The effect of rectal heterogeneity on wall dose in high dose rate brachytherapy.

When treating prostate cancer using high dose rate (HDR) brachytherapy, overdosing the rectal wall may lead to post-treatment rectal complications. An area of concern is related to how the rectal wall dose is calculated by treatment planning systems (TPSs). TPSs are used to calculate the dose delivered to the rectal wall, but they assume that the rectum is a water-equivalent homogeneous medium of infinite size and do not consider the effect that an air-filled "empty" rectal cavity would have on the dose absorbed along the rectal wall. The aim of this research is to quantify the effect that an air cavity has on the rectal wall dose, as its presence changes the backscatter conditions in the region. The MO Skin and RADFET dosimeters proved capable of measuring absolute dose with increasing distance from the HDR Ir-192 brachytherapy source. However, the anterior rectal wall doses measured by the MOSkin and RADFET in an empty rectal cavity were 14.7 +/- 0.2% and 13.7 +/- 0.6% lower than the dose measured in a homogeneous rectal phantom. Monte Carlo simulations corroborated the experimentally obtained results, reporting a -13.2 +/- 0.6% difference. The dose measured at the posterior wall of an empty rectal cavity was between 22% and 26% greater than the dose measured in a full rectal cavity. The heterogeneity of the rectal volume appears to have a significant effect on the rectal dose when compared to calculated rectal dose.

Monitoring of stimulated cycles in assisted reproduction (IVF and ICSI).

BACKGROUND: Traditional monitoring of ovarian hyperstimulation during in vitro fertilisation (IVF) treatment has included ultrasonography plus serum estradiol concentration to ensure safe practice by reducing the incidence and severity of ovarian hyperstimulation syndrome (OHSS). The need for intensive monitoring during ovarian stimulation in IVF is controversial. It has been suggested that close monitoring is time consuming, expensive and inconvenient for the woman and simplification of IVF therapy by using ultrasound only should be considered. This systematic review assessed the effects of ovarian monitoring by ultrasound only versus ultrasound plus serum estradiol measurement on IVF outcomes and the occurrence of OHSS in women undergoing stimulated cycles in IVF and intra-cytoplasmic sperm injection (ICSI) treatment. OBJECTIVES: To quantify the effect of monitoring controlled ovarian stimulation in IVF and ICSI cycles with ultrasound plus serum estradiol concentration versus ultrasound only in terms of live birth rates, pregnancy rates and the incidence of OHSS. SEARCH STRATEGY: We searched the Menstrual Disorders and Subfertility Group Specialised Register of controlled trials, Cochrane Central Register of Controlled Trials (CENTRAL) on the latest issue of The Cochrane Library, MEDLINE (1966 to May 2007), EMBASE (1980 to May 2007), CINAHL (1982 to May 2007), the National Research Register, and web-based trial databases such as Current Controlled Trials. There was no language restriction. Additionally all references in the identified trials and background papers were checked and authors were contacted to identify relevant published and unpublished data. SELECTION CRITERIA: Only randomised controlled trials that compared monitoring with ultrasound plus serum estradiol concentration versus ultrasound only in women undergoing ovarian hyperstimulation for IVF and ICSI treatment were included. DATA COLLECTION AND ANALYSIS: Two review authors independently examined the electronic search results for relevant trials, extracted data and assessed trial quality. They resolved disagreements by discussion with two other authors. Outcomes data were pooled when appropriate and summary statistics presented when limited data did not allow meta-analysis. MAIN RESULTS: Our search strategy identified 1119 potentially eligible reports, of which two met our inclusion criteria. These involved 411 women who underwent controlled ovarian stimulation monitoring. Our primary outcome of live birth rate was not reported in either study. One trial reported clinical pregnancy rate per woman (33% versus 31%; RR 1.07, 95% CI 0.77 to 1.49), the second trial reported clinical pregnancy rate per oocyte retrieval (22% versus 25%). There was no significant difference between the ultrasound plus estradiol group and the ultrasound alone group in the mean number of oocytes retrieved (WMD -0.55, 95% CI -1.79 to 0.69) and the incidence of ovarian hyperstimulation (RR 0.73, 95% CI 0.30 to 1.78) for the two studies. AUTHORS' CONCLUSIONS: There is no evidence from randomised trials to support cycle monitoring by ultrasound plus serum estradiol as more efficacious than cycle monitoring by ultrasound only on outcomes of live birth and pregnancy rates. A large well-designed randomised controlled trial is needed that reports on live birth rates and pregnancy, with economic evaluation of the costs involved and the views of the women undergoing cycle monitoring. A randomised trial with sufficiently large sample size to test the effects of different monitoring protocols on OHSS, a rare outcome, will pose a great challenge. Until such a trial is considered feasible, cycle monitoring by transvaginal ultrasound plus serum estradiol may need to be retained as a precautionary good practice point.

