Biomedical subjects
Publications and source records attributed to C Hughes.
TolC and its many homologues comprise an alpha-helical transperiplasmic tunnel embedded in the bacterial outer membrane by a contiguous beta-barrel channel, providing a large exit duct for diverse substrates. The 'channel-tunnel' is closed at its periplasmic entrance, but can be opened by an 'iris-like' mechanism when recruited by substrate-engaged proteins in the cytosolic membrane.
Anecdotal evidence suggests that there is an increase in the incidence of pressure damage to women in labour. This appears to be associated with epidural anaesthesia. Epidural anaesthesia used to control pain in childbirth causes loss of sensation and a degree of motor block, which removes the women's reflexes and ability to reposition to prevent pressure damage. The large amount of fluids present during childbirth may also increase the risk of pressure damage, especially in association with shear and friction. A combination of unfamiliarity of pressure ulcer prevention techniques among midwives, and the type of delivery room equipment, that is currently available, may leave young healthy women at risk of developing pressure ulcers.
Peer problems are almost universal among children with disruptive behavior disorders, and have been linked to social information processing deficits that lead to heightened threat responses. This 2-year longitudinal study uses direct observations to examine the real-life significance of this finding. Forty "hard-to-manage" children and 40 typically developing control children were filmed at ages 5 and 7 playing a rigged competitive game in which they experienced a clear threat of losing. Group differences in negative behavior (hard-to-manage > controls) were stable over time and independent of verbal ability. Predictors of individual differences in negative behavior were also examined. Previous studies with this sample have shown that at 4 years of age, the hard-to-manage children displayed elevated frequencies of violent pretend play, coupled with poor performance on tests of executive function and theory of mind. In this study, 4-year-olds whose pretend play indicated a preoccupation with violence were more likely to respond negatively to the threat of losing a competitive game at age 5 and at age 7. Four-year-olds who performed poorly on tests of theory of mind and executive function showed higher rates of negative behavior at age 5 but not age 7. These findings highlight just a few of the multiple paths leading to peer problems among children with disruptive behavior problems.
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The flagellar proteins FlgN and FliT have been proposed to act as substrate-specific export chaperones, facilitating incorporation of the enterobacterial hook-associated axial proteins (HAPs) FlgK/FlgL and FliD into the growing flagellum. In Salmonella typhimurium flgN and fliT mutants, the export of target HAPs was reduced, concomitant with loss of unincorporated flagellin into the surrounding medium. Gel filtration chromatography of wild-type S. typhimurium cell extracts identified stable pools of FlgN and FliT homodimers in the cytosol, but no chaperone-substrate complexes were evident. Nevertheless, stable unique complexes were assembled efficiently in vitro by co-incubation of FlgN and FliT with target HAPs purified from recombinant Escherichia coli. The sizes of the chaperone-substrate complexes indicated that, in each case, a chaperone homodimer binds to a substrate monomer. FlgN prevented in vitro aggregation of FlgK monomers, generating a soluble form of the HAP. Recombinant polypeptides spanning the potentially amphipathic C-terminal regions of FlgN or FliT could not complement in trans the chaperone deficiency of the respective flgN and fliT mutants, but efficient flagellar assembly was restored by homodimeric translational fusions of these domains to glutathione S-transferase, which bound FlgK and FlgL like the wild-type FlgN. These data provide further evidence for the substrate-specific chaperone function of FlgN and FliT and indicate that these chaperones comprise common N- and C-terminal domains mediating homodimerization and HAP substrate binding respectively. In support of this view, the flgN mutation was specifically complemented by a hybrid chaperone comprising the N-terminal half of FliT and the C-terminal half of FlgN.
Escherichia coli hemolysin (HlyA) is a membrane-permeabilizing protein belonging to the family of RTX-toxins. Lytic activity depends on binding of Ca2(+) to the C-terminus of the molecule. The N-terminus of HlyA harbors hydrophobic sequences that are believed to constitute the membrane-inserting domain. In this study, 13 HlyA cysteine-replacement mutants were constructed and labeled with the polarity-sensitive fluorescent probe 6-bromoacetyl-2-dimethylaminonaphthalene (badan). The fluorescence emission of the label was examined in soluble and membrane-bound toxin. Binding effected a major blue shift in the emission of six residues within the N-terminal hydrophobic domain, indicating insertion of this domain into the lipid bilayer. The emission shifts occurred both in the presence and absence of Ca2(+), suggesting that Ca2(+) is not required for the toxin to enter membranes. However, binding of Ca2(+) to HlyA in solution effected conformational changes in both the C-terminal and N-terminal domain that paralleled activation. Our data indicate that binding of Ca2(+) to the toxin in solution effects a conformational change that is relayed to the N-terminal domain, rendering it capable of adopting the structure of a functional pore upon membrane binding.
We present an unusual case of a patient with an inferior infarct caused by saphenous vein graft compression by an extracardiac malignant spindle cell tumour, a mechanism of myocardial ischaemia rarely described. This case also illustrates how chest X-ray and angiography can be useful for making an early diagnosis of a cardiac mass.
