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1.
Sci Rep ; 13(1): 1535, 2023 01 27.
Article in English | MEDLINE | ID: mdl-36707642

ABSTRACT

Pelvic organ prolapse, urinary, bowel and sexual dysfunction, collectively called pelvic floor dysfunction (PFD) affects 1 in 3 women and has a significant public health impact. The causes of PFD are not fully understood but involve injury to connective tissue and motor nerve during childbirth. Women with PFD also have sensory nerve impairment, and it is likely this occurs during childbirth, but this has never been investigated. In the current study 150 women underwent quantitative sensory testing for vibration sensation at the vagina and clitoris, and stretch sensation at the vagina and introitus, in the third trimester, 3 and 6 months postnatal. Antenatally vibration sensation was reduced but stretch sensation was normal. Postnatally vibration sensation deteriorated whilst stretch sensation initially deteriorated but recovered by 6 months postnatal to antenatal levels (all p < 0.001). Mode of birth had a significant impact on sensation, with caesarean section appearing neuroprotective, normal vaginal birth resulted in a transient deterioration in sensation that recovered by 6 months, whilst assisted vaginal delivery was prolonged suggesting persistent neurological impairment (all p < 0.015). Further research is required to study the clinical effect of these changes on pelvic floor dysfunction in the medium and long-term.


Subject(s)
Cesarean Section , Pelvic Organ Prolapse , Female , Pregnancy , Humans , Prospective Studies , Parturition , Sensation/physiology , Delivery, Obstetric , Pelvic Floor
2.
Int Urogynecol J ; 34(1): 67-78, 2023 01.
Article in English | MEDLINE | ID: mdl-36018353

ABSTRACT

INTRODUCTION AND HYPOTHESIS: Our aim was to compare the mid-term results of native tissue, biological xenograft and polypropylene mesh surgery for women with vaginal wall prolapse. METHODS: A total of 1348 women undergoing primary transvaginal repair of an anterior and/or posterior prolapse were recruited between January 2010 and August 2013 from 35 UK centres. They were randomised by remote allocation to native tissue surgery, biological xenograft or polypropylene mesh. We performed both 4- and 6-year follow-up using validated patient-reported outcome measures. RESULTS: At 4 and 6 years post-operation, there was no clinically important difference in Pelvic Organ Prolapse Symptom Score for any of the treatments. Using a strict composite outcome to assess functional cure at 6 years, we found no difference in cure among the three types of surgery. Half the women were cured at 6 years but only 10.3 to 12% of women had undergone further surgery for prolapse. However, 8.4% of women in the mesh group had undergone further surgery for mesh complications. There was no difference in the incidence of chronic pain or dyspareunia between groups. CONCLUSIONS: At the mid-term outcome of 6 years, there is no benefit from augmenting primary prolapse repairs with polypropylene mesh inlays or biological xenografts. There was no evidence that polypropylene mesh inlays caused greater pain or dyspareunia than native tissue repairs.


Subject(s)
Dyspareunia , Pelvic Organ Prolapse , Uterine Prolapse , Humans , Female , Uterine Prolapse/surgery , Follow-Up Studies , Dyspareunia/etiology , Dyspareunia/epidemiology , Polypropylenes , Surgical Mesh/adverse effects , Gynecologic Surgical Procedures/methods , Pelvic Organ Prolapse/surgery , Treatment Outcome
3.
Neurourol Urodyn ; 40(3): 783-790, 2021 03.
Article in English | MEDLINE | ID: mdl-33527509

ABSTRACT

AIMS: To determine terminology and methods for raising intra-abdominal pressure (IAP) currently used by clinicians to assess pelvic floor dysfunction (PFD) and to measure the effect of these maneuvers on IAP. METHODS: Three-hundred questionnaires were distributed at two scientific meetings in the United Kingdom to determine methods clinicians used to raise IAP and their perceptions of these methods. Twenty healthy volunteers were also recruited to measure the effect of two methods of raising IAP: Valsalva maneuver (VM) and bear down maneuver (BDM). IAP pressure was measured with rectal catheters connected to pressure sensors. The IAP was measured during each maneuver in both standing and supine positions. RESULTS: Maneuvers used in practice were cough (79%), BDM (60%), and VM (38%). 44% of clinicians felt patients found it difficult to raise their IAP. There was uncertainty among clinicians as to which method was the most effective in raising IAP and whether the different methods produced the same rise in IAP. On testing IAP in 20 healthy volunteers, median (interquartile range) IAP generated during BDM; 101 (59.1) cmH2 O was significantly higher than that generated during VM; 80.3 (43.6) cmH2 O (p < .0001). CONCLUSION: Clinicians varied widely in the maneuvers they used to raise patients' IAP to test for PFD and there was uncertainty about the maneuvers' effect on IAP. In healthy volunteers, BDM produced significantly higher IAP than VM. We recommend standardization of terminology and techniques used to raise IAP when assessing PFD, to ensure consistency of diagnosis and assessment of treatment outcomes.