Characterization of a functional NF-kappa B site in the human interleukin 1 beta promoter: evidence for a positive autoregulatory loop.

The -300 region of the interleukin 1 beta (IL-1 beta) promoter contains a functional NF-kappa B binding site composed of the decamer sequence 5'-GGGAAAATCC-3'. Probes representing the -300 region or the NF-kappa B site alone interacted with NF-kappa B proteins present in phorbol myristate acetate-, lipopolysaccharide-, or Sendai virus-induced myeloid cell extracts as well as recombinant NFKB1 (p50) and RelA (p65); furthermore, NF-kappa B protein-DNA complex formation was dissociated in vitro by the addition of recombinant I kappa B alpha. Mutation of the NF-kappa B site in the context of the IL-1 beta promoter reduced the responsiveness of the IL-1 beta promoter to various inducers, including phorbol ester, Sendai virus, poly(rI-rC), and IL-1 beta. A 4.4-kb IL-1 beta promoter fragment linked to a chloramphenicol acetyltransferase reporter gene was also preferentially inducible by coexpression of individual NF-kappa B subunits compared with a mutated IL-1 beta promoter fragment. When multiple copies of the IL-1 beta NF-kappa B site were linked to an enhancerless simian virus 40 promoter, this element was able to mediate phorbol ester- or lipopolysaccharide-inducible gene expression. In cotransfection experiments, RelA (p65) and c-Rel (p85) were identified as the main subunits responsible for the activation of the IL-1 beta NF-kappa B site; also, combinations of NFKB1 (p50) and RelA (p65) or c-Rel and RelA were strong transcriptional activators of reporter gene activity. The presence of a functional NF-kappa B binding site in the IL-1 beta promoter suggests that IL-1 positively autoregulates its own synthesis, since IL-1 is a strong inducer of NF-kappa B binding activity. Thus, the IL-1 beta gene may be considered as an important additional member of the family of cytokine genes regulated in part by the NF-kappa B/rel family of transcription factors.

Methods to increase response rates to postal questionnaires.

