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Biomedical subjects

P Warner

Publications and source records attributed to P Warner.

At least 19 recordsLinked to original sources

What is the impact of change in diagnostic test method on surveillance data trends in Chlamydia trachomatis infection?

OBJECTIVE: To describe the impact of change from culture to more sensitive nucleic acid amplification testing (NAAT) tests on the detection of Chlamydia trachomatis in a genitourinary medicine (GUM) clinic population. METHODS: Data were collected between January 1992 and December 2003 on results of C trachomatis tests on male and female attenders at the Lothian GUM clinic (n = 81 590). Routine diagnosis switched from culture to NAAT methods in September 1998. Association of test result with age, sex, year of test, and test type was analysed using logistic regression. RESULTS: 6.1% (95% CI: 5.7% to 6.5%) of women and 7.1% of men (95% CI: 6.7% to 7.5%) tested positive with culture and 9.9% of women (95% CI: 9.4% to 10.3%) and 11.1% of men (95% CI: 10.7% to 11.5%) tested positive with NAATs. This corresponds to a 56% increase for men (95% CI: 47% to 66%) and 62% for women (95% CI: 50% to 67%). Logistic regression showed that a positive test result was strongly associated with test type with or without adjustment for year of test, sex, and young age. CONCLUSIONS: The significant increase in chlamydial infections detected following a change from culture to NAATs has important implications for interpretation of trends ascertained from surveillance data. Not all of this can be a direct effect of enhanced sensitivity and there may be indirect effects that improve ascertainment of existing infections. As more laboratories switch to NAATs similar patterns of stepwise increases in positive results are expected and trend analysis based on such surveillance data might thus show an artefactual rise in chlamydia infection rates. Accumulated surveillance data should therefore include timing of introduction of NAAT, so as to take account of under-ascertainment by previous methods.

Adult↗

Piezoelectric sensors for dioxins: a biomimetic approach.

The aim of this work was to design a fast, cheap and easy to use analytical system for dioxins. Piezoelectric sensors coupled with the pentapeptides as biomimetic traps (the receptors), selective for the dioxins, were used for the realisation of this analytical system. A methodology to select specific receptors among all possible pentapeptides randomly generated was represented by the use of molecular modelling software. Three peptides called later on A, B and C (A:[N]Asn-Phe-Gln-Gly-Ile[C]; B:[N]Asn-Phe-Gln-Gly-Gln[C]; C:[N]Asn-Phe-Gln-Gly-Phe[C]), were selected and evaluated for their potential usage as artificial receptors in solid-gas analysis by using a quartz crystal microbalance (QCM) sensors array. The peptide sequences were functionalised by two terminal cysteine residues in order to achieve a covalent interaction with the QCM gold surface. A manganese-porphyrin complex and two other pentapeptides, a pentaglutamine (pentapeptide D) and a pentalysine (pentapeptide E), were used as negative control sensors. The QCM sensors (A, B and C) gave a good linearity against different sample concentrations of the 2,3,7,8-tetrachlorinated dibenzo-p-dioxin (TCDD) and a mixture of dioxins. In particular, the selectivity against 2,3,7,8-TCDD was nicely correlated to the estimated binding energy of the receptors calculated by computational modelling. The cross-reactivity of the system was quantified using commercial polychlorinated biphenyls (PCBs) mixtures (dioxin-like compounds).

Biomimetics↗

Evaluation of abnormal uterine bleeding: comparison of three outpatient procedures within cohorts defined by age and menopausal status.