Subject(s)
Pelvic Floor Disorders/diagnosis , Valsalva Maneuver/physiology , Female , Humans , Pressure , Surveys and Questionnaires
4.
Trials ; 17(1): 441, 2016 09 08.
Article in English | MEDLINE | ID: mdl-27609058

ABSTRACT

BACKGROUND: One in three women who have a prolapse operation will go on to have another operation, though not necessarily in the same compartment. Surgery can result in greater impairment of quality of life than the original prolapse itself (such as the development of new-onset urinary incontinence, or prolapse at a different site). Anterior and posterior prolapse surgery is most common (90 % of operations), but around 43 % of women also have a uterine (34 %) or vault (9 %) procedure at the same time. There is not enough evidence from randomised controlled trials (RCTs) to guide management of vault or uterine prolapse. The Vault or Uterine prolapse surgery Evaluation (VUE) study aims to assess the surgical management of upper compartment pelvic organ prolapse (POP) in terms of clinical effectiveness, cost-effectiveness and adverse events. METHODS/DESIGN: VUE is two parallel, pragmatic, UK multicentre, RCTs (Uterine Trial and Vault Trial). Eligible for inclusion are women with vault or uterine prolapse: requiring a surgical procedure, suitable for randomisation and willing to be randomised. Randomisation will be computer-allocated separately for each trial, minimised on: requiring concomitant anterior and/or posterior POP surgery or not, concomitant incontinence surgery or not, age (under 60 years or 60 years and older) and surgeon. Participants will be randomly assigned, with equal probability to intervention or control arms in either the Uterine Trial or the Vault Trial. Uterine Trial participants will receive either a vaginal hysterectomy or a uterine preservation procedure. Vault Trial participants will receive either a vaginal sacrospinous fixation or an abdominal sacrocolpopexy. Participants will be followed up by postal questionnaires (6 months post surgery and 12 months post randomisation) and also reviewed in clinic 12 months post surgery. The primary outcome is the participant-reported Pelvic Organ Prolapse Symptom Score (POP-SS) at 12 months post randomisation. DISCUSSION: Demonstrating the efficacy of vault and uterine prolapse surgeries is relevant not only to patients and clinicians but also to health care providers, both in the UK and globally. TRIAL REGISTRATION: Current controlled trials ISRCTN86784244 (assigned 19 October 2012), and the first subject was randomly assigned on 1 May 2013.


Subject(s)
Gynecologic Surgical Procedures/methods , Hysterectomy, Vaginal , Laparoscopy , Pelvic Organ Prolapse/surgery , Suture Techniques , Uterine Prolapse/surgery , Clinical Protocols , Female , Gynecologic Surgical Procedures/adverse effects , Gynecologic Surgical Procedures/instrumentation , Humans , Hysterectomy, Vaginal/adverse effects , Laparoscopy/adverse effects , Laparoscopy/instrumentation , Middle Aged , Pelvic Organ Prolapse/diagnosis , Postoperative Complications/etiology , Quality of Life , Research Design , Surgical Mesh , Surveys and Questionnaires , Suture Techniques/adverse effects , Time Factors , Treatment Outcome , United Kingdom , Uterine Prolapse/diagnosis
5.
Int Urogynecol J ; 25(1): 15-20, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24085142

ABSTRACT

This paper was delivered as the Ulf Ulmsten Memorial Lecture in Brisbane, QLD, Australia, in 2012. It emphasises how urogynaecology as a young specialty needs to learn some lessons from its forebears as to how new knowledge should be analysed and incorporated into practice. The paper highlights the value of mentorship and teamwork and the need to be aware of increasing patient expectations.