BACKGROUND: Postal questionnaires are widely used for data collection in epidemiological studies but non-response reduces the effective sample size and can introduce bias. Finding ways to increase response rates to postal questionnaires would improve the quality of health research. OBJECTIVES: To identify effective strategies to increase response rates to postal questionnaires. SEARCH STRATEGY: We aimed to find all randomised controlled trials of strategies to increase response rates to postal questionnaires. We searched 14 electronic databases to February 2003 and manually searched the reference lists of relevant trials and reviews, and all issues of two journals. We contacted the authors of all trials or reviews to ask about unpublished trials. Where necessary, authors were also contacted to confirm methods of allocation used and to clarify results presented. We assessed the eligibility of each trial using pre-defined criteria. SELECTION CRITERIA: Randomised controlled trials of methods to increase response rates to postal questionnaires. DATA COLLECTION AND ANALYSIS: We extracted data on the trial participants, the intervention, the number randomised to intervention and comparison groups and allocation concealment. For each strategy, we estimated pooled odds ratios and 95% confidence intervals in a random effects model. Evidence for selection bias was assessed using Egger's weighted regression method and Begg's rank correlation test and funnel plot. Heterogeneity among trial odds ratios was assessed using a chi-square test at a 5% significance level and the degree of inconsistency between trial results was quantified using I(2). MAIN RESULTS: We found 372 eligible trials. The trials evaluated 98 different ways of increasing response rates to postal questionnaires and for 62 of these the combined trials included over 1,000 participants. We found substantial heterogeneity among trial results in half of the strategies. The odds of response were at least doubled using monetary incentives (odds ratio 1.99, 95% CI 1.81 to 2.18; heterogeneity p<0.00001, I(2)=78%), recorded delivery (2.04, 1.60 to 2.61; p=0.0004, I(2)=69%), a teaser on the envelope - e.g. a comment suggesting to participants that they may benefit if they open it (3.08, 1.27 to 7.44) and a more interesting questionnaire topic (2.44, 1.99 to 3.01; p=0.74, I(2)=0%). The odds of response were substantially higher with pre-notification (1.50, 1.29 to 1.74; p<0.00001, I(2)=90%), follow-up contact (1.44, 1.25 to 1.65; p<0.0001, I(2)=68%), unconditional incentives (1.61, 1.27 to 2.04; p<0.00001, I(2)=91%), shorter questionnaires (1.73, 1.47 to 2.03; p<0.00001, I(2)=93%), providing a second copy of the questionnaire at follow-up (1.51, 1.13 to 2.00; p<0.00001, I(2)=83%), mentioning an obligation to respond (1.61, 1.16 to 2.22; p=0.98, I(2)=0%) and university sponsorship (1.32, 1.13 to 1.54; p<0.00001, I(2)=83%). The odds of response were also increased with non-monetary incentives (1.13, 1.07 to 1.21; p<0.00001, I(2)=71%), personalised questionnaires (1.16, 1.07 to 1.26; p<0.00001, I(2)=67%), use of coloured as opposed to blue or black ink (1.39, 1.16 to 1.67), use of stamped return envelopes as opposed to franked return envelopes (1.29, 1.18 to 1.42; p<0.00001, I(2)=72%), an assurance of confidentiality (1.33, 1.24 to 1.42) and first class outward mailing (1.12, 1.02 to 1.23). The odds of response were reduced when the questionnaire included questions of a sensitive nature (0.94, 0.88 to 1.00; p=0.51, I(2)=0%), when questionnaires began with the most general questions (0.80, 0.67 to 0.96), or when participants were offered the opportunity to opt out of the study (0.76, 0.65 to 0.89; p=0.46, I(2)=0%). AUTHORS' CONCLUSIONS: Health researchers using postal questionnaires can increase response rates using the strategies shown to be effective in this systematic review.

Interventions for increasing pedestrian and cyclist visibility for the prevention of death and injuries.

BACKGROUND: Pedestrians and cyclists account for nearly one in three of all road users killed and seriously injured in road traffic crashes. Late detection of other road users is one of the basic driver failures responsible for collisions. Aids to improve pedestrians and cyclist visibility have been used to avert potential collisions. However, the impact of these strategies on drivers' responses, and on pedestrian and cyclist safety is not known. OBJECTIVES: 1. To quantify the effect of visibility aids versus no visibility aids, and of different visibility aids on the occurrence of pedestrian and cyclist-motor vehicle collisions and injuries. 2. To quantify the effect of visibility aids versus no visibility aids, and of different visibility aids on drivers' detection and recognition responses. SEARCH STRATEGY: We searched the CENTRAL, the Cochrane Injuries Group specialised register, MEDLINE, TRANSPORT, National Research Register, PsycInfo and PsycLit. We searched the reference lists of included trials, contacted authors and searched the websites of relevant transport research organisations. The searches were last updated in April 2005. SELECTION CRITERIA: 1. Randomised controlled trials and controlled before-and-after studies of the effect of visibility aids on the occurrence of pedestrian and cyclist-motor collisions and injuries. 2. Randomised controlled trials of the effect of visibility aids on drivers' detection and recognition responses. This included trials where the order of presentation of visibility aids was randomised or balanced using a Latin square design. DATA COLLECTION AND ANALYSIS: Two authors independently screened records, extracted data and assessed trial quality. MAIN RESULTS: We found no trials assessing the effect of visibility aids on pedestrian and cyclist-motor vehicle collisions and injuries. We identified 39 trials assessing the effect of visibility aids on drivers' responses. Fluorescent materials in yellow, red and orange colours improve detection and recognition in the daytime. For night-time visibility, lamps, flashing lights and retroreflective materials in red and yellow colours increase detection and recognition. Retroreflective materials arranged in a 'biomotion' configuration also enhance recognition. Substantial heterogeneity between and within the trials limited the possibility for meta-analysis. Summary statistics and descriptive summaries of the outcomes were presented for individual trials when appropriate. AUTHORS' CONCLUSIONS: Visibility aids have the potential to increase visibility and enable drivers to detect pedestrians and cyclists earlier. Public acceptability of these strategies would merit further development. However, the effect of visibility aids on pedestrian and cyclist safety remains unknown. Studies which collect data on simple, meaningful outcomes are required.