OBJECTIVES: To compare three outpatient methods of endometrial evaluation in terms of performance, patient acceptability and cost-effectiveness. DESIGN: Pragmatic unblinded trial randomised separately within three groups determined by risk of endometrial cancer. SETTING: The gynaecology outpatient clinic of a large city hospital in Edinburgh, Scotland. PARTICIPANTS: Women referred for investigation and management of abnormal bleeding between January 1999 and May 2001. INTERVENTIONS: Investigations were: blind biopsy alone, hysteroscopy with biopsy, ultrasound evaluation including transvaginal ultrasound, and, in the low-risk group, the option of no investigation. Within this design, two devices for obtaining endometrial biopsy were compared, the Pipelle sampler and the Tao brush. MAIN OUTCOME MEASURES: Successful (informative) completion of the investigation, acceptability of the investigation method to women, women's satisfaction with clinic care in the short term and at 10 months and 2 years of follow-up, and cost-effectiveness to the end of investigation. RESULTS: Minor adverse events (e.g. shock, patient distress) did not occur for ultrasound, but occurred in 16% and 10% of women for hysteroscopy and biopsy procedures respectively. Pipelle biopsy provided an acceptable endometrial sample for 79% of moderate-risk women, but only 43% of high-risk women. The Tao brush gave similar performance in moderate-risk women (77%), but was more successful than the Pipelle sampler in postmenopausal (high-risk) women (72%). There were significantly more successful visualizations for ultrasound than for hysteroscopy in both the low-risk and the moderate-risk group, and a similar but non-significant trend in the high-risk group. Ultrasound was significantly better than hysteroscopy at detecting fibroids, but hysteroscopy significantly better for polyps. At the 10-month follow-up, high-risk women who had been investigated by hysteroscopy (with biopsy) had the most positive views of their clinic experience, but this effect had largely disappeared by 24 months. In the moderate-risk group, the subgroup randomised to biopsy alone gave the most negative responses about their clinic experience and health now. Women wishing they had more investigation comprised 22% of moderate-risk women and 38% of low-risk women, but only 14% of postmenopausal women. At follow-up the moderate-risk women (with menstrual bleeding problems), compared with postmenopausal women, had much worse ratings for clinic experience and health now. Resource use tended to be higher in the moderate- and low-risk women. There was minimal difference in cost-effectiveness between investigation options in the high-risk group, with the option involving hysteroscopy being marginally better than ultrasound. The most cost-effective investigation in the moderate-risk group was biopsy alone and in the low-risk group ultrasound. CONCLUSIONS: Decision-making about investigation would be clarified if postmenopausal women were studied separately from premenopausal women with menstrual bleeding problems. For postmenopausal women exclusion of cancer is a main objective, so once investigation has been completed discharge follows, but in the woman with abnormal menstrual bleeding, even if serious pathology is excluded, the original presenting symptoms require management. About 60% of premenopausal women with abnormal bleeding reported that their symptoms were not 'much improved' at 10 months. Research is needed to understand this phenomenon, and to explore ways to integrate patient factors into optimising evaluation and treatment. The significance of benign pathologies in this group also requires clarification. Given the relatively small differences observed in cost-effectiveness, there is justification for allowing other issues (such as clinician preferences and women's perspectives) to influence decisions as to the investigation method. There is scope to make better use of patient factors to inform decisions as to the most efficient and acceptable method of investigation for an individual woman. Additional analyses, using data available as a result of this study, will contribute to this agenda.

Adult↗

About time: diagnostic guidelines that help clinicians.

Clinical guidelines often make recommendations on the use of diagnostic tests. Compared with sensitivity and specificity, the use of pre- and post-test probabilities allows a more explicit and rational selection and interpretation of diagnostic tests. Ideally, clinical guidelines relating to diagnosis should routinely incorporate this information to enhance individualised decision making. We report our experience of incorporating pre- and post-test probabilities into a guideline on the investigation of women with postmenopausal bleeding developed by the Scottish Intercollegiate Guidelines Network. Issues relating to their application are highlighted, including the limitations of available evidence on diagnostic tests and prevalence of disease, acceptability to guideline users, and the uncertain impact on actual clinical decision making. Despite these potential difficulties, the incorporation of data on pre- and post-test probabilities into the development and presentation of guideline recommendations may offer an important opportunity to make clinical decision making more transparent for both clinicians and patients.

Decision Making↗

Hysterectomy and ovarian function: levels of follicle stimulating hormone and incidence of menopausal symptoms are not affected by hysterectomy in women under age 45 years.

