specific product ions following low-energy collisional activation. Protonation of pre-charged derivatives (yielding doubly charged ions) restores favorable fragmentation properties; the effect is attributed to the fragmentation-directing properties of the proton which may occupy one of several sites. Similarly, a doubly protonated peptide which incorporates a C-terminal arginine residue as a single strongly favored site of protonation exhibits favored low-energy fragmentations attributable to location of the second proton at one of several sites remote from the C-terminus.

Origin of the tailing signal on the low-energy side of the main beam in mass-analyzed ion kinetic energy spectra.

The tailing signal on the low-energy side of the precursor ion signal observed during fast atom bombardment (FAB) mass-analyzed ion kinetic energy spectrometric (MIKES) analyses is due largely to ions of higher m/z value than the chosen precursor. The majority of these ions are independent, unfragmented species that emerge from the ion source with less than the full amount of kinetic energy predicted by the source potential. The tailing precursor ion signal observed under helium collision-activated decomposition conditions is too short to account for the protracted MIKES tail (as judged from mass-to-charge ratio-deconvoluted MIKES analyses performed on a BEqQ hybrid instrument), and a tailing precursor signal is not observed under unimolecular decomposition conditions. Measurements of the mass-to-charge ratios of the ionic species comprising the MIKES tail demonstrated that ions higher in mass-to-charge ratio than the chosen precursor are present throughout the tail, with the mass-to-charge ratio increasing as kinetic energy decreases. These ions possess the same momentum as the chosen precursor, and thus were formed prior to the magnetic field. The existence of intact, source-formed [M + H](+) ions with reduced kinetic energy was demonstrated through several types of tandem mass spectrometric experiments. These [M + H](+) ions with reduced kinetic energy do not appear to have undergone collisional deceleration, because they do not possess increased internal energy (as judged by observation of their fragmentation patterns). The kinetic energy profiles of unfragmented FAB-desorbed ions were determined and found to exhibit a tailing character similar in appearance to that of the MIKES tail. The population of ions emerging from the source under FAB conditions thus incorporates the characteristics necessary to account for the MIKES tail, namely, the presence of ions of a mass-to-charge ratio higher than the chosen precursor (due to matrix and other background ions), which possess reduced kinetic energy such that their momentum is identical to that of the selected precursor. These ions may arise via desolvation and declustering processes in the acceleration region of the ion source, or via FAB or chemical ionization processes in regions removed from the FAB target.

Multiple scan modes in the hybrid tandem mass spectrometric screening and characterization of the glutathione conjugate of 2-furamide.

The glutathione conjugate of 2-furamide has been screened for and structurally characterized by tandem mass spectrometry (MS(MS) by using a hybrid instrument of BEqQ design. Mass spectrometry experiments employed fast atom bombardment (FAB) ionization of a crude bile extract from a rat dosed with a 1:1 mixture of unlabeled and [ (13)C12-furamide. Initial screening for glutathione conjugates employed constant neutral loss scanning to detect the loss of 129 u, corresponding to the loss of the γ-glutamyl moiety of the conjugates. By direct comparison with control bile, [M + H] (+) ions of m/z 417 and 418 were readily identified as candidate ions corresponding to the glutathione conjugates of unlabeled and (13)C-labeled 2-furamide. Complementary screening information was generated by using a methylated bile extract, with constant neutral loss scanning to detect the loss of the methylated γ-glutamyl moiety (143 u). An alternative screening procedure employing parent ion scanning to detect the sodium adducts of methylated glutathione conjugates was also developed. Structural information was generated by frrst-generation product ion scanning of the protonated and sodium cationized forms of the candidate species, both native and derivatized. This provided a body of internally consistent evidence that the conjugate retains the pseudoaromatic furan ring system without ring hydroxylation. The utility of sequential mass spectrometry (MS(MS(MS) capability of the hybrid instrument in the analysis of complex biological mixtures was also demonstrated. Using the bile extract, first-generation product ions that formed in either the first or second field-free region of the double-focusing portion of the instrument were subsequently collisionally activated in the rf-only quadrupole followed by mass analysis of the second-generation product ions. Structural information so provided for the glutathione conjugate of 2-furamide further substantiated its retention of the pseudoaromatic furan ring system and facilitated plausible assignment of structures to ionic species generated through multiple decomposition events.

