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Biomedical subjects

Stephen Jones

Publications and source records attributed to Stephen Jones.

At least 19 recordsLinked to original sources
PubMed2006

Neurovascular preservation in orthotopic cystectomy: impact on female sexual function.

OBJECTIVES: The published data regarding female orthotopic cystectomy have focused primarily on urethral recurrence and urinary continence. In a new era of sexuality, evaluating postoperative sexual outcome has become a new surgical endpoint. In this study, we focused on the impact of neurovascular preservation after radical cystectomy and neobladder construction. METHODS: We assessed female sexuality in 13 patients after orthotopic cystectomy using a standardized questionnaire, Female Sexual Function Index (FSFI). Six patients had undergone nerve-sparing cystectomy and seven had undergone contemporary non-nerve-sparing cystectomy. Intraoperatively, the tumor was deemed oncologically safe for neurovascular preservation. All 13 patients were sexually active preoperatively, were younger than 65 years old, had recurrence-free follow-up findings after 1 year, and had undergone no pelvic irradiation. The 19-item FSFI questionnaire analyzed six domains (desire, arousal, lubrication, orgasm, satisfaction, and pain) of sexual function. RESULTS: In the nerve-sparing group (mean age 55.9 years), the baseline and 12-month postoperative scores showed a minimal decline in results, with a total mean FSFI score of 24.5 versus 22.3, respectively. In analyzing each of the six domains, no significant decline or difference was observed. Conversely, in the non-nerve-sparing group (mean age 56.7 years), a significant decline or difference was found in the 12-month total mean FSFI scores between the baseline and postoperative FSFI scores (25.0 versus 11.0, respectively). In the non-nerve-sparing group, 6 of 7 patients ultimately discontinued sexual intercourse. CONCLUSIONS: Female sexual function was preserved in patients who received neurovascular preservation. In contrast, all domains of sexual function declined in patients who had undergone non-neurovascular preservation.

Cystectomy↗
PubMed2006

The prevalence and onset of gaze modulation of tinnitus and increased sensitivity to noise after translabyrinthine vestibular schwannoma excision.

OBJECTIVE: To determine the prevalence and timing of onset of gaze-modulated tinnitus and increased sensitivity to noise in patients who had undergone translabyrinthine excision of a vestibular schwannoma. STUDY DESIGN: Retrospective questionnaire study. SETTING: University hospital departments of audiology and neurotology. PATIENTS: A cohort of 359 patients who had undergone translabyrinthine excision of a vestibular schwannoma in the period 1997 to 2003. INTERVENTION: Translabyrinthine excision of a unilateral sporadic vestibular schwannoma. MAIN OUTCOME MEASURES: Patient reports and visual analogue scale measures of the timing of onset of gaze-modulated tinnitus and the presence, timing of onset, and persistence of increased sensitivity to noise after surgery. RESULTS: Completed questionnaires were returned by 275 patients (77%), of whom 132 (48%) were men and 143 (52%) were women. Preoperative tinnitus was reported in 150 patients (55%). In 124 of these 150 (83%) the tinnitus persisted, and in 26 of 150 (17%) it abated. Of the 125 patients without preoperative tinnitus, 43 (34%) developed it postoperatively. In 167 (61%) patients of the total group of 275, postoperative tinnitus was reported. Gaze-modulated tinnitus was reported in 53 patients (19%). Somatic-evoked or -modulated tinnitus was reported in 38 patients (14%). In response to the question, "Did you notice being extra sensitive to noise after your operation?," 138 patients (50%) replied that they did. In 111 patients, this persisted. The onset of the modulation of tinnitus was distributed throughout the postoperative period, whereas the onset of increased sensitivity to noise was overwhelmingly in the first 2 months after surgery. CONCLUSION: Gaze modulation of tinnitus after vestibular schwannoma removal was identified in 19% of patients in this series. The onset data did not convincingly argue for any specific mechanism. The prevalence of increased sensitivity to noise is surprising and may represent central hyperacusis in response to unilateral deafferentation of the auditory system.

Adult↗
PubMed2005

Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1.

High-throughput screening against the human sirtuin SIRT1 led to the discovery of a series of indoles as potent inhibitors that are selective for SIRT1 over other deacetylases and NAD-processing enzymes. The most potent compounds described herein inhibit SIRT1 with IC50 values of 60-100 nM, representing a 500-fold improvement over previously reported SIRT inhibitors. Preparation of enantiomerically pure indole derivatives allowed for their characterization in vitro and in vivo. Kinetic analyses suggest that these inhibitors bind after the release of nicotinamide from the enzyme and prevent the release of deacetylated peptide and O-acetyl-ADP-ribose, the products of enzyme-catalyzed deacetylation. These SIRT1 inhibitors are low molecular weight, cell-permeable, orally bioavailable, and metabolically stable. These compounds provide chemical tools to study the biology of SIRT1 and to explore therapeutic uses for SIRT1 inhibitors.