Subject(s)
Gynecology/education , Learning , Teaching , Urology/education , Humans
6.
Neurourol Urodyn ; 31(3): 309-12, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22415935

ABSTRACT

AIMS: Bladder neck hypermobility (BNH, also called urethral hypermobility), and intrinsic sphincteric deficiency (ISD) are terms frequently used in the clinical evaluation and management of stress urinary incontinence, and as subject qualifiers in clinical research. The terms also infer pathophysiologic concepts, as BNH and ISD appear to represent two different aspects of failure of the continence mechanism. Unfortunately, neither term is well-defined, and the various clinical and urodynamic characterizations of these terms do not correlate well with one another. METHODS: The value of these concepts and these specific terms was debated at the ICI-RS meeting, Bristol, UK, June 2011. Two clinicians were asked to take opposing viewpoints, with three weeks lead-time prior to the meeting. Each discussant presented one viewpoint, "for" or "against," followed by a brief discussion to review the presentations. RESULTS: The consensus was that, while we currently cannot adequately define these terms, there is a need to develop terminology employing these concepts. CONCLUSIONS: Terminology should permit improved definition of the sphincteric mechanism, allow individual patient characterization and serve as useful waypoints in treatment decisions.


Subject(s)
Terminology as Topic , Urethra/physiopathology , Urinary Bladder/physiopathology , Urinary Incontinence, Stress/classification , Diagnostic Techniques, Urological/standards , Humans , Predictive Value of Tests , Prognosis , Severity of Illness Index , Urinary Incontinence, Stress/diagnosis , Urinary Incontinence, Stress/physiopathology , Urination , Urodynamics
8.
Nano Lett ; 11(8): 3476-81, 2011 Aug 10.
Article in English | MEDLINE | ID: mdl-21766838

ABSTRACT

The creation of a single electron-hole pair (i.e., exciton) per incident photon is a fundamental limitation for current optoelectronic devices including photodetectors and photovoltaic cells. The prospect of multiple exciton generation per incident photon is of great interest to fundamental science and the improvement of solar cell technology. Multiple exciton generation is known to occur in semiconductor nanostructures with increased efficiency and reduced threshold energy compared to their bulk counterparts. Here we report a significant enhancement of multiple exciton generation in PbSe quasi-one-dimensional semiconductors (nanorods) over zero-dimensional nanostructures (nanocrystals), characterized by a 2-fold increase in efficiency and reduction of the threshold energy to (2.23 ± 0.03)E(g), which approaches the theoretical limit of 2E(g). Photovoltaic cells based on PbSe nanorods are capable of improved power conversion efficiencies, in particular when operated in conjunction with solar concentrators.

9.
Neurourol Urodyn ; 30(5): 771-4, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21661028

ABSTRACT

This article reviews the literature on the assessment and management of women whose previous mid-urethral tape surgery to manage stress urinary incontinence symptoms has failed to produce a satisfactory outcome. In many areas the literature is deficient and the article includes consensus statements drawn from the International Continence Society Research Society meeting in Bristol in June 2010. The need for a structured approach to assessment and management is highlighted, so that further research into areas of uncertainty can be prioritized. The article concludes with a number of research recommendations.


Subject(s)
Postoperative Complications/therapy , Suburethral Slings , Urinary Incontinence, Stress/surgery , Urologic Surgical Procedures/instrumentation , Biomedical Research , Cystoscopy , Evidence-Based Medicine , Female , Humans , Postoperative Complications/diagnosis , Postoperative Complications/physiopathology , Prosthesis Design , Prosthesis Failure , Recurrence , Reoperation , Treatment Failure , Urinary Incontinence, Stress/physiopathology , Urodynamics , Urologic Surgical Procedures/adverse effects
10.
Int Urogynecol J ; 22(2): 157-63, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20838987