Disruption of I kappa B alpha regulation by antisense RNA expression leads to malignant transformation.

NF-kappa B transcription factors regulate the expression of a variety of genes involved in immune regulation and cell growth. In most cell types NF-kappa B proteins are localized in an inactive form in the cytoplasm coupled to the inhibitory I kappa B proteins. Viruses, cytokines, lipopolysaccharides and other stimulating agents promote the dissociation of the cytosolic NF-kappa B/I kappa B complexes, via phosphorylation and degradation of I kappa B, resulting in the translocation of DNA binding, NF-kappa B complexes to the nucleus. To further understand the association of I kappa B with cell growth regulation, the effect of ectopic expression of sense and antisense I kappa B genes was examined in NIH3T3 cells. Overexpression of I kappa B alpha antisense RNA but not I kappa B gamma antisense RNA decreased the steady state levels of I kappa B alpha protein, altered NF-kappa B DNA binding and gene activity and, most importantly, induced malignant transformation as measured by saturation density, growth in soft agar and tumorigenicity in nude mice. In contrast, overexpression of I kappa B alpha resulted in decreased saturation density, a flattened cellular morphology and decreased NF-kappa B dependent reporter gene activity. These results indicate that overexpression of an I kappa B alpha antisense RNA may disrupt the NF-kappa B/I kappa B autoregulatory loop, leading to cellular transformation. Our results raise the interesting possibility that I kappa B alpha represents a potential tumor suppressor activity.

Conscious sedation and analgesia for oocyte retrieval during in vitro fertilisation procedures.

BACKGROUND: Various methods of sedation and analgesia have been used for pain relief during oocyte recovery in IVF/ICSI procedures. The choice of agents has also been influenced by quality of analgesia as well as by concern about possible detrimental effects on reproductive outcome. OBJECTIVES: To assess the efficacy of conscious sedation and analgesia versus alternative methods on pregnancy outcomes and pain relief in patients undergoing transvaginal oocyte retrieval. SEARCH STRATEGY: We searched the Specialised Register of the Menstrual Disorders and Subfertility Group, The Central Register of Controlled Trials (CENTRAL) , MEDLINE (1966 to present), EMBASE (1980 to present), CINAHL (1982 to present), the National Research Register, and Current Controlled Trials. There was no language restriction. All references in the identified trials and background papers were checked and authors contacted to identify relevant published and unpublished data. SELECTION CRITERIA: Only randomised controlled trials comparing conscious sedation and analgesia versus alternative methods for pain relief during oocyte recovery were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently scanned abstracts of the reports identified by electronic searching to identify relevant papers, extracted data and assessed trial quality. Interventions were classified and analysed under broad categories/strategies of pain relief comparing conscious sedation/analgesia with alternative methods and administration protocols. MAIN RESULTS: Our search strategy identified 390 potentially eligible reports and 12 papers met our inclusion criteria. There were no significant differences in clinical pregnancy rates per woman and patient satisfaction between the methods compared. Women's perception of pain showed conflicting results. Due to considerable heterogeneity, in terms of types and dosages of sedation or analgesia used, and tools used to assess the principal outcomes of pain and satisfaction, a meta-analysis of all the studies was not attempted. Of the three trials which compared the effect of conventional medical analgesia plus paracervical block versus electro-acupuncture plus paracervical block, there was no significant difference in clinical pregnancy rates per woman in the two groups (OR 1.01; 95% CI 0.73 to 1.4). For intra-operative pain score as measured by visual analogue scale (VAS), there was a significant difference (WMD -4.95; 95% CI -7.84 to -2.07), favouring conventional medical analgesia plus paracervical block . There was also a significant difference in intra-operative pain by VAS between patient-controlled sedation and physician-administered sedation (WMD 5.98; 95% CI 1.63 to 10.33), favouring physician -administered sedation. However, as different types and dosages of sedative and analgesic agents were used in these trials, these data should be interpreted with caution. For the rest of the trials, a descriptive summary of the outcomes was presented. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine the effect of different methods of pain relief when compared with conscious sedation and analgesia used during oocyte recovery. In this review, no one particular pain relief method or delivery system appeared to be better than the other. In future, greater consensus is needed to determine both the tools used to evaluate pain and the timing of pain evaluation during and after the procedure. Pain assessment using both subjective and objective measures may merit consideration. In addition, future trials should include intra- and post-operative adverse respiratory and cardiovascular events as outcomes.