Animals↗
PubMed2005

Capecitabine plus docetaxel combination therapy.

BACKGROUND: For patients with anthracycline-pretreated metastatic breast carcinoma, capecitabine plus docetaxel significantly increased overall survival compared with docetaxel alone. The current study evaluated the cost-effectiveness of the capecitabine/docetaxel combination versus docetaxel monotherapy, comparing the gain in quality-adjusted survival with associated health care costs. METHODS: Patients were randomized to receive 21-day cycles of oral capecitabine 1250 mg/m2 twice daily, on Days 1-14, plus docetaxel 75 mg/m2 Day 1 (n = 255), or docetaxel 100 mg/m2 on Day 1 (n = 256). Health and cost outcomes in the two arms were compared, and cost-effectiveness was estimated. Data on survival time and medical care resource use were prospectively collected in the trial. Costs associated with medical care resource use and quality-of-life adjustments were obtained from the published literature. The incremental cost-effectiveness ratio was calculated as the cost per quality-adjusted life year (QALY) gained. RESULTS: Capecitabine/docetaxel increased the median overall survival by 3 months compared with docetaxel alone (14.5 vs. 11.5 months). The mean quality-adjusted survival was increased by 1.8 months in the capecitabine/docetaxel group. The total medical-resource utilization cost per patient was 8.9% higher with the combination: 24,475 dollars for combination therapy versus 22,477 dollars for single-agent docetaxel. The mean cost per QALY gained with combination therapy was 13,558 dollars (standard deviation, 6742 dollars). Cost savings due to reduced docetaxel dose and hospital use were the major cost offsets with the combination. Sensitivity analyses showed that varying the mean hospital cost per day from the 5th to the 95th percentile resulted in cost-utility ratios ranging from 20,326 dollars to as low as 6360 dollars. CONCLUSIONS: Capecitabine/docetaxel was a cost-effective treatment in patients with anthracycline-pretreated advanced breast carcinoma, and had an incremental cost-effectiveness ratio that compares very favorably with that of many other oncology therapies.

Adult↗
PubMed2005

The inhibitory effect of intravenous lidocaine infusion on tinnitus after translabyrinthine removal of vestibular schwannoma: a double-blind, placebo-controlled, crossover study.

OBJECTIVE: Intravenous infusion of lidocaine has previously been demonstrated to have a transient inhibitory effect on tinnitus in 60% of individuals. The site of action has variously been proposed as the cochlea, the cochlea nerve, and the central auditory pathways. To determine whether a central site of action exists, this study investigated the effect of intravenous infusion of lidocaine in individuals with tinnitus who had previously undergone translabyrinthine excision of a vestibular schwannoma, which involves division of the cochlear nerve. STUDY DESIGN: Double-blind, placebo-controlled, crossover study. SETTING: University hospital. PATIENTS: Patients who had undergone translabyrinthine removal of a unilateral, sporadic, and histologically proven vestibular schwannoma in the last decade and who had reported postoperative tinnitus at follow-up were identified from a departmental database. Sixteen patients participated (12 men and 4 women). The mean age (+/- standard deviation) of the patients was 58 +/- 8.6 years, and the meantime since operation was 24.3 +/- 7.3 months. INTERVENTION: Solutions of 2% lidocaine hydrochloride and sodium chloride 0.9% were prepared in identical randomized vials. The volume required for 1.5 ml/kg body weight lidocaine was calculated, and this volume was given over 5 minutes for either vial. Blood pressure, pulse oximetry, and cardiac monitoring were set up and performed throughout the infusions. All investigators were blinded. OUTCOME MEASURES: Patient-completed visual analogue scale measures of tinnitus intensity, pitch, and distress, performed before infusion, 5 minutes after infusion onset, and 20 minutes after infusion onset. RESULTS: A significant difference (Wilcoxon signed-rank test, p < 0.05) between placebo and lidocaine infusion conditions was demonstrated for change in visual analogue scale estimates (preinfusion versus 5 min postinfusion) of tinnitus loudness (p = 0.036), pitch (p = 0.026), and distress (p = 0.04). No significant difference between placebo and lidocaine infusion conditions was demonstrated for change in visual analogue scale estimates (preinfusion versus 20 min postinfusion) of tinnitus loudness (p = 0.066), pitch (p = 0.173), and distress (p = 0.058). The indication is of a short-lasting inhibitory effect on tinnitus of lidocaine infusion compared with saline placebo in patients who have undergone translabyrinthine excision of a vestibular schwannoma. CONCLUSION: Intravenous infusion of lidocaine has a statistically significant inhibitory effect on tinnitus in patients who have previously undergone translabyrinthine removal of a vestibular schwannoma. The site of action of lidocaine in this instance must be in the central auditory pathway, as the cochlear and vestibular nerves are sectioned during surgery, and this finding has important implications for the task of identifying other agents that will have a similar tinnitus-inhibiting effect.