ABSTRACT

INTRODUCTION AND HYPOTHESIS: Assessment of the 2-year outcome of anterior Prolift™ for women with recurrent anterior vaginal wall prolapse. This is a prospective study which was conducted in a tertiary unit in the North West of England and comprised 36 consecutive women with recurrent anterior vaginal wall prolapse. METHODS: Women were assessed preoperatively and postoperatively at 6 months and 2 years. Women completed the Prolapse Quality of Life Questionnaire (P-QOL), Prolapse and Incontinence Sexual Function Questionnaire-Short Form (PISQ-12), and postoperatively, the Global Impression of Improvement Questionnaire. Women were examined using the Pelvic Organ Prolapse Quantification System (POP-Q). Anatomical success was defined as stage ≤1 prolapse in the anterior compartment. Main outcome measures Postoperative POP-Q stage, quality of life domains and mesh exposure rate. RESULTS: Preoperatively all but two women had stage 2 or greater anterior vaginal wall prolapse. At a mean follow-up of 24.6 months, 19 women (53%) had stage ≤1 anterior wall prolapse. Fifteen women had stage 2 anterior wall prolapse and two women had stage 3 prolapse. Twenty-nine women felt improvement in their prolapse symptoms. 16 women were sexually active preoperatively, of whom seven reported worsening dyspareunia. There was poor correlation between anatomical and functional outcomes. Seven women had mesh exposure. Five needed revision in theatre. CONCLUSIONS: Anterior Prolift™ for recurrent anterior vaginal wall prolapse has 53% anatomical success rate in the medium term, with mesh exposure rate of 19%. Majority of patients felt overall improvement in their symptoms, but this did not correlate with the anatomical outcome.


Subject(s)
Pelvic Organ Prolapse/surgery , Suburethral Slings , Aged , Female , Humans , Prospective Studies , Recurrence , Surgical Mesh
11.
Am J Obstet Gynecol ; 203(6): 587.e1-8, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20934681

ABSTRACT

OBJECTIVE: The purpose of this study was to evaluate outcomes after standardized transvaginal prolapse repair with nonanchored mesh and a vaginal support device. STUDY DESIGN: Postoperative vaginal support was assessed by pelvic organ prolapse quantitative examination after repair of symptomatic stage II/III prolapse. Validated questionnaires assessed pelvic symptoms and sexual function. Visual analog scales quantified experience with the vaginal support device. RESULTS: One hundred thirty-six women received the planned surgery; 95.6% of the women returned for the 1-year assessment: 76.9% of the cases were stage 0/I; however, in 86.9% of the cases, the leading vaginal edge was above the hymen. Pelvic symptoms, quality of life, and sexual function improved significantly from baseline (P < .05). Median visual analog scale scores for vaginal support device awareness and discomfort were 2.6 and 1.2, respectively (0 = none; 10 = worst possible). CONCLUSION: Vaginal support, pelvic symptoms, and sexual function improved at 1 year, compared with baseline, after trocar-free prolapse repair with nonanchored mesh and a vaginal support device.


Subject(s)
Gynecologic Surgical Procedures/methods , Quality of Life , Suburethral Slings , Surgical Mesh , Uterine Prolapse/surgery , Aged , Cohort Studies , Female , Follow-Up Studies , Humans , Middle Aged , Patient Satisfaction , Postoperative Care/methods , Prospective Studies , Prosthesis Design , Prosthesis Implantation/methods , Risk Assessment , Time Factors , Treatment Outcome , Uterine Prolapse/diagnosis
12.
Transl Res ; 156(1): 15-25, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20621033

ABSTRACT

Mitochondrial membrane hyperpolarization and morphologic changes are important in inflammatory cell activation. Despite the pathophysiologic relevance, no valid and reproducible method for measuring mitochondrial homeostasis in human inflammatory cells is available currently. The purpose of this study was to define and validate reproducible methods for measuring relevant mitochondrial perturbations and to determine whether these methods could discern mitochondrial perturbations in type 2 diabetes mellitus (T2DM), which is a condition associated with altered mitochondrial homeostasis. We employed 5,5',6,6'-tetrachloro-1,1'3,3'-tetraethylbenzamidazol-carboncyanine (JC-1) to estimate mitochondrial membrane potential (Psi(m)) and acridine orange 10-nonyl bromide (NAO) to assess mitochondrial mass in human mononuclear cells isolated from blood. Both assays were reproducible. We validated our findings by electron microscopy and pharmacologic manipulation of Psi(m). We measured JC-1 and NAO fluorescence in the mononuclear cells of 27 T2DM patients and 32 controls. Mitochondria were more polarized (P = 0.02) and mitochondrial mass was lower in T2DM (P = 0.008). Electron microscopy demonstrated diabetic mitochondria were smaller, were more spherical, and occupied less cellular area in T2DM. Mitochondrial superoxide production was higher in T2DM (P = 0.01). Valid and reproducible measurements of mitochondrial homeostasis can be made in human mononuclear cells using these fluorophores. Furthermore, potentially clinically relevant perturbations in mitochondrial homeostasis in T2DM human mononuclear cells can be detected.