The effect of a special nurse on patients' knowledge of epilepsy and their emotional state. Epilepsy Evaluation Care Group.

BACKGROUND: People with epilepsy often report being given insufficient information and support. However, there is little evidence from general practice about how much they know and how they feel. AIM: To describe social differences in the knowledge of epilepsy of people with the condition and test the potential effect of a nurse intervention in general practice on patients' knowledge and depression levels. METHOD: A questionnaire that included measures of knowledge, anxiety, and depression was sent to people with epilepsy aged over 15 years who were registered with 37 general practitioners. Responders were randomized to a controlled trial, offering either two appointments with an epilepsy nurse or usual care. Six months later they were reassessed. RESULTS: Two hundred and fifty-one out of 283 (89%) of the patients with epilepsy completed questionnaires and entered the study at Stage 1. One hundred and ninety-six out of 232 (84%) of those who entered the study, who remained in the practices and were eligible, returned questionnaires at Stage 2. The average duration of epilepsy was 23 years (range 2-79 years). There were significant differences in patients' levels of knowledge of epilepsy at Stage 1. Younger people, those who had left school after 16 years of age, those with GCSEs, and people who belonged to self-help groups had higher knowledge levels, and these were independent effects. Older people and those with a recent epilepsy attack had significantly higher depression scores. Knowledge scores did not differ significantly after the nurse intervention (Stage 2). At Stage 2, the risk of depression was less in the group randomized to be offered nurse input; the effect was mainly in a subgroup of patients with no recent epilepsy attack; their risk of depression was a third of the risk in the control group. CONCLUSIONS: Knowledge of epilepsy differs significantly, with social factors and self-help group membership having independent effects. A nurse-run clinic reduced the risk of depression for people with no recent epilepsy attack, but knowledge levels were not affected. This does not exclude the potential for patients learning more about epilepsy; it may be useful to suggest that patients join self-help groups early on.

Interventions for increasing pedestrian and cyclist visibility for the prevention of death and injuries.

BACKGROUND: Pedestrians and cyclists account for nearly one in three of all road users killed and seriously injured in road traffic crashes. Late detection of other road users is one of the basic driver failures responsible for collisions. Aids to improve pedestrians and cyclist visibility have been used to avert potential collisions. However, the impact of these strategies on drivers' responses, and on pedestrian and cyclist safety is not known. OBJECTIVES: 1. To quantify the effect of visibility aids vs no visibility aids, and of different visibility aids on the occurrence of pedestrian and cyclist-motor vehicle collisions and injuries. 2. To quantify the effect of visibility aids vs no visibility aids, and of different visibility aids on drivers' detection and recognition responses. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, the Injuries Group Specialised Register, MEDLINE, TRANSPORT, TRANSDOC from ECMT (European Conference of Ministers of Transport), IRRD (International Road Research Documentation), TRIS (Transportation Research Information Services), NRR (National Research Register), PsycInfo and PsycLit. SELECTION CRITERIA: 1. Randomised controlled trials and controlled before/after trials of the effect of visibility aids on the occurrence of pedestrian and cyclist-motor collisions and injuries. 2. Randomised controlled trials of the effect of visibility aids on drivers' detection and recognition responses. This included trials where the order of presentation of visibility aids was randomised or balanced using a Latin square design. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened records, extracted data and assessed trial quality. MAIN RESULTS: We found no trials assessing the effect of visibility aids on the occurrence of pedestrian and cyclist-motor vehicle collisions and injuries. We identified 37 trials assessing the effect of visibility aids on drivers' responses. Fluorescent materials in yellow, red and orange colours improve detection and recognition in the daytime. For night-time visibility, lamps, flashing lights and retroreflective materials in red and yellow colours increase detection and recognition. Retroreflective materials arranged in a 'biomotion' configuration also enhance recognition. Substantial heterogeneity between and within the trials limited the possibility for meta-analysis. Summary statistics and descriptive summaries of the outcomes were presented for individual trials when appropriate. REVIEWER'S CONCLUSIONS: Visibility aids have the potential to increase visibility and enable drivers to detect pedestrians and cyclists earlier. Public acceptability of these strategies would merit further development. However, the effect of visibility aids on pedestrian and cyclist safety remains unknown. Studies which collect data on simple, meaningful outcomes are required.