OBJECTIVE: To investigate levels of follicle stimulating hormone (FSH), as a measure of ovarian function and menopausal symptoms prior to and following hysterectomy in women under the age of 45 years. DESIGN: This was a prospective controlled study. SAMPLE: A total of 56 hysterectomy patients and 34 controls, up to the age of 42 years, were recruited. METHODS: Women undergoing hysterectomy were recruited prior to their operation and were matched, where possible, with controls for age, parity and smoking. Five blood samples were taken over 2 years, two before the operation (or at a 1-month interval in the control group) and then at 6 months, 1 year and 2 years. Questionnaires were completed at each sampling to assess symptoms associated with reduced estrogen secretion. RESULTS: No significant differences in FSH levels between patients and controls were found. Modest differences in FSH levels between different time-points were identified (p = 0.03), but this disappeared if age and smoking were included as covariates. For the questionnaire data, there were no significant differences between the two groups on the somatic and vasomotor scales, but for psychological symptoms the patients scored significantly higher than the controls (p = 0.007), particularly at the pre-operation time-point. CONCLUSION: The study found no evidence of compromise of ovarian function, as reflected in FSH levels, within 2 years of hysterectomy. Psychological symptoms were higher in women undergoing hysterectomy both before and after the operation.

Adult↗

Referral for menstrual problems: cross sectional survey of symptoms, reasons for referral, and management.

OBJECTIVES: To describe the menstrual experience of women referred for menstrual problems, in particular menorrhagia (excessive menstrual loss), and to assess associations with reasons for referral given by their general practitioners, the women's understanding of the reasons for their attendance at the hospital clinics, and clinic outcome. DESIGN: Questionnaire survey, with partial review of case notes after 8 months. SETTING: Three hospital gynaecology clinics in Glasgow and Edinburgh. PARTICIPANTS: 952 women completed the questionnaire, and the first 665 were reviewed. OUTCOME MEASURES: Reason for referral, women's reported menstrual problems and reason for clinic attendance, diagnosis, and treatment. RESULTS: Only 38% (95% confidence interval 34% to 41%) of women reported excessive menstrual loss as a severe problem. However 60% (57-63%) gave it as reason for attending a clinic, and 76% (73-79%) of general practitioners gave it as reason for referral. Reason for referral was significantly biased towards bleeding (McNemar odds ratio 4.01, 3.0 to 5.3, P<0.001) and against pain (0.54, 0.4 to 0.7, P<0.001). Dysfunctional uterine bleeding was diagnosed in 37% (31-42%) of the 259 women who gave as reason for attendance something other than bleeding. Women who were economically disadvantaged differed in prevalence of the main diagnoses and were more likely to fail to reattend. Hysterectomy was associated with referral for bleeding (relative risk 4.9, 1.6 to 15.6, P<0.001) but not with the patient stating bleeding as the reason for clinic attendance. CONCLUSIONS: Intolerance of the volume of their bleeding is not a key feature among women attending clinics for bleeding problems. Broad menstrual complaint tends to be reframed as excessive bleeding at referral and during management. This may result in women receiving inappropriate care. Conceptualisation and assessment of menorrhagia requires reconsideration.

Adult↗

Estimating menstrual blood loss in women with normal and excessive menstrual fluid volume.

OBJECTIVE: To examine the relationship between total fluid volume at menstruation and the volume of blood loss, and to assess the feasibility of using total fluid volume to estimate menstrual blood loss. METHODS: Fifty-three women were studied over two menstrual periods each. Hemoglobin in menstrual pads and tampons was measured using the alkaline hematin technique; total menstrual fluid volume was simultaneously measured using a weighing technique and meticulous care to avoid evaporation. RESULTS: Despite period-to-period change in measured total menstrual fluid and menstrual blood loss volumes, there was a significant correlation between total fluid volume and blood loss (r =.93, P <.001). Blood comprised 48% of total menstrual flow for women with moderately heavy blood loss (>60 mL) and 50% for women with excessive blood loss (>100 mL). Regression estimation of blood loss from total fluid volume was reasonably accurate. For clinical purposes, estimated blood volumes correctly classified 98% of periods in terms of actual blood loss as normal (<60 mL blood), moderately heavy (60-100 mL), or excessive (>100 mL). CONCLUSION: If total fluid volume is measured carefully, the estimate of actual blood loss is sufficiently accurate for clinical purposes. This simple technique has considerable clinical potential, and inexpensive commercial packs for this purpose could easily be developed.