Subject(s)
Diabetes Mellitus, Type 2/metabolism , Lymphocytes/metabolism , Membrane Potential, Mitochondrial/physiology , Mitochondria/ultrastructure , Monocytes/metabolism , Adult , Aged , Aminoacridines/metabolism , Benzimidazoles/metabolism , Biomarkers , Carbocyanines/metabolism , Cardiolipins/metabolism , Case-Control Studies , Cross-Sectional Studies , Female , Fluorescent Dyes/metabolism , Humans , Lymphocytes/cytology , Lymphocytes/ultrastructure , Male , Middle Aged , Mitochondria/metabolism , Monocytes/cytology , Monocytes/ultrastructure , Reproducibility of Results , Superoxides/metabolism
13.
Neurourol Urodyn ; 29(4): 676-8, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20432334

ABSTRACT

The introduction of the tension free vaginal tape over a decade ago heralded the adoption of sub-urethral sling placement under the mid-urethra rather than the proximal urethra. This paper reviews the literature which led to the change in practice and also looks at which factors concerning tape position influence surgical outcome with particular reference to the position along the urethra. There is conflicting evidence on the importance of the mid-urethral position and there is also evidence that other factors such as the configuration of the tape under the urethra at rest and under strain and the proximity of the tape to the urethral mucosa may be as important in influencing outcome. Further research is required.


Subject(s)
Suburethral Slings , Urethra/surgery , Urinary Incontinence, Stress/surgery , Urologic Surgical Procedures/methods , Female , Humans , Treatment Outcome
14.
Biochim Biophys Acta ; 1790(10): 1149-60, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19664690

ABSTRACT

Alpha-lipoic acid (LA) has become a common ingredient in multivitamin formulas, anti-aging supplements, and even pet food. It is well-defined as a therapy for preventing diabetic polyneuropathies, and scavenges free radicals, chelates metals, and restores intracellular glutathione levels which otherwise decline with age. How do the biochemical properties of LA relate to its biological effects? Herein, we review the molecular mechanisms of LA discovered using cell and animal models, and the effects of LA on human subjects. Though LA has long been touted as an antioxidant, it has also been shown to improve glucose and ascorbate handling, increase eNOS activity, activate Phase II detoxification via the transcription factor Nrf2, and lower expression of MMP-9 and VCAM-1 through repression of NF-kappa B. LA and its reduced form, dihydrolipoic acid, may use their chemical properties as a redox couple to alter protein conformations by forming mixed disulfides. Beneficial effects are achieved with low micromolar levels of LA, suggesting that some of its therapeutic potential extends beyond the strict definition of an antioxidant. Current trials are investigating whether these beneficial properties of LA make it an appropriate treatment not just for diabetes, but also for the prevention of vascular disease, hypertension, and inflammation.


Subject(s)
Dietary Supplements , Thioctic Acid/administration & dosage , Animals , Diabetic Neuropathies/metabolism , Diabetic Neuropathies/prevention & control , Humans , Hypertension/metabolism , Hypertension/prevention & control , Inflammation/metabolism , Inflammation/prevention & control , Models, Biological , Molecular Structure , Thioctic Acid/chemistry , Thioctic Acid/metabolism , Vascular Diseases/metabolism , Vascular Diseases/prevention & control
15.
Article in English | MEDLINE | ID: mdl-19137230

ABSTRACT

INTRODUCTION AND HYPOTHESIS: The aim of this study is to provide long-term outcome data, at least 10 years, following laparoscopic colposuspension. METHODS: The study includes a control group who underwent open colposuspension. A consecutive series of 139 women who had undergone laparoscopic colposuspension were reviewed and compared to 52 women who had an open colposuspension in the same unit. Subjects were contacted by telephone, at least 10 years post-operatively, at which time a structured interview was performed which included the short-form Bristol Female Lower Urinary Tract Symptom questionnaire. RESULTS: There was deterioration in subjective cure rates from 71% and 67% at 6 months to 52% and 36% at 10 years for the laparoscopic and open procedures, respectively. CONCLUSION: This study provides evidence that laparoscopic colposuspension is probably as durable as open colposuspension. However, cure rates for both procedures appear to deteriorate over time, emphasising the importance of long-term follow-up.