Spinal immobilisation for trauma patients.

BACKGROUND: Spinal immobilisation involves the use of a number of devices and strategies to stabilise the spinal column after injury and thus prevent spinal cord damage. The practice is widely recommended and widely used in trauma patients with suspected spinal cord injury in the pre-hospital setting. OBJECTIVES: To quantify the effect of different methods of spinal immobilisation (including immobilisation versus no immobilisation) on mortality, neurological disability, spinal stability and adverse effects in trauma patients. SEARCH STRATEGY: We searched the Cochrane Controlled Trial Register (CCTR), the specialised register of the Cochrane Injuries Group, MEDLINE, EMBASE, CINAHL, PubMed and the National Research Register. We checked reference lists of all articles and contacted experts in the field to identify eligible trials. Manufacturers of spinal immobilisation devices were also contacted for information. SELECTION CRITERIA: Randomised controlled trials comparing spinal immobilisation strategies in trauma patients with suspected spinal cord injury. Trials in healthy volunteers were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied eligibility criteria to trial reports and extracted data. MAIN RESULTS: We found no randomised controlled trials of spinal immobilisation strategies in trauma patients. REVIEWER'S CONCLUSIONS: We did not find any randomised controlled trials that met the inclusion criteria. The effect of spinal immobilisation on mortality, neurological injury, spinal stability and adverse effects in trauma patients remains uncertain. Because airway obstruction is a major cause of preventable death in trauma patients, and spinal immobilisation, particularly of the cervical spine, can contribute to airway compromise, the possibility that immobilisation may increase mortality and morbidity cannot be excluded. Large prospective studies are needed to validate the decision criteria for spinal immobilisation in trauma patients with high risk of spinal injury. Randomised controlled trials in trauma patients are required to establish the relative effectiveness of alternative strategies for spinal immobilisation.

Timing and volume of fluid administration for patients with bleeding following trauma.

BACKGROUND: Treatment of haemorrhagic shock involves maintaining blood pressure and tissue perfusion until bleeding is controlled. Different resuscitation strategies have been used to maintain the blood pressure in trauma patients until bleeding is controlled. However, while maintaining blood pressure may prevent shock, it may worsen bleeding. OBJECTIVES: To assess the effects of early versus delayed, and larger versus smaller volume of fluid administration in trauma patients with bleeding. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, the specialised register of the Injuries Group, MEDLINE, EMBASE, the National Research Register and the Science Citation Index. We checked reference lists of identified articles and contacted authors and experts in the field. SELECTION CRITERIA: Randomised trials of the timing and volume of intravenous fluid administration in trauma patients with bleeding. Trials in which different types of intravenous fluid were compared were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. MAIN RESULTS: We did not combine the results quantitatively because the interventions and patient populations were so diverse. Early versus delayed fluid administration: Three trials reported mortality and two coagulation data. In the first trial (n=598) relative risk (RR) for death with early fluid administration was 1.26 (95% confidence interval of 1.00-1.58). The weighted mean differences (WMD) for prothrombin time and partial thromboplastin time were 2.7 (95% CI 0.9-4.5) and 4.3 (95% CI 1.74-6.9) seconds respectively. In the second trial (n=50) RR for death with early blood transfusion was 5.4 (95% CI 0.3-107.1). The WMD for partial thromboplastin time was 7.0 (95% CI 6.0-8.0) seconds. In the third trial (n=1309) RR for death with early fluid administration was 1.06 (95% CI 0.77-1.47). Larger versus smaller volume of fluid administration: Three trials reported mortality and one coagulation data. In the first trial (n=36) RR for death with a larger volume of fluid resuscitation was 0.80 (95% CI 0.28-22.29). Prothrombin time and Partial thromboplastin time were 14.8 and 47.3 seconds in those who received a larger volume of fluid as compared to 13.9 and 35.1 seconds in the comparison group. In the second trial (n=99) RR for death with a high (100 mm Hg) compared to low (70 mm Hg) systolic blood pressure resuscitation target was 1.02 (95% CI 0.27-3.85). In the third trial (n=25) there were no deaths. REVIEWER'S CONCLUSIONS: We found no evidence from randomised controlled trials to support early or larger volume of intravenous fluid administration in uncontrolled haemorrhage. There is continuing uncertainty about the best fluid administration strategy in bleeding trauma patients. Further randomised controlled trials are needed to establish the most effective fluid resuscitation strategy.