Quantitative analysis of adenosine: statistical comparison of radioimmunoassay and gas chromatography-mass spectrometry-selected ion monitoring methods.

A new method for quantitating adenosine concentration by capillary gas chromatography-mass spectrometry-selected ion monitoring (GC-MS-SIM) has been developed and used as a reference method for evaluating a newly developed radioimmunoassay (RIA) for adenosine. Details of the GC-MS-SIM method are presented, along with the comparative results and uncertainties of both methods. General considerations in the statistical analysis of method comparison data are discussed with particular reference to studies using quantitative mass spectrometry as the standard method; the adenosine methods are used as specific examples in this discussion. Simultaneous estimation of the y-intercept and slope of the least squares regression line relating the results of the two methods using the 95% joint confidence ellipse demonstrated the absence of either constant or proportional error between the two methods. The relatively small uncertainty in the GC-MS-SIM measurements had no significant effect on the linear regression. Random error between the two methods was detected, and was estimated by the coefficient of variation in the RIA data as ten percent of the RIA value.

Effects of captopril on limiting infarct size in conscious dogs.

The effects of angiotensin-converting enzyme inhibitor captopril on infarct size and cardiovascular hemodynamics were studied in 35 conscious dogs subjected to 24 h of coronary occlusion. Following occlusion of the left anterior descending coronary artery, 10 dogs were infused with captopril 0.25 mg/kg/h i.v. (group 1), eight dogs received captopril 0.5 mg/kg/h i.v. (group 2), and 17 dogs served as saline-infused controls. All infusions were started 10 min following occlusion and continued for 15 h. Eighty-eight percent of untreated dogs and 80% of group 1 captopril dogs survived the 24-h duration of the study. No experimental deaths occurred in group 2 captopril dogs. Arterial blood pressure had decreased 10-12 mm Hg in both captopril groups by 4 h and remained relatively stable for the remainder of the study period. In untreated dogs, blood pressure was unchanged for 6 h, then began a gradual decline. There were no significant differences in infarct size among the groups. When infarct size is expressed as percent of left ventricle at risk the values were: control, 39.9 +/- 5.6; captopril group 1, 44.8 +/- 4.9; and captopril group 2, 43.8 +/- 7.8%. Creatine kinase levels were not different among the groups. Heart rate and incidence of arrhythmias also did not differ among the groups. These data show that captopril had no detrimental or beneficial effects on infarct size or on cardiovascular hemodynamics associated with myocardial infarction in conscious dogs.

Videotape modeling for preschool children with low levels of social interaction and low peer involvement in play.

This research evaluated a videotape modeling intervention for six preschool children who showed low levels of social involvement with peers in natural free-play settings. Observations across 14 weeks gave frequency and topographic data on social interactions and assessment of social involvement in play using the Parten Scale. Simultaneous observation of three children gave data on two comparison children for each target child. A multiple-baseline across-subjects design was used with two data analysis strategies. Averaged group data showed statistically significant increases in both interactions and social involvement in play. Visual analysis of the single-subject data, however, indicated no clear treatment outcome for two children, while four subjects showed a variable increase in social responding after viewing the modeling videotape. Session-by-session variability was a feature of the interaction rate measure for comparison children and for posttreatment phase data for target subjects.

Behavioral self-management in story writing with elementary school children.

The effect of self-management procedures on objective writing responses and on the subjectively assessed quality of children's writing was investigated. All experimental procedures were applied to each of the 37 children in a regular Grade 3 class, and 14 of these children were randomly selected for data collection. Following baseline conditions, self-assessment plus self-recording of writing responses was introduced. This did not increase the number of sentences, number of different action words, or number of different describing words, or improve the quality of the stories. Self-determined and self-administered reinforcement was added to the self-assessment and self-recording procedures contingent on each of the writing responses in turn. Rates of responding were substantially increased and the stories received higher subjective ratings of quality from two independent judges. An increase in on-task behavior was correlated with self-reinforcement of writing responses.