The successful treatment of primary cardiac lymphoma with a dose-dense schedule of rituximab plus CHOP.
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Aged↗
Biomedical subjects
A Taylor
Publications and source records attributed to A Taylor.
Selectivity of the ubiquitin pathway for oxidatively modified proteins: relevance to protein precipitation diseases.
There is now consensus that the accumulation of oxidatively modified proteins is cytotoxic and causally related to several age-related diseases, including the amyloid diseases and age-related cataracts. There is also general agreement that proteolytic pathways provide a quality control mechanism to limit accumulation of damaged proteins. Although many researchers assume that the ubiquitin pathway is involved in recognition and proteolytic removal of oxidatively modified proteins, which are produced upon cellular stress, there has been no direct evidence to support this hypothesis. In this work, we used a novel proteolysis-resistant ubiquitin variant to demonstrate that ubiquitin conjugates isolated from oxidatively stressed mammalian cells are enriched 3.3-15-fold for oxidatively modified proteins and that failure to execute ubiquitin-dependent proteolysis renders various cell types more susceptible to oxidative stress-related cytotoxicity. These results were corroborated using several inhibitors of the ubiquitin proteasome pathway, including PS-341, an anticancer drug in clinical use. Taken together the data indicate that the ubiquitin proteolytic pathway recognizes and removes oxidatively modified proteins, and that failure of this system, as occurs upon aging or stress, may be involved in and exacerbate cytotoxicity and age-related syndromes in which accumulation of ubiquitinated and oxidatively modified proteins has an etiologic role.
Adenoviridae↗
Fertility- and menopause-related information needs of younger women with a diagnosis of early breast cancer.
PURPOSE: The use of chemotherapy and endocrine therapies in the treatment of premenopausal women carries with it reproductive and gynecologic implications that young women may find distressing and discordant with plans for childbearing. This multicenter study aimed to investigate fertility- and menopause-related information needs among young women with a diagnosis of early-stage breast cancer. PATIENTS AND METHODS: Two hundred twenty-eight women with a diagnosis of early-stage breast cancer who were aged 40 years or younger at diagnosis and who were 6 to 60 months after diagnosis were entered onto the trial. Participants completed a mailed self-report questionnaire that included a purposely designed fertility- and menopause-related information needs survey and standardized measures of distress, anxiety, quality of life, menopausal symptoms, and information-seeking style. RESULTS: Seventy-one percent of participants discussed fertility-related issues with a health professional as part of their breast cancer treatment, and 86% discussed menopause-related issues. Consultation with a fertility or menopause specialist was the most preferred method of obtaining this information. Receiving fertility-related information was rated as being significantly more important than receiving menopause-related information at time of diagnosis (P < .001) and at treatment decision making (P = .058). Receiving menopause-related information was rated as being significantly more important than receiving fertility-related information during adjuvant treatment (P < .05), at completion of adjuvant treatment (P < .001), and during follow-up (P < .001). Common questions, sources of information, and correlates of perceived importance were identified. CONCLUSION: The results of this study suggest that younger women have unmet needs for fertility- and menopause-related information and provide preliminary empirical data to guide the development of better fertility- and menopause-related patient education materials for younger women with a diagnosis of early breast cancer.
Adult↗
Decreases in phosphoinositide-3-kinase/Akt and extracellular signal-regulated kinase 1/2 signaling activate components of spinal motoneuron death.
Motoneuron dependence on target-derived trophic factors during development is well established, with loss of trophic support leading to the death of these cells. A complete understanding of the intracellular signal transduction machinery associated with extracellular survival signals requires the examination of individual pathways in various cellular and environmental contexts. In cells deprived of trophic support, and hence compromised for survival, phosphoinositide-3-kinase (PI3K) is decreased when compared with healthy cells supplied with trophic support. Extracellular signal-regulated kinase 1/2 (ERK1/2) signaling is dramatically decreased in deprived cells. We have examined the role of these two pathways to understand how changes in their activity regulate motoneuron survival and death. Pharmacological inhibition of PI3K attenuated motoneuron survival and was important in the regulation of Bcl-2 serine phosphorylation, limited release of cytochrome c into the cytoplasm and caspase activation. Bax translocation from cytoplasm to mitochondria was not altered when PI3K was inhibited. High levels of ERK1/2 inhibition robustly attenuated motoneuron survival in cells supplied with trophic support, whereas moderate inhibition of ERK1/2 activation had little effect. ERK1/2 inhibition in these cells decreased Bcl-2 phosphorylation and resulted in release of cytochrome c from the mitochondria. Bax translocation and caspase activation were not affected by ERK1/2 inhibition. These data reveal that changes in PI3K and ERK1/2 signaling lead to individual and overlapping effects on the cell-death machinery. Characterizing the role of these pathways is critical for a fundamental understanding of the development and degeneration of specific neuronal populations.
Animals↗
A new Mother-to-Infant Bonding Scale: links with early maternal mood.
Some mothers find it hard to relate to their new baby, and such failure may have long-term effects on the infant. This has been a neglected area of research. A new simple 8 item self-rating mother-to-infant bonding questionnaire has been designed to assess the feelings of a mother towards her new baby. A principal components and reliability analysis demonstrated an alpha score of 0.71. One hundred and sixty two women filled in the Kennerley Blues Scale, the Edinburgh Postnatal Depression Scale (EPDS) the Highs Scale and the new Mother to Infant Bonding Scale on day 3 postpartum. Twelve weeks later they were sent the EPDS and the Bonding scales again. One hundred and forty four returned all questionnaires. There was a strong correlation between the Bonding scores at 3 days and at 12 weeks (r(s)=0.54 p<0.001). Multiple regression analysis showed that those with raised Blues scores had worse, and those with raised Highs scores had better bonding at 3 days. Those with raised EPDS scores at 3 days (13 and over) had worse bonding scores in the "first few weeks" (median 4 versus 1, p = 0.028), as recalled at 12 weeks. This simple questionnaire is acceptable for use with mothers and gives significant correlations with their early mood.
Adult↗
Stretch reflex instability compared in three different human muscles.
The possibility of causing instability in the stretch reflex has been examined in three different human muscles: biceps, first dorsal interosseous (FDI) of the hand and digastric. Tremor recorded as fluctuation of isometric force was compared with that occurring during contraction against a spring load. The spring compliance was selected to make the natural frequency of the part in each case appropriate for oscillations in the short latency stretch reflex. A computer model of the whole system was used to predict the frequency at which oscillations should be expected and to estimate the reflex gain required in each case to cause sustained oscillations. Estimates were computed of the autospectra of the force records and of the rectified surface EMG signals and of the coherence functions. Normal subjects showed no evidence of a distinct spectral peak during isometric recording from any of the three muscles. However, in anisometric conditions regular oscillations in force occurred in biceps, but not in FDI or digastric. The oscillations in biceps at 8-9 Hz were accompanied by similar oscillations in the EMG which were highly coherent with the force signal. The results are consistent with the presence of a strong segmental stretch reflex effect in biceps and weak or absent reflex in FDI. Digastric is known to contain no muscle spindles and therefore to lack a stretch reflex. In two subjects who volunteered that they had more tremor than normal, but had no known neurological abnormality, there was a distinct peak in the force spectrum at 8-9 Hz in biceps and FDI in isometric conditions with coherent EMG activity. The peak increased in size in anisometric conditions in biceps but not in FDI. This component appears to be of central rather than of reflex origin. No equivalent component was found in digastric records. The results are discussed in relation to the possible role of the short latency stretch reflex in the genesis of physiological tremor in different muscles.
Adult↗
Preoperative staging of rectal cancer by MRI; results of a UK survey.