Timing and volume of fluid administration for patients with bleeding.

BACKGROUND: Treatment of haemorrhagic shock involves maintaining blood pressure and tissue perfusion until bleeding is controlled. Different resuscitation strategies have been used to maintain the blood pressure in trauma patients until bleeding is controlled. However, while maintaining blood pressure may prevent shock, it may worsen bleeding. OBJECTIVES: To assess the effects of early versus delayed, and larger versus smaller volume of fluid administration in trauma patients with bleeding. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, the specialised register of the Injuries Group, MEDLINE, EMBASE, the National Research Register and the Science Citation Index. We checked reference lists of identified articles and contacted authors and experts in the field. SELECTION CRITERIA: Randomised trials of the timing and volume of intravenous fluid administration in trauma patients with bleeding. Trials in which different types of intravenous fluid were compared were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. MAIN RESULTS: We did not combine the results quantitatively because the interventions and patient populations were so diverse. Early versus delayed fluid administration. Three trials reported mortality and two coagulation data. In the first trial (n=598) relative risk (RR) for death with early fluid administration was 1.26 (95% confidence interval of 1.00-1.58). The weighted mean differences (WMD) for prothrombin time and partial thromboplastin time were 2.7 (95% CI 0.9-4.5) and 4.3 (95% CI 1.74-6.9) seconds respectively. In the second trial (n=50) RR for death with early blood transfusion was 5.4 (95% CI 0.3-107.1). The WMD for partial thromboplastin time was 7.0 (95% CI 6.0-8.0) seconds. In the third trial (n=1309) RR for death with early fluid administration was 1.06 (95% CI 0.77-1.47). Larger versus smaller volume of fluid administration. Three trials reported mortality and one coagulation data. In the first trial (n=36) RR for death with a larger volume of fluid resuscitation was 0.80 (95% CI 0.28-22.29). Prothrombin time and partial thromboplastin time were 14.8 and 47.3 seconds in those who received a larger volume of fluid, as compared to 13.9 and 35.1 seconds in the comparison group. In the second trial (n=110) RR for death with a high systolic blood pressure resuscitation target (100mmHg) maintained with a larger volume of fluid, as compared to low systolic blood pressure resuscitation target (70mmHg) maintained with a smaller volume of fluid was 1.00 (95% CI 0.26-3.81). In the third trial (n=25) there were no deaths. REVIEWER'S CONCLUSIONS: We found no evidence from randomised controlled trials for or against early or larger volume of intravenous fluid administration in uncontrolled haemorrhage. There is continuing uncertainty about the best fluid administration strategy in bleeding trauma patients. Further randomised controlled trials are needed to establish the most effective fluid resuscitation strategy.

Advanced trauma life support training for ambulance crews.

BACKGROUND: There is an increasing global burden of disease from injuries. Models of trauma care initially developed in high-income countries are also being adopted in low and middle-income countries (LMIC). Amongst these ambulance crews with Advanced Life Support (ALS) training are being promoted in LMIC as a strategy for improving outcomes for victims of trauma. However there is controversy as to the effectiveness of this health service intervention, and the evidence has yet to be rigorously appraised. OBJECTIVES: To quantify the effectiveness of ambulance crews with ALS training versus crews with any other level of training in reducing mortality and morbidity in trauma patients. SEARCH STRATEGY: We searched the Cochrane Controlled Trial Register (CCTR), the specialised register of the Cochrane Injuries Group, MEDLINE, EMBASE, CINAHL, PubMed and the National Research Register. We checked references of background papers and contacted authors to identify additional published or unpublished data. SELECTION CRITERIA: Randomised controlled trials, quasi-randomised controlled trials and controlled before-and-after studies comparing effectiveness of ambulance crews with ALS training versus crews with any other levels of training in reducing mortality and morbidity in trauma patients. Studies which compared crews staffed by physicians versus others were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied eligibility criteria to trial reports for inclusion and extracted data. MAIN RESULTS: We found one randomised controlled trial, which included 16 trauma cases. However, outcome data were added to the main non-randomised cohort in the analysis, and data on these 16 cases are not yet available. REVIEWER'S CONCLUSIONS: In the absence of evidence of the effectiveness of advanced life support, strong argument could be made that it should not be promoted outside the context of a properly concealed and otherwise rigorously conducted randomised controlled trial.