Blood Volume↗

Opportunistic screening for chlamydia infection in general practice: can we reach young women?

OBJECTIVE: To study opportunistic screening in primary care, in such a way that would include teenage women. Setting-Screening for chlamydia infection was offered opportunistically in eight general practices in Edinburgh to women aged < or = 35 years attending for cervical smear, and women aged < or = 20 years attending for contraception. The numbers of women eligible to be offered screening were 901 in the cervical smear group, and 595 in the contraception group. RESULTS: Effective screening rate (offered test, consented, and urine sample returned) was 30% for the cervical smear group compared with 23% for the contraception group. Among those tested, chlamydia prevalence was strongly associated with young age, ranging from 11.8% in those <18 years, to 0% in those >25 years. Number of sexual partners in past year did not improve prediction of infection. CONCLUSION: These findings raise concerns regarding the feasibility of opportunistic screening in general practice, particularly for those with highest prevalence of chlamydia--teenage women.

Adolescent↗

Altered cadherin and catenin complexes in the Barrett's esophagus-dysplasia-adenocarcinoma sequence: correlation with disease progression and dedifferentiation.

The maintenance of adult tissue architecture is largely dependent on the function of cadherins. E-cadherin is expressed in most epithelia, although it may be co-expressed with P-cadherin in basal layers of stratified epithelia. Adhesive function of cadherins relies on interactions with catenins. Many reports have characterized reduced expression of cadherins and catenins in tumors, including those of the gastrointestinal tract. This study aimed to characterize expression of E- and P-cadherins, and the catenins, in the progression of Barrett's esophagus to adenocarcinoma. Immunohistochemical analysis and Western blotting were performed on paraffin-embedded and fresh-frozen tissue using antisera to the selected cadherins and catenins. The results of this study have shown inappropriate expression of cadherins and catenins in neoplastic Barrett's mucosa. There was a significant reduction of E-cadherin expression as the Barrett's metaplasia-dysplasia-adenocarcinoma sequence progressed (P < 0.01). In contrast, P-cadherin, expressed in basal layers of squamous esophagus, was usually absent from Barrett's and dysplasia but was expressed in 17 of 24 carcinomas, especially at the advancing tumor edge. Reduced expression of catenins was also seen, but in some specimens, immunoreactivity was observed in neoplastic nuclei, suggesting mediation of a nuclear function such as transcriptional regulation.

Adenocarcinoma↗

Safety, tolerability, and pharmacokinetics of sumatriptan suppositories following single and multiple doses in healthy volunteers.

A suppository formulation of the 5HT1 agonist sumatriptan could prove an important therapeutic option in migraine patients who dislike or poorly tolerate injectable therapy and where oral tablet administration is unsuitable because of severe migraine-related vomiting. Two independent double-blind, randomized clinical studies were conducted to evaluate the safety, tolerability and pharmacokinetics of sumatriptan suppositories following ascending single doses (four different dose levels) and multiple doses. In the four-period, crossover, single-dose study, 24 healthy male subjects were randomized to receive a suppository containing 12.5, 25, 50, or 100 mg on separate occasions 3-14 days apart. The suppositories were generally well tolerated; transient asthenia, drowsiness, and headache were the most frequently reported adverse events, and these were not dose-related. Peak plasma concentrations (Cmax) of sumatriptan were proportional to dose from 25 to 100 mg; area under the plasma concentration-time curve (AUC infinity) values were proportional to dose except at the highest doses, when they were greater than those predicted from lower doses. For all doses, the tmax of sumatriptan occurred within 2.5 h, and the t1/2 was approximately 2 h. In the two-period, placebo-controlled, crossover, repeat-dose study, 12 healthy adult male subjects were randomized to receive either a 50-mg sumatriptan suppository or placebo suppository, administered rectally twice a day, for 11 doses (5 1/2 days). Adverse events were no more frequent with sumatriptan than with placebo, and stool guaiac, rectal examinations, and physical examinations remained normal. No significant differences were noted between Day 1 and Day 6 values in the AUC, Cmax, time of peak serum concentration (tmax), elimination half-life (t 1/2), fraction of the dose excreted in the urine (fe), or renal clearance (Clr) of sumatriptan or its pharmacologically inactive indole acetic acid metabolite. Serum metabolite concentrations were two to three-fold higher than corresponding sumatriptan concentrations. No clinically significant accumulation of sumatriptan or its metabolite occurred. Overall, these studies show that sumatriptan administration via a suppository formulation is well tolerated, allows rapid absorption of sumatriptan, results in sumatriptan Cmax values that are proportional to dose from 25 to 100 mg, and is not associated with accumulation of sumatriptan or its metabolite.