AIM: To determine current day-to-day practice of and access to preoperative MRI for patients with rectal cancer in the UK, with the aim of identifying constraining factors. MATERIALS AND METHODS: A questionnaire asking for details of rectal cancer workload, multidisciplinary team (MDT) practice, preoperative MRI, the use of alternative imaging methods where appropriate, and an assessment of local access to MRI, was mailed to 283 UK departments of radiology. Replies were received from 142 departments (50.2% response rate). These were collated and response frequencies were determined. RESULTS: According to their replies, 135 (95%) of respondents always discussed rectal cancer cases within the context of an MDT, usually including a radiologist. Only 49% of respondents attempted to offer preoperative MRI to all rectal cancer patients, and 35% of respondents used MRI in less than 25% of cases. Of the 142 respondents, 73 (51%) felt their practice was currently constrained by lack of MR resources. The most frequently cited constraint was an available but over-subscribed MRI scanner. Limited radiology manpower was the next most frequently cited constraint. A significant minority stated that no MRI scanner was available. CONCLUSIONS: The MDT is a well established forum for the discussion of patients with rectal cancer, and a radiologist is usually involved. However, in the face of current guidelines, less than 50% of the units studied were able to offer preoperative MRI to all of their rectal cancer cases. Improved access to MRI and increased radiological manpower are necessary if current management guidelines are to be observed.
Health Care Surveys↗
Severe illness and death among injecting drug users in Scotland: a case-control study.
Between April and September 2000, 60 injecting drug users in Scotland died or were hospitalized with severe illness. Laboratory investigations suggested that Clostridium novyi and other bacteria were important aetiological agents. To determine associated environmental/behavioural factors a case-control study was undertaken with 19 'definite' and 32 'probable' cases in Glasgow, Scotland. For every deceased case (n=19), up to three proxy individuals were interviewed. Three controls were identified for each case. Multivariate logistic regression analyses compared (i) all cases and controls; (ii) definite cases and matched controls; (iii) probable cases and matched controls. In all three analyses injecting into muscle or skin and injecting most of the time with a filter used by someone else were the variables most strongly associated with illness. Comparing only muscle-injecting cases and controls, cases were significantly more likely to have injected larger amounts of heroin per average injection than were controls. The findings make an important epidemiological contribution to the understanding of the public health and clinical implications of the contamination of illicit drugs by histotoxic clostridia.
Adult↗
One stop fertility clinic.
UNLABELLED: The objective of this study was to determine the feasibility and acceptability of out-patient based investigation of infertile couples using a prospective observational study based in a large undergraduate teaching hospital. We studied couples referred to secondary care for investigation of their infertility. Investigations involved pelvic ultrasound, diagnostic hysteroscopy and culdoscopy. The main outcome measures were feasibility of investigations, findings, patient views, and a management plan. RESULTS: 199 of 347 (57.3%) couples referred met our selection criteria, and 162 of this group have attended. Thirty-one (19.1%) were judged to be unsuitable for culdoscopy, and culdoscopy failed in a further 29 (17.9%). The average time for the three procedures was 41.2 (SD 17.2) minutes, and over 1/3 of patients were found to have pelvic pathology. The investigations were well tolerated and there was only one complication necessitating admission to hospital. Most patients appreciated the need for a single hospital visit and the availability of immediate results. CONCLUSIONS: A One Stop approach to the investigation of infertility is attractive but not suitable for or desired by all infertile couples. Organisational issues were also identified.
Adult↗
Maternal reactivity to fetal alloantigens is related to newborn immune responses and subsequent allergic disease.
BACKGROUND: Maternal allergy confers stronger allergy risk (than paternal allergy) suggesting that maternal patterns of immune response can directly influence immune development in offspring. Women prone to allergic immune responses to allergens may also have altered immune responses to other antigens including fetal antigens. OBJECTIVE: This exploratory study examines relationships between maternal immune responses to fetal antigens and the subsequent risk of allergy. METHODS: Mononuclear cells (MNC) were collected from 36 mother-infant pairs to compare maternal (and fetal) cellular immune responses to alloantigens (fetal, maternal or unrelated donor [URD]), and allergens in allergic (18 pairs) and non-allergic (18 pairs) mothers. Thirty children had documented allergic outcomes at 6 years of age. RESULTS: In this population, allergic outcomes in the offspring were associated more strongly with materno-fetal immune interactions than with a maternal family history of allergy. Specifically, allergic disease at 6 years of age was associated with significantly higher maternal responses to fetal alloantigens (lymphoproliferation, P=0.008; IL-13, P=0.02 and IFN-gamma, P=0.015), whereas associations with maternal allergy did not reach significance (P=0.07). Fetal IFN-gamma alloantigen responses were significantly correlated with the degree of human lymphocyte antigen (HLA) mismatch (maternal HLA class II antibodies) (tau=0.3, P=0.03). The capacity of the fetus to produce IL-13 (tau=0.4, P=0.001) and IL-10 (tau=0.3, P=0.029) was directly related to the level of these cytokines produced by the mother in response to fetal antigens. Allergic mothers showed a non-significant trend for stronger lymphoproliferation to fetal alloantigens. The number of previous pregnancies (gravidity) was associated with stronger maternal responses to fetal alloantigens, as shown by lymphoproliferation (Kendall tau=0.3, P=0.04) and IFN-gamma (tau=0.3, P=0.04) synthesis, but did not affect fetal responses to the various stimuli. CONCLUSIONS: Maternal responses to fetal antigens were related to fetal immune responses and subsequent allergy. This novel observation suggests that events at the materno-fetal interface have an important influence on early immune development and should be investigated further.