Subject(s)
Colposcopy/methods , Laparoscopy/methods , Urinary Incontinence, Stress/surgery , Adult , Cohort Studies , Female , Follow-Up Studies , Health Surveys , Humans , Interviews as Topic , Longitudinal Studies , Middle Aged , Retrospective Studies , Treatment Outcome
16.
Biodegradation ; 19(5): 669-81, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18172576

ABSTRACT

Burkholderia cepacia 2a inducibly degraded 2,4-dichlorophenoxyacetate (2,4-D) sequentially via 2,4-dichlorophenol, 3,5-dichlorocatechol, 2,4-dichloromuconate, 2-chloromuconolactone and 2-chloromaleylacetate. Cells grown on nutrient agar or broth grew on 2,4-D-salts only if first passaged on 4-hydroxybenzoate- or succinate-salts agar. Buffered suspensions of 4-hydroxybenzoate-grown cells did not adapt to 2,4-D or 3,5-dichlorocatechol, but responded to 2,4-dichlorophenol at concentrations <0.4 mM. Uptake of 2,4-dichlorophenol by non-induced cells displayed a type S (cooperative uptake) uptake isotherm in which the accelerated uptake of the phenol began before the equivalent of a surface monolayer had been adsorbed, and growth inhibition corresponded with the acquisition of 2.2-fold excess of phenol required for the establishment of the monolayer. No evidence of saturation was seen even at 2 mM 2,4-dichlorophenol, possibly due to absorption by intracellular poly-beta-hydroxybutyrate inclusions. With increasing concentration, 2,4-dichlorophenol caused progressive cell membrane damage and, sequentially, leakage of intracellular K(+), P(i), ribose and material absorbing light at 260 nm (presumed nucleotide cofactors), until at 0.4 mM, protein synthesis and enzyme induction were forestalled. Growth of non-adapted cells was inhibited by 0.35 mM 2,4-dichlorophenol and 0.25 mM 3,5-dichlorocatechol; the corresponding minimum bacteriocidal concentrations were 0.45 and 0.35 mM. Strain 2a grew in chemostat culture on carbon-limited media containing 2,4-D, with an apparent growth yield coefficient of 0.23, and on 2,4-dichlorophenol. Growth on 3,5-dichlorocatechol did not occur without a supplement of succinate, probably due to accumulation of toxic quantities of quinonoid and polymerisation products. Cells grown on these compounds were active towards all three, but not when grown on other substrates. The enzymes of the pathway therefore appeared to be induced by 3,5-dichlorocatechol or some later metabolite. A possible reason is offered for the environmental persistence of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T).


Subject(s)
2,4-Dichlorophenoxyacetic Acid/metabolism , Burkholderia cepacia/enzymology , 2,4-Dichlorophenoxyacetic Acid/toxicity , Burkholderia cepacia/growth & development , Enzyme Induction , Microbial Sensitivity Tests , Spectrophotometry, Ultraviolet
17.
Biodegradation ; 19(1): 65-75, 2008 Feb.
Article in English | MEDLINE | ID: mdl-17431803