Adolescent↗

Food craving during the menstrual cycle and its relationship to stress, happiness of relationship and depression; a preliminary enquiry.

The associations between retrospective ratings of food craving and depression during the premenstrual, menstrual and postmenstrual phases of the preceding menstrual cycle and ratings of current levels of stress and happiness of relationship were examined in 5,546 women. In each phase examined, the severity of food craving was very strongly related to the reported severity of depression. Overall levels of food craving were inversely related to happiness of relationship and there was some interaction of this effect with on-going stress. However, once the effect of depression was accounted for there was no effect of either current stress or happiness of relationship on the cycle-related pattern of food craving and in general the magnitude of the effect of these psychosocial variables was very small compared with that of depression. Food cravings were also reported in the absence of depression, tending to show a cycle-related pattern, maximal premenstrually, declining during menstruation and further postmenstrually. Whilst this is consistent with a cycle-related biological explanation, it remains unclear whether the striking amplification of food craving ratings in association with co-existing depression, in all three phases examined, is also biologically based or dependent on psychological mechanisms. In view of the retrospective nature of the ratings of mood and craving and the limited assessment of stress and happiness of relationship, these findings should be regarded as preliminary. They are, however, of potential importance and the association between these two common phenomena deserves further study.

Adult↗

Nonpeptidic inhibitors of human leukocyte elastase. 2. Design, synthesis, and in vitro activity of a series of 3-amino-6-arylopyridin-2-one trifluoromethyl ketones.

A series of potent nonpeptidic inhibitors of the enzyme human leukocyte elastase (HLE) is reported. These inhibitors contain a 3-amino-2-pyridone ring as a central template in which the pyridone carbonyl and 3-position NH group are thought to form important hydrogen bonding interactions with the Val-216 residue of HLE. Substitution of the 6-position of the pyridone ring by various alkyl and aryl groups was found to afford increases in the in vitro potency of these inhibitors. A 6-position phenyl group, compound 10f, was found to result in a large increase in binding affinity, which was not obtained when the phenyl group was placed in either the 4- or 5-position of the molecule. Compound 10f was found to have good selectivity for HLE over other proteolytic enzymes, with the exception of bovine pancreatic chymotrypsin (BPC). Substitution of the 6-phenyl group in these molecules was found to decrease binding affinity for BPC without adversely affecting affinity for HLE.

Acetamides↗

Non-peptidic inhibitors of human leukocyte elastase. 1. The design and synthesis of pyridone-containing inhibitors.

Human leukocyte elastase (HLE) is a serine protease produced by neutrophils that has been implicated in diseases such as emphysema and cystic fibrosis. An HLE inhibitor may have therapeutic value in these diseases. An active site model of HLE bound to a tripeptidic trifluoromethyl ketone (TFMK) inhibitor, 2, was created from X-ray structures of HLE and porcine pancreatic elastase. Analysis of the model indicated a preferred binding conformation for the tripeptide and potentially important interactions between it and the enzyme. This information was used to aid in the design of a series of novel, pyridone-containing, non-peptidic HLE inhibitors such as 2-[3-[[(benzyloxy)carbonyl]amino]-2-oxo- 1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)ace tam ide (5b) (Ki = 280 +/- 78 nM). Inspection of the active site model suggested that a benzyl substituent at the 5-position of the pyridone ring might improve potency by forming a lipophilic interaction with the enzyme S2 pocket. Synthesis and biological evaluation of a series of 5-benzylpyridone TFMKs provided evidence for this proposition. Further analysis of the model indicated that substitution on the 3-amino group of the pyridone ring with a hydrogen bond acceptor could potentially lead to interactions with the NH atoms of glycine-218 and/or -219. The oxalate derivative 2-[5-benzyl- 3-(carboxycarbonyl)-2-oxo-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifl uor o-1- isopropyl-2-oxopropyl)acetamide (5v) was synthesized and found to have a Ki of 48 +/- 9 nM. Unfortunately, none of the compounds tested was active in an in vivo model of HLE-induced lung injury when dosed orally.