Papillary fibroelastomas are rare benign tumours that are seldom diagnosed during life. We report three cases of this tumour; two patients had recurrent embolic events, and one was diagnosed incidentally. Although rare, these tumours are a potentially treatable cause of cardiac emboli. Prompt identification allows excision, which generally is curative.
OBJECTIVES: to examine the instruction in pelvic floor exercises given to women during pregnancy or following delivery, to assess the quality of any instruction provided, and to consider these in light of the women's views about the service. DESIGN: a postal questionnaire was sent to a sample of women when they reached 34 weeks of pregnancy and a second at 8 weeks postpartum. A sub-sample of women who reported symptoms of stress incontinence at 8 weeks postpartum were interviewed about the instruction in pelvic floor exercises that they received during their pregnancy, or in the puerperium. PARTICIPANTS: of the 918 women who were sent the first questionnaire, 717 returned it completed (78%). Five-hundred-and-seventy-two of 894 women (64%) completed the second questionnaire. Forty-two of 179 symptomatic women (23%) took part in an interview. FINDINGS: 55% of women received some form of instruction in pelvic floor exercises by 34 weeks of pregnancy. Eighty-six percent received instruction following birth. The way the information was given varied, ranging from a brief reminder, to exercising in a class with an instructor. The information was provided by a range of health professionals, and no single profession appeared to undertake responsibility for the service. As a result, the views of the service varied. A few women reported that they had received good quality instruction, others were critical of it, and a small number reported that they had received no instruction at all. The widespread practice of leaving a leaflet by the women's beds during their stay in hospital, was criticised by a large proportion of the women. KEY CONCLUSION: the instruction in pelvic floor exercises by health service professionals was provided on an ad hoc basis. In many instances, the programme of instruction did not meet recommendations made in the literature. It is likely that the success of randomised controlled trials reported in the literature would not be repeated in the 'real world' Implications for practice: there is a need for the service to be reorganised so that all women receive high-quality instruction during pregnancy, with a reminder to exercise following birth. This could help to prevent, or relieve, the symptoms of stress incontinence that frequently occur at these times.
OBJECTIVE: to identify whether women were made aware of stress incontinence around the time of childbirth, whether symptomatic women sought help from professionals caring for them at this time, to look at what help they receive in the first instance and to understand why some of those experiencing it chose not to seek help. DESIGN: a qualitative survey was conducted using semi-structured interviews. SETTING: interviews were conducted in participants' own homes. PARTICIPANTS: 42 women who reported symptoms of stress incontinence at eight weeks postpartum, and 15 women who were symptomatic one year following the birth of their baby. FINDINGS: women were reluctant to seek help, although they were often inconvenienced and troubled by the condition. This was predominantly due to the nature of the condition itself, although the relationship with their health care professionals was also a consideration in some cases. The majority of women were not provided with information on the condition but wanted health professionals to provide a warning that the condition could occur. They also wanted health professionals to seek out information about symptoms, rather than the women themselves having to broach the subject. The first line of treatment at this time was usually a recommendation to perform pelvic floor exercises. IMPLICATIONS FOR PRACTICE: health professionals caring for women during pregnancy or following the birth of their baby need to raise awareness of the condition, the treatment available, and to be pro-active in seeking out those experiencing incontinence rather than expecting women to approach them for help.
Platelet-rich plasma (PRP) is postulated to decrease postoperative mediastinal chest tube drainage (MCTD) and allogeneic blood transfusions (ABT) after surgery with cardiopulmonary bypass. However, recent metaanalysis of the literature reveals that few good quality (therapeutic yield) trials that show a benefit have been published. The potential hemodynamic instability caused by plateletpheresis has not been emphasized. We studied the effect of plateletpheresis on MCTD, ABT, and hemodynamic stability in reoperative coronary artery bypass graft patients, a group perceived to be at high risk for ABT. Ninety patients were randomly assigned to Pheresis or Control groups. epsilon-Aminocaproic acid was given to all patients. Hemodynamic instability was assessed by degree of volume and inotrope resuscitation required. Part of the sequestered platelet volume was used to make autologous platelet gel, which was applied as a wound sealant. Mean pheresis yield was 30% +/- 7% of the circulating platelet mass or 6.4 +/- 2.2 allogeneic platelet unit equivalents. Total MCTD did not differ between the groups. There were no differences in mean packed red blood cell, platelet, and plasma transfusion rates. Overall, 52% of the Pheresis group received ABT, versus 55% of the Control group. Fifty-three percent of the Pheresis group patients exhibited significant hemodynamic instability, versus 27% of the Control group (P < 0.05). This study was unable to show any reduction in MCTD or ABT, although the plateletpheresis technique may offset platelet dysfunction caused by aspirin or increased blood exposure to nonbiologic surfaces, or it may compensate for lack of antifibrinolytic use. The significantly increased incidence of hemodynamic instability in the Pheresis group means that the risk/benefit ratio must be determined for individual cardiac surgical units.
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Cephamycin C production was blocked in wild-type cultures of the clavulanic acid-producing organism Streptomyces clavuligerus by targeted disruption of the gene (lat) encoding lysine epsilon-aminotransferase. Specific production of clavulanic acid increased in the lat mutants derived from the wild-type strain by 2- to 2.5-fold. Similar beneficial effects on clavulanic acid production were noted in previous studies when gene disruption was used to block the production of the non-clavulanic acid clavams produced by S. clavuligerus. Therefore, mutations in lat and in cvm1, a gene involved in clavam production, were introduced into a high-titer industrial strain of S. clavuligerus to create a double mutant with defects in production of both cephamycin C and clavams. Production of both cephamycin C and non-clavulanic acid clavams was eliminated in the double mutant, and clavulanic acid titers increased about 10% relative to those of the parental strain. This represents the first report of the successful use of genetic engineering to eliminate undesirable metabolic pathways in an industrial strain used for the production of an antibiotic important in human medicine.
The 1,024-amino-acid acylated hemolysin of Escherichia coli subverts host cell functions and causes cell lysis. Both activities require insertion of the toxin into target mammalian cell membranes. To identify directly the principal toxin sequences dictating membrane binding and insertion, we assayed the lipid bilayer interaction of native protoxin, stably active toxin, and recombinant peptides. Binding was assessed by flotation of protein-liposome mixtures through density gradients, and insertion was assessed by labeling with a photoactivatable probe incorporated into the target lipid bilayer. Both the active acylated hemolysin and the inactive unacylated protoxin were able to bind and also insert. Ca(2+) binding, which is required for toxin activity, did not influence the in vitro interaction with liposomes. Three overlapping large peptides were expressed separately. A C-terminal peptide including residues 601 to 1024 did not interact in either assay. An internal peptide spanning residues 496 to 831, including the two acylation sites, bound to phospholipid vesicles and showed a low level of insertion-dependent labeling. In vitro acylation had no effect on the bilayer interaction of either this peptide or the full-length protoxin. An N-terminal peptide comprising residues 1 to 520 also bound to phospholipid vesicles and showed strong insertion-dependent labeling, ca. 5- to 25-fold that of the internal peptide. Generation of five smaller peptides from the N-terminal region identified the principal determinant of lipid insertion as the hydrophobic sequence encompassing residues 177 to 411, which is conserved among hemolysin-related toxins.
Persons living with HIV/AIDS face many issues that make them highly vulnerable to a number of health and social problems. As the demographics of the epidemic have shifted in recent years, many members of traditionally underserved groups have encountered barriers to entering the services system. This article uses data from seven national demonstration projects funded to enroll persons with HIV/AIDS who tend to "fall through the cracks" and help them access needed services. Data on the initial perceptions of the participants about barriers to accessing services were related to 17 indicators of traditionally underserved status including demographic characteristics and behavioral variables using the data modeling method of Exhaustive CHAID (Chi-squared Automatic Interaction Detector). Through the modeling methods, the groups most likely to experience a large number of barriers to service participation are identified. Having children needing care is particularly predictive of the level of barriers to care.
OBJECTIVE: This study aimed to measure the outcomes of a harmonised, structured pharmaceutical care programme provided to elderly patients (> or =65 years of age) by community pharmacists in a multicentre international study performed in 7 European countries. DESIGN AND SETTING: The study was a randomised, controlled, longitudinal, clinical trial with repeated measures performed over an 18-month period. A total of 104 intervention and 86 control pharmacy sites participated in the research and 1290 intervention patients and 1164 control patients were recruited into the study. MAIN OUTCOME MEASURES AND RESULTS: A general decline in health-related quality of life over time was observed in the pooled data; however, significant improvements were achieved in patients involved in the pharmaceutical care programme in some countries. Intervention patients reported better control of their medical conditions as a result of the study and cost savings associated with pharmaceutical care provision were observed in most countries. The new structured service was well accepted by intervention patients and patient satisfaction with the services improved during the study. The pharmacists involved in providing pharmaceutical care had a positive opinion on the new approach, as did the majority of general practitioners surveyed. The positive effects appear to have been achieved via social and psychosocial aspects of the intervention, such as the increased support provided by community pharmacists, rather than via biomedical mechanisms. CONCLUSIONS: This study is the first large-scale, multicentre study to investigate the effects of pharmaceutical care provision by community pharmacists to elderly patients. Future research methodology and implementation will be informed by the experience gained from this challenging trial.
Using the monitoring process model (MPM), the authors examined the immediate effects of coping style and test results on the psychological distress of women at increased risk for breast and/or ovarian cancers. Cases selected for analysis were 107 probands and relatives of positive probands participating in genetic counseling and testing for heritable cancer risk. Specifically, the authors explored the relationships among coping style (high and low monitoring), test results (BRCA1 and BRCA2 mutation carrier and noncarrier status), and psychological distress (state anxiety). Consistent with the MPM, higher monitoring was associated with greater psychological distress while anticipating genetic test results. After test results were disclosed, greater distress was associated with testing positive for a mutation. The implications of the findings for breast and ovarian cancer patients are discussed.
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