Child↗
Cytosine-phosphate-guanine motifs fail to promote T-helper type 1-polarized responses in human neonatal mononuclear cells.
BACKGROUND: The T-helper type 1 (Th1) trophic properties of bacterial cytosine-phosphate-guanine (CpG) motifs have made them logical adjuvants both for the suppression of Th2-mediated allergic disease in early life and for promoting vaccine responses in neonates who have relatively immature Th1 function. However, little is known about their effects on immature immune responses in this period. OBJECTIVES: To compare the effects of CpG on adult and neonatal cellular immune responses to various stimuli. METHODS: The immune responses of mononuclear cells (MC) derived from neonates (n=25) and their mothers (n=25) were compared in vitro. These were stimulated with house dust mite (HDM), CpG B, CpG C, non-CpG oligodeoxynucleotides (ODN) or diphtheria toxoid (DT) in optimized conditions. In parallel cultures, CpGs were combined with HDM or DT antigens to assess the effect of the various ODN on these antigen-specific responses. Lymphoproliferation and cytokine responses IL-13, IFN-gamma, IL-6, IL-10, TNF-alpha) were measured for all of the cultures described above. RESULTS: Although neonates showed attenuated lymphoproliferation to CpG, the production of antigen-presenting cell-derived cytokines such as IL-6 and IL-10 and the up-regulation of major histocompatibility complex class II (HLA-DR) were detected at adult levels. T cell-derived cytokines (IL-13 and IFN-gamma) were not detectable in response to CpG alone. Most neonates also failed to produce detectable IFN-gamma to HDM or DT (unlike adults), but readily produced IL-13 to these stimuli. The addition of CpG resulted in an increase in neonatal IFN-gamma production in response to HDM (P=0.011) and a similar but non-significant trend with DT. However, rather than inhibiting Th2 IL-13 responses, the addition of CpGs was associated with a significant increase in the IL-13 responses to HDM (P=0.016) and DT (P=0.03), effects not seen in adults. CONCLUSIONS: This study provides further evidence that neonatal MC responses to CpG are functionally different from adults, and do not show clear Th1 polarization. The CpG associated increase in Th2 responses may reflect a potentiation of the normal neonatal Th2 propensity, or non-specific activation of neonatal MC.
Adjuvants, Immunologic↗
Routine cervical cytology has no role after primary chemoradiation for cervical cancer.
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Combined Modality Therapy↗
Prevalence of, and risk factors for, hepatitis C virus infection among recent initiates to injecting in London and Glasgow: cross sectional analysis.
Our aim was to compare the prevalence of antibody to hepatitis C virus (anti-HCV) among recently initiated injecting drug users (IDUs) in London and Glasgow, and to identify risk factors which could explain differences in prevalence between the cities. Complementary studies of community recruited IDUs who had initiated injection drug use since 1996 were conducted during 2001-2002. Data on HCV risk behaviours were gathered using structured questionnaires with identical core questions and respondents were asked to provide an oral fluid specimen which was tested anonymously for anti-HCV but was linked to the questionnaire. Sensitivities of the anti-HCV assays for oral fluid were 92-96%. Prevalence of anti-HCV was 35% (122/354) in London and 57% (207/366) in Glasgow (P < 0.001). Multifactorially, factors significantly associated with raised odds of anti-HCV positivity were increasing length of injecting career, daily injection, polydrug use, having had a needlestick injury, and having served a prison sentence. In addition lower odds of anti-HCV positivity were associated with non-injection use of crack cocaine and recruitment from drug agencies. After adjustment for these factors, the increased odds of anti-HCV associated with being a Glasgow IDU were diminished but remained significant. HCV continues to be transmitted among the IDU population of both cities at high rates despite the availability of syringe exchange and methadone maintenance. Effectiveness of harm reduction interventions may be compromised by inadequate coverage and failure to reduce sufficiently the frequency of sharing different types of injecting equipment, as well as the high background prevalence of HCV, and its high infectivity. Comprehensive action is urgently required to reduce the incidence of HCV among injectors.
Adult↗
Do all dry powder inhalers show the same pharmaceutical performance?
Important measures of pharmaceutical performance of dry powder inhalers include total emitted dose (TED, the quantity of drug emitted from the device when used at a fixed flow rate, typically 60 l/min or the flow rate achieved at a pressure drop of 4 kPa) and fine particle mass (FPM, the quantity of drug with small particles, typically with an aerodynamic diameter of less than 5 microns emitted from the device at a fixed flow rate). There is a wide range of dry powder inhalers available. The complexity of design decisions means that dry powder inhalers are very diverse, with identical designs unlikely. It is not surprising therefore that evidence from in vitro studies shows considerable variation in pharmaceutical performance of dry powder inhalers. Although neither TED nor FPM can accurately predict in vivo performance, it may be expected that highly variable or inhalation flow sensitive in vitro behaviour will be reflected in variable performance when used by patients.
Administration, Inhalation↗
Can patients use all dry powder inhalers equally well?
If patients are unable to use their inhaler, drug delivery may be unsatisfactory and the patients may fail to benefit from the prescribed medication. It is important to consider whether patients can use all dry powder inhalers equally well. Changing a patient from a dry powder inhaler used well to one that the patient is unable to operate effectively could compromise asthma control. The many marketed dry powder inhalers reflect differences in design decisions that could affect lung deposition. Studies using different dry powder inhalers have confirmed that different lung deposition patterns are observed. Furthermore, there may be considerable individual variability in lung deposition. Differences in lung deposition patterns could have clinical effects. Studies may show similar clinical effectiveness with two inhalers, because most products are used at the plateau phase of the dose-response curve, although there may be differences in the adverse event profile. The ideal inhaler does not yet exist. Different dry powder inhalers show some but not all features of the ideal inhaler; hence, patients may prefer some aspects of one inhaler while favouring a different inhaler for other features. The individual balance of features will govern the overall preference for one inhaler over others. The method for operation of dry powder inhalers varies. Ease of use is seen as an important consideration when selecting an inhaler device, which should be evaluated in real-life studies using unselected patient populations. In conclusion, the evidence suggests that patients cannot use all dry powder inhalers equally well.
Administration, Inhalation↗
Implementation of national diabetes retinal screening programme is associated with a lower proportion of patients referred to ophthalmology.
AIMS: To examine the impact of a new national retinal screening programme on screening attendance, technical quality of images, and referrals to the ophthalmology clinic. METHODS: Results from the previous ad hoc retinal screening service were compared with data from the first year of the new Scottish Diabetes Retinal Screening Programme in Dundee, which was administered according to criteria recommended by the Health Technology Board Scotland. RESULTS: Of 5150 patients invited for screening, 10.3% of patients did not attend. Overall, 4574 patients underwent single-field digital retinal photography and 25.4% required mydriasis for an adequate image. After screening, 1.9 and 90.5% were recalled for repeat photography at 6 months and 1 year, respectively, whilst 4.6% were ungradable and 3.0% were referred to the ophthalmology clinic. Compared with the last 18 months of the previous scheme, with the new programme a smaller proportion of patients were referred to ophthalmology (3.0 vs. 5.9%; P < 0.001, difference 2.9%: 95% confidence interval 2.1-3.7%). Moreover, the attendance was higher (89 vs. 82%; P < 0.01) and there were fewer ungradable images (4.6 vs. 7.1%; P < 0.001). CONCLUSIONS: Introduction of a systematic retinal screening programme can reduce the proportion of patients referred to the ophthalmology clinic, and use ophthalmology services more efficiently.