ABSTRACT

The secondary structure of the trimeric protein 4-chlorobenzoyl coenzyme A dehalogenase from Arthrobacter sp. strain TM-1, the second of three enzymes involved in the dechlorination of 4-chlorobenzoate to form 4-hydroxybenzoate, has been examined. E(mM) for the enzyme was 12.59. Analysis by circular dichroism spectrometry in the far uv indicated that 4-chlorobenzoyl coenzyme A dehalogenase was composed mostly of alpha-helix (56%) with lesser amounts of random coil (21%), beta-turn (13%) and beta-sheet (9%). These data are in close agreement with a computational prediction of secondary structure from the primary amino acid sequence, which indicated 55.8% alpha-helix, 33.7% random coil and 10.5% beta-sheet; the enzyme is, therefore, similar to the 4-chlorobenzoyl coenzyme A dehalogenase from Pseudomonas sp. CBS-3. The three-dimensional structure, including that of the presumed active site, predicted by computational analysis, is also closely similar to that of the Pseudomonas dehalogenase. Study of the stability and physicochemical properties revealed that at room temperature, the enzyme was stable for 24 h but was completely inactivated by heating to 60 degrees C for 5 min; thereafter by cooling at 1 degrees C min(-1) to 45 degrees C, 20.6% of the activity could be recovered. Mildly acidic (pH 5.2) or alkaline (pH 10.1) conditions caused complete inactivation, but activity was fully recovered on returning the enzyme to pH 7.4. Circular dichroism studies also indicated that secondary structure was little altered by heating to 60 degrees C, or by changing the pH from 7.4 to 6.0 or 9.2. Complete, irreversible destruction of, and maximal decrease in the fluorescence yield of the protein at 330-350 nm were brought about by 4.5 M urea or 1.1 M guanidinium chloride. Evidence was obtained to support the hypothetical three-dimensional model, that residues W140 and W167 are buried in a non-polar environment, whereas W182 appears at or close to the surface of the protein. At least one of the enzymes of the dehalogenase system (the combined 4-chlorobenzoate:CoA ligase, the dehalogenase and 4-hydroxybenzoyl coenzyme A thioesterase) appears to be capable of association with the cell membrane.


Subject(s)
Hydrolases/chemistry , Amino Acid Sequence , Arthrobacter/enzymology , Arthrobacter/growth & development , Enzyme Stability , Guanidine/pharmacology , Hydrogen-Ion Concentration , Hydrolases/antagonists & inhibitors , Molecular Sequence Data , Protein Denaturation , Protein Structure, Secondary , Sequence Alignment , Temperature , Urea/pharmacology
18.
Altern Med Rev ; 12(4): 343-51, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18069903

ABSTRACT

BACKGROUND: The racemic mixture, RS-(+/-)-alpha-lipoic acid (rac-LA) has been utilized clinically and in a variety of disease models. Rac-LA and the natural form, R-lipoic acid (RLA), are widely available as nutritional supplements, marketed as antioxidants. Rac-LA sodium salt (NaLA) or rac-LA potassium salt (KLA) has been used to improve the aqueous solubility of LA. STUDY RATIONALE: Several in vitro and animal models of aging and age-related diseases have demonstrated efficacy for the oral solutions of LA salts in normalizing age-related changes to those of young animals. Other models and studies have demonstrated the superiority of RLA, the naturally occurring isomer over rac-LA. Despite this, RLA pharmacokinetics (PK) is not fully characterized in humans, and it is unknown whether the concentrations utilized in animal models can be achieved in vivo. Due to its tendency to polymerize, RLA is relatively unstable and suffers poor aqueous solubility, leading to poor absorption and low bioavailability. A preliminary study demonstrated the stability and bioavailability were improved by converting RLA to its sodium salt (NaRLA) and pre-dissolving it in water. The current study extends earlier findings from this laboratory and presents PK data for the 600-mg oral dosing of 12 healthy adult subjects given NaRLA. In addition, the effect of three consecutive doses was tested on a single subject relative to a one-time dosing in the same subject to determine whether plasma maximum concentration (Cmax) and the area under the plasma concentration versus time curve (AUC) values were comparable to those in animal studies and those achievable via intravenous infusions in humans. METHODS: Plasma RLA was separated from protein by a modification of a published method. Standard curves were generated from spiking known concentrations of RLA dissolved in ethanol and diluted in a phosphate-buffered saline (PBS) into each individual's baseline plasma to account for inter-individual differences in protein binding and to prevent denaturing of plasma proteins. Plasma RLA content was determined by the percent recovery using high-performance liquid chromatography (electrochemical/coulometric detection) (HPLC/ECD). RESULTS: As anticipated from the preliminary study, NaRLA is less prone to polymerization, completely soluble in water, and displays significantly higher Cmax and AUC values and decreased time to maximum concentration (Tmax) and T1/2 values than RLA or rac-LA. In order to significantly extend Cmax and AUC, it is possible to administer three 600-mg RLA doses (as NaRLA) at 15-minute intervals to achieve plasma concentrations similar to those from a slow (20-minute) infusion of LA. This is the first study to report negligible unbound RLA even at the highest achievable plasma concentrations.