Adult↗
PubMed2004

A single chromosome addition from Thinopyrum elongatum confers a polycarpic, perennial habit to annual wheat.

Annual wheat displays monocarpic senescence, but amphiploids between wheat and its wild perennial relatives in the genus Thinopyrum generally display a polycarpic, perennial growth habit. In order to determine the chromosomal basis of this phenomenon, life-history characteristics were examined using Chinese Spring wheat and a complete Thinopyrum elongatum (2n=2x=14) chromosome addition series in a Chinese Spring background. Both monosomic and disomic additions and substitutions of Th. elongatum chromosome 4E conferred a polycarpic life history to annual Chinese Spring wheat. Disomic addition lines were found to be perennial under field conditions. This is the first report of a single alien chromosome conferring a polycarpic growth habit to a monocarpic species. Chromosome 4E altered the timing of tiller initiation, such that two growth phases could be clearly identified, the first phase being indistinguishable from the growth of euploid Chinese Spring, followed by a second phase of tiller initiation after the sexual cycle of the first phase tillers was complete (post-sexual cycle regrowth).

Chimera↗
PubMed2004

Female sexual dysfunction after radical cystectomy: a new outcome measure.

OBJECTIVES: To assess, in our contemporary radical cystectomy (RC) series, female sexual dysfunction and whether the type of diversion affected the occurrence of sexual dysfunction. Outcome data after RC with and without orthotopic diversion has focused primarily on cure, urethral recurrence, and continence. METHODS: The baseline and follow-up data from 27 sexually active female patients (mean age 54.79 +/- 12.7 years) who underwent RC from 1997 to 2002 for transitional cell carcinoma of the bladder (16 with Stage T1-T2 and 11 with Stage T3-T4) were obtained. Thirteen patients were premenopausal before RC. Of the 27 patients, 10 (37%) underwent Studor orthotopic diversion, 7 (26%) Indiana cutaneous diversion, and 10 (37%) ileal conduit diversion. A 10-item version of the self-administered Index of Female Sexual Function questionnaire was used to assess sexual dysfunction. The specific domains analyzed in the Index of Female Sexual Function include the degree of vaginal lubrication, ability to achieve orgasm, degree of pain during intercourse, overall sexual desire and interest, and overall sexual satisfaction, with responses graded on a scale of 1 (almost never, never) to 5 (almost always, always). RESULTS: With a mean follow-up of 24.2 months (range 15 to 65.1), the total mean baseline Index of Female Sexual Function score decreased from 17.4 +/- 7.23 to 10.6 +/- 6.62 after RC (P < or =0.05). The most common symptoms reported by the patients included diminished ability or inability to achieve orgasm in 12 (45%), decreased lubrication in 11 (41%), decreased sexual desire in 10 (37%), and dyspareunia in 6 patients (22%). Only 13 (48%) of the 27 patients were able to have successful vaginal intercourse, with 14 (52%) reporting decreased satisfaction in overall sexual life after RC. Eight partners (30%) had a decrease in desire for sexual activity owing to apprehension after cancer diagnosis and treatment. Although the numbers were small, the preliminary data suggested no differences in sexual function between patients undergoing Studor orthotopic diversions and those undergoing Indiana cutaneous diversions. CONCLUSIONS: Sexual dysfunction is a prevalent problem after female RC. The nature of the dysfunction involves multiple domains, including decreased orgasm, decreased lubrication, lack of sexual desire, and dyspareunia. Our early results suggest that the type of continent diversion does not affect sexual function. Surgical modifications such as urethral and vaginal sparing, neurovascular preservation, and tubular vaginal reconstruction sparing may improve female sexual function after RC.

Carcinoma, Transitional Cell↗
PubMed2004

Apoptosis associated with deregulated E2F activity is dependent on E2F1 and Atm/Nbs1/Chk2.

The retinoblastoma protein (Rb)/E2F pathway links cellular proliferation control to apoptosis and is critical for normal development and cancer prevention. Here we define a transcription-mediated pathway in which deregulation of E2F1 by ectopic E2F expression or Rb inactivation by E7 of human papillomavirus type 16 signals apoptosis by inducing the expression of Chk2, a component of the DNA damage response. E2F1- and E7-mediated apoptosis are compromised in cells from patients with the related disorders ataxia telangiectasia and Nijmegen breakage syndrome lacking functional Atm and Nbs1 gene products, respectively. Both Atm and Nbs1 contribute to Chk2 activation and p53 phosphorylation following deregulation of normal Rb growth control. E2F2, a related E2F family member that does not induce apoptosis, also activates Atm, resulting in phosphorylation of p53. However, we found that the key commitment step in apoptosis induction is the ability of E2F1, and not E2F2, to upregulate Chk2 expression. Our results suggest that E2F1 plays a central role in signaling disturbances in the Rb growth control pathway and, by upregulation of Chk2, may sensitize cells to undergo apoptosis.

Animals↗
PubMed2003

Erythropoietin mimics the acute phase response in critical illness.

BACKGROUND: In a prospective observational study, we examined the temporal relationships between serum erythropoietin (EPO) levels, haemoglobin concentration and the inflammatory response in critically ill patients with and without acute renal failure (ARF). PATIENTS AND METHOD: Twenty-five critically ill patients, from general and cardiac intensive care units (ICUs) in a university hospital, were studied. Eight had ARF and 17 had normal or mildly impaired renal function. The comparator group included 82 nonhospitalized patients with normal renal function and varying haemoglobin concentrations. In the patients, levels of haemoglobin, serum EPO, C-reactive protein, IL-1beta, IL-6, serum iron, ferritin, vitamin B12 and folate were measured, and Coombs test was performed from ICU admission until discharge or death. Concurrent EPO and haemoglobin levels were measured in the comparator group. RESULTS: EPO levels were initially high in patients with ARF, falling to normal or low levels by day 3. Thereafter, almost all ICU patients demonstrated normal or low EPO levels despite progressive anaemia. IL-6 exhibited a similar initial pattern, but levels remained elevated during the chronic phase of critical illness. IL-1beta was undetectable. Critically ill patients could not be distinguished from nonhospitalized anaemic patients on the basis of EPO levels. CONCLUSION: EPO levels are markedly elevated in the initial phase of critical illness with ARF. In the chronic phase of critical illness, EPO levels are the same for patients with and those without ARF, and cannot be distinguished from noncritically ill patients with varying haemoglobin concentrations. Exogenous EPO therapy is unlikely to be effective in the first few days of critical illness.

Acute Kidney Injury↗
PubMed2003

Was it something she ate? Case report and discussion of scombroid poisoning.

We report the case of a 51-year old woman who developed headache, nausea, palpitations, tachycardia and hypertension 30 minutes after eating a tuna fish salad. Elevated histamine levels in the salad helped to confirm a suspected diagnosis of scombroid poisoning. The signs, symptoms, pathophysiology and management of poisoning from spoiled scombroid fish are discussed.

Animals↗
PubMed2003

Neurological associations of absent P60 component of the posterior tibial nerve somatosensory evoked potential.

The cortically generated P60 component of the posterior tibial nerve somatosensory evoked potential (PTSEP) is occasionally found to be absent in neurological patients,while the preceding P40 is preserved ("Absent P60" pattern). A retrospective analysis of 24 such cases showed them to represent a different clinical population from that represented by 24 age- and sex-matched but otherwise unselected patients with entirely normal PTSEPs. The most frequent diagnoses of the patients with normal PTSEPs (conversion disorder and definite or suspected multiple sclerosis) were significantly less prevalent in the patients with the Absent P60 pattern, while miscellaneous other diseases affecting the peripheral and/or central sensory pathways were more frequent. In comparison with a second matched patient group with abnormal P40 in addition to P60, the patients with the Absent P60 pattern had a significantly lower incidence of "large fibre" sensory deficits (impaired vibration and/or joint-position sense). The incidence of "small fibre" deficits (impaired pain and/or temperature sensation) was similar in both groups with PTSEP changes. In conjunction with previously published findings in normal subjects, the data suggest that the P60 is a late response of the primary sensorimotor cortex due to activation of large diameter myelinated sensory fibres, but which is also tonically influenced by small fibre input. The Absent P60 pattern may be recognized as a distinct PTSEP abnormality, although its occurrence in some normal individuals should be noted.

Adult↗
PubMed2002

Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results.