Adult↗
Reducing blood loss at open myomectomy using triple tourniquets: a randomised controlled trial.
OBJECTIVES: To evaluate triple tourniquets in controlled conditions and for the first time to investigate the hypothesis that leaving a semi-permanent tourniquet around the uterine artery reduces post-operative bleeding from the uterine incisions. DESIGN: A randomised controlled trial. SETTING: Two University teaching hospitals. POPULATION: Twenty-eight patients with symptomatic fibroids and uterine sizes ranging from 14 to 24 weeks of gestation undergoing open myomectomy. METHODS: A number 1 polyglactin suture was tied around the cervix to occlude the uterine arteries, and polythene tourniquets were tied around the infundibulopelvic ligament to obstruct the ovarian vessels. At the end of the procedure, the ovarian ties were released but the uterine artery suture remained in situ. MAIN OUTCOME MEASURES: Intra-operative blood loss, post-operative blood loss, blood transfusion rates, operative morbidity, uterine blood flow and ovarian function. RESULTS: There was significantly less blood lost in the tourniquet group than in the control group (difference between means 1870 mL, 95% CI 1159-2580 mL, P < 0.0001; transfusion rates of 7% and 79%, P= 0.0003). The volume in the pelvic drain 20 min post-operatively and after 48 hours failed to reach statistical significance between the two groups (P= 0.10 and P= 0.165). There were no differences in uterine artery Doppler resistance indices at five days (P= 0.54), six weeks (P= 0.47), three months (P= 0.49) and at six months (P= 0.18). Day two serum FSH concentrations after surgery were unchanged (P= 0.45), compared with baseline values. CONCLUSIONS: Triple tourniquets are effective in reducing bleeding and transfusion rates. There appears no obvious adverse effect on uterine perfusion or ovarian function.
Adult↗
Outpatient hysteroscopy: traditional versus the 'no-touch' technique.
OBJECTIVE: To assess whether outpatient hysteroscopy using the 'no-touch' technique confers any advantages in terms of patient discomfort over the traditional technique. DESIGN: Prospective randomised controlled study. SETTING: Outpatient hysteroscopy clinic in a large university undergraduate teaching hospital. POPULATION: All women referred for outpatient hysteroscopy in a 12-month period. INTERVENTIONS: Women were randomised to undergo either traditional saline hysteroscopy requiring the use of a speculum and tenaculum, or a 'no-touch' vaginoscopic hysteroscopy which does not require a speculum or tenaculum. Each group was further subdivided to have hysteroscopy with either a 2.9-mm or 4-mm hysteroscope. Patients were asked to complete pre- and postprocedure questionnaires ranking pain scores. MAIN OUTCOME MEASURES: The relative success of each of these techniques, requirement for local anaesthetic and pain scores at different times during the hysteroscopy were recorded at the end of the procedure. The time taken to carry out each procedure was also measured. RESULTS: One hundred and twenty women were recruited in this study: 60 were randomised to traditional hysteroscopy and 60 to 'no-touch' hysteroscopy. The overall success rate for hysteroscopy was 99%. There was no significant difference in the requirement for local anaesthetic between the two groups, but those who underwent 'no-touch' hysteroscopy with a 2.9-mm hysteroscope had the lowest requirement of local anaesthetic (10% compared with 27% in the no-touch hysteroscopy with a 4-mm hysteroscope group). The time taken to perform hysteroscopy and biopsy was significantly shorter with 'no-touch' hysteroscopy (5.9 vs 7.8 min; difference 1.9, 95% CI 0.7-3.1). There were no differences in pain scores between the groups at different times during hysteroscopy. CONCLUSIONS: 'No-touch' or vaginoscopic hysteroscopy is significantly faster to perform than the traditional technique. Although there was no difference in pain scores between the two techniques, local anaesthetic requirements were least in those who underwent 'no-touch' hysteroscopy with a narrow bore hysteroscope.
Adult↗