Subject(s)
Thioctic Acid/pharmacokinetics , Area Under Curve , Biological Availability , Female , Humans , Isomerism , Male , Middle Aged , Thioctic Acid/administration & dosage , Thioctic Acid/chemistry
19.
Int Urogynecol J Pelvic Floor Dysfunct ; 18(10): 1179-83, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17968481

ABSTRACT

The aim of this study is to assess the accuracy of pre-operative evaluation of pelvic organ prolapse. The design is a prospective observational audit set at the gynaecology department, Teaching Hospital, UK. The population is composed of patients undergoing surgery for prolapse. One hundred and four patients admitted for prolapse surgeries were enrolled in the audit. Patients' notes were initially reviewed for adequacy of prolapse assessment in the clinic. Patients were then interviewed by the researchers and assessed using a validated Prolapse Quality of Life (P-QOL) questionnaire. The presence of unrecorded symptoms was noted. Prolapse examination in theatre under anaesthesia was compared to the findings in the clinic and the operation performed compared to the proposed operation. The outcome measures were as follows: (1) number of patients who had accurate prolapse symptom assessment before surgery when comparing clinical records with entries on P-QOL questionnaires; (2) number of patients having symptoms related to their pelvic organ prolapse that were not accurately assessed pre-operatively; and (3) the differences, if any, between pre-operative and intra-operative examination of prolapse. Sixteen patients in our cohort (15%) had adequate assessment of their prolapse pre-operatively. Symptoms that were not adequately assessed in descending order were the impact of prolapse on quality of life (76%), sexual function (75%), bowel function (27%) and lower urinary tract symptoms (12.5%). Thirty one patients (30%) had sexual dysfunction, 24 (23%) had bowel symptoms and 23 patients (22%) had urinary symptoms that were not recorded before surgery. Prolapse physical examination was adequate in 59% of the cases. Examinations in theatre were different from clinic findings in 38 cases (37%); 16 cases (42%) had a greater or lesser degree of prolapse than that described in the notes; and 11 cases (29%) had prolapse in a different compartment in the vagina. A combination of both (i.e. different degree of prolapse and prolapse in a different vaginal compartment) was found in another 11 cases (29%). The operation performed was different from the one proposed in the clinic in 21% of the cases (n=22). Clinical evaluation and examination of patients with vaginal prolapse is often inadequate. Prolapse physical examination in a clinic setting could be different from findings under anaesthesia. This can affect the operation to repair the prolapse. Patients should be counselled about this when listed for surgery.


Subject(s)
Quality of Life , Uterine Prolapse/diagnosis , Adult , Female , Humans , Medical Audit , Physical Examination , Prospective Studies , Urodynamics , Uterine Prolapse/physiopathology , Uterine Prolapse/surgery
20.
Curr Opin Obstet Gynecol ; 19(4): 345-9, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17625416

ABSTRACT

PURPOSE OF REVIEW: The aim of this review is to present a summary of recently published research comparing laparoscopic and open colposuspension. It also examines the place of colposuspension in light of the continuing development other minimally invasive procedures for stress urinary incontinence. RECENT FINDINGS: The results of two large multicentre randomised controlled trials were published in 2006 comparing open and laparoscopic colposuspension. Carey et al. randomised 200 women to open or laparoscopic colposuspension. The primary outcome objective was cure 6 months postoperatively. Cure was defined as the absence of urodynamic stress incontinence. Patients' subjective outcomes were assessed 3-5 years postoperatively. Kitchener et al. reported a randomised controlled trial in which 291 women were recruited. The primary end point of the study was objective cure at 2 years. This was defined as <1 g of urinary leakage during a 1 h standardised pad test. Both trials demonstrated no significant differences between laparoscopic and open colposuspension in objective and subjective measures of cure of stress urinary incontinence at 24 months. SUMMARY: There is now level 1 evidence that the clinical outcomes with laparoscopic Burch colposuspension are similar to open Burch colposuspension.


Subject(s)
Colposcopy/methods , Laparoscopy/methods , Urinary Incontinence, Stress/surgery , Urologic Surgical Procedures/methods , Female , Humans , Minimally Invasive Surgical Procedures/methods , Patient Satisfaction , Randomized Controlled Trials as Topic , Treatment Outcome
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