PURPOSE: Docetaxel and capecitabine, a tumor-activated oral fluoropyrimidine, show high single-agent efficacy in metastatic breast cancer (MBC) and synergy in preclinical studies. This international phase III trial compared efficacy and tolerability of capecitabine/docetaxel therapy with single-agent docetaxel in anthracycline-pretreated patients with MBC. PATIENTS AND METHODS: Patients were randomized to 21-day cycles of oral capecitabine 1,250 mg/m(2) twice daily on days 1 to 14 plus docetaxel 75 mg/m(2) on day 1 (n = 255) or to docetaxel 100 mg/m(2) on day 1 (n = 256). RESULTS: Capecitabine/docetaxel resulted in significantly superior efficacy in time to disease progression (TTP) (hazard ratio, 0.652; 95% confidence interval [CI], 0.545 to 0.780; P =.0001; median, 6.1 v 4.2 months), overall survival (hazard ratio, 0.775; 95% CI, 0.634 to 0.947; P =.0126; median, 14.5 v 11.5 months), and objective tumor response rate (42% v 30%, P =.006) compared with docetaxel. Gastrointestinal side effects and hand-foot syndrome were more common with combination therapy, whereas myalgia, arthralgia, and neutropenic fever/sepsis were more common with single-agent docetaxel. More grade 3 adverse events occurred with combination therapy (71% v 49%, respectively), whereas grade 4 events were slightly more common with docetaxel (31% v 25% with combination). CONCLUSION: The significantly superior TTP and survival achieved with the addition of capecitabine to docetaxel 75 mg/m(2), with the manageable toxicity profile, indicate that this combination provides clear benefits over single-agent docetaxel 100 mg/m(2). Docetaxel/capecitabine therapy is an important treatment option for women with anthracycline-pretreated MBC.

Administration, Oral↗
PubMed2002

p53 mutant mice that display early ageing-associated phenotypes.

The p53 tumour suppressor is activated by numerous stressors to induce apoptosis, cell cycle arrest, or senescence. To study the biological effects of altered p53 function, we generated mice with a deletion mutation in the first six exons of the p53 gene that express a truncated RNA capable of encoding a carboxy-terminal p53 fragment. This mutation confers phenotypes consistent with activated p53 rather than inactivated p53. Mutant (p53+/m) mice exhibit enhanced resistance to spontaneous tumours compared with wild-type (p53+/+) littermates. As p53+/m mice age, they display an early onset of phenotypes associated with ageing. These include reduced longevity, osteoporosis, generalized organ atrophy and a diminished stress tolerance. A second line of transgenic mice containing a temperature-sensitive mutant allele of p53 also exhibits early ageing phenotypes. These data suggest that p53 has a role in regulating organismal ageing.

Adipose Tissue↗
PubMed2002

E2F1 induces phosphorylation of p53 that is coincident with p53 accumulation and apoptosis.

It has been proposed that the E2F1 transcription factor serves as a link between the Rb/E2F proliferation pathway and the p53 apoptosis pathway by inducing the expression of p19ARF, a protein that regulates p53 stability. We find that although p19ARF contributes to p53 accumulation in response to E2F expression, p19ARF is not required for E2F1-mediated apoptosis. E2F1 can signal p53 phosphorylation in the absence of p19ARF, similar to the observed modifications to p53 in response to DNA damage. These modifications are not observed in the absence of p19ARF following expression of E2F2, an E2F family member that does not induce apoptosis in mouse embryo fibroblasts but can induce p19ARF and p53 protein expression. p53 modification is found to be crucial for E2F1-mediated apoptosis, and this apoptosis is compromised when E2F1 is coexpressed with a p53 mutant lacking many N- and C-terminal phosphorylation sites. Additionally, E2F1-mediated apoptosis is abolished in the presence of caffeine, an inhibitor of phosphatidylinositol 3-kinase-related kinases that phosphorylate p53. These findings suggest that p53 phosphorylation is a key step in E2F1-mediated apoptosis and that this modification can occur in the absence of p19ARF.

Animals↗
PubMed2002

Mutualism promotes diversity and stability in a simple artificial ecosystem.

This work investigates the effect of ecological interactions between organisms on the evolutionary dynamics of a community. A spatially explicit, individual-based model is presented, in which organisms compete for space and resources. We investigated how introducing the potential for mutualistic relationships (where the presence of one type of organism stimulates the growth of another type, and vice versa) affected the evolutionary dynamics of the system. Without this potential, one or a small number of individual types of organisms dominated the simulated community from the onset. When mutualistic relationships were allowed, many persisting types arose, with new types appearing continually. Furthermore, we investigated how the stability of the community differed when mutualistic relationships were allowed and disallowed. Our results suggest that the existence of mutualistic relationships improved community stability.

Biological Evolution↗