Amino Acid Sequence↗

Posttranslational modifications in microcin B17 define an additional class of DNA gyrase inhibitor.

Drugs that inhibit the activity of DNA gyrase fall almost exclusively into two structural classes, the quinolones and the coumarins. A third class of DNA gyrase inhibitor is defined by the ribosomally synthesized peptide antibiotic microcin B17 (MccB17). MccB17 contains 43 amino acid residues, but 14 of these are posttranslationally modified. Here we describe the characterization of the structure of these modifications. We propose that four cysteine and four serine side chains undergo condensation with the carbonyl group of the preceding residue, followed by alpha/beta dehydrogenation to yield four thiazole and four oxazole rings, respectively. The three proteins implicated in catalyzing these modifications (McbBCD) would constitute the only thiazole/oxazole biosynthetic enzymes identified. These results open up possibilities for the design of DNA gyrase inhibitors and add to the repertoire of posttranslational modifications with potential for protein engineering. Escherichia coli sbmA mutants, which lack the inner membrane protein (SbmA) involved in MccB17 uptake, were found to be resistant to bleomycin. Bleomycin is structurally unrelated to MccB17 except for the fact that it contains two thiazole rings. This suggests that thiazole rings are part of the MccB17 structure recognized by SbmA. This observation and the finding that SbmA homologs are widely conserved and can play developmental roles [Glazebrook, J., Ichige, A. & Walker, G. C. (1993) Genes Dev. 7, 1485-1497] suggest that thiazole- and oxazole-containing compounds may serve as signaling molecules for a wide variety of bacteria in diverse environments, including pathogen interactions with plant and animal hosts.

Amino Acid Sequence↗

The effect of exercise training on pulmonary function in persons with quadriplegia.

The purpose of this study is to determine if measures of pulmonary function are different between endurance trained and nontrained groups of persons with quadriplegia. After minimum criteria were met, 57 subjects with spinal cord injuries ranging from C5-T1 were surveyed to determine type, duration and intensity of exercise training for the previous 6 months. Subjects were assigned to the trained or untrained groups based on the operational definitions of 'trained' vs 'untrained'. A computerized spirometer was used to test forced vital capacity (FVC), forced mid-expiratory flow (FEF25-75%) and maximum voluntary ventilation (MVV) as indicators of respiratory muscle strength, airway patency and respiratory muscle endurance, respectively. Independent t tests and Wilcoxon-Mann-Whitney nonparametric tests revealed no significant differences between the 'trained' and 'untrained' groups for the pulmonary functions. Correlation analysis revealed a moderate relationship (r = 0.498; p < or = 0.0001) between a derived continuous variable called the weighted training equivalent (WTE) and FVC. Regression analysis revealed that WTE and level of injury accounted for approximately 30% of the variance of FVC with WTE contributing 25%. Exercise training may positively affect FVC in persons with quadriplegia.

Adult↗

Obstetric postanesthesia nursing: a staff education program.

The same standards of nursing care must be provided to all postanesthesia patients, whether these are general surgical patients or those who have received regional or general anesthesia associated with vaginal or cesarean birth. Because obstetric nursing personnel have not had the benefit of didactic and skills training in the area of postanesthesia nursing, additional training is mandated. The article describes a staff education program designed as an educational framework to enhance the knowledge base and assessment skills of obstetric nurses providing postanesthesia care.

Education, Nursing, Continuing↗