How can a nurse intervention help people with newly diagnosed epilepsy? A qualitative study (of patients' views).

The aim was to describe the patients' views of the challenges posed by a new diagnosis of epilepsy and their assessment of a nurse intervention. Neurologists in South-East England referred patients into the study. Following a trial of a nurse intervention a subgroup of patients were purposefully identified for in-depth interviews. Transcriptions of tape-recorded interviews were analysed using qualitative methodology. We found that younger people with epilepsy seemed to experience more trouble with driving, jobs and managing their lives in the context of new epilepsy, while older people saw epilepsy as just another illness to cope with. Patients reported difficulty in remembering what their doctors told them which they attributed partly to lack of time available in the consultation. They valued the time, and the technique of probing with explanations used by the nurse. The nurse intervention was seen as useful in making sense of symptoms, tests, risk management, and driving regulations and in helping manage their medicine taking. We conclude that people with newly diagnosed epilepsy face different challenges, some of which are related to their age at diagnosis. Patients reported help from the nurse with understanding the diagnosis, tests, risk management and taking their medication. Follow-up is necessary to measure behavioural effects on self-management in the long run.

How can a nurse intervention help people with newly diagnosed epilepsy? A qualitative study of patients' views.

The aim was to describe the patients' views of the challenges posed by a new diagnosis of epilepsy and their assessment of a nurse intervention. Neurologists in South-East England referred patients into the study. Following a trial of a nurse intervention a subgroup of patients were purposefully identified for in depth interviews. Transcriptions of tape-recorded interviews were analysed using qualitative methodology. We found that younger people with epilepsy seemed to experience more trouble with driving, jobs and managing their lives in the context of new epilepsy, while older people saw epilepsy as just another illness to cope with. Patients reported difficulty in remembering what their doctors told them which they attributed partly to lack of time available in the consultation. They valued the time, and the technique of probing with explanations used by the nurse. The nurse intervention was seen as useful in making sense of symptoms, tests, risk management, and driving regulations and in helping manage their medicine taking. We conclude that people with newly diagnosed epilepsy face different challenges, some of which are related to their age at diagnosis. Patients reported help from the nurse with understanding the diagnosis, tests, risk management and taking their medication. Follow-up is necessary to measure behavioural effects on self-management in the long-run.

An epilepsy care package: the nurse specialist's role.

Deficiencies in existing primary care for people with epilepsy are well-recognized in the United Kingdom and include a lack of structure and an inability to meet the patients' needs for information and support to cope with their epilepsy. The introduction of clinics set up by nurse specialists within family practice in a few United Kingdom cities has met with a high degree of acceptability and satisfaction from patients. A package of care was developed to support epilepsy management in the community in the United Kingdom. It includes provision of advice and information, counseling, and interdisciplinary liaison. Nurse specialists with a sound training in epilepsy can adopt a proactive role and effectively deliver this package.

Identification of pY654-ß-catenin as a critical co-factor in hypoxia-inducible factor-1α signaling and tumor responses to hypoxia.

Hypoxia is linked to epithelial-mesenchymal transition (EMT) and tumor progression in numerous carcinomas. Responses to hypoxia are thought to operate via hypoxia-inducible factors (HIFs), but the importance of co-factors that regulate HIF signaling within tumors is not well understood. Here, we elucidate a signaling pathway that physically and functionally couples tyrosine phosphorylation of ß-catenin to HIF1α signaling and HIF1α-mediated tumor EMT. Primary human lung adenocarcinomas accumulate pY654-ß-catenin and HIF1α. All pY654-ß-catenin, and only the tyrosine phosphorylated form, was found complexed with HIF1α and active Src, both within the human tumors and in lung tumor cell lines exposed to hypoxia. Phosphorylation of Y654, generated by hypoxia mediated, reactive oxygen species (ROS)-dependent Src kinase activation, was required for ß-catenin to interact with HIF1α and Src, to promote HIF1α transcriptional activity, and for hypoxia-induced EMT. Mice bearing hypoxic pancreatic islet adenomas, generated by treatment with anti-vascular endothelial growth factor antibodies, accumulate HIF1α/pY654-ß-catenin complexes and develop an invasive phenotype. Concurrent administration of the ROS inhibitor N-acetylcysteine abrogated ß-catenin/HIF pathway activity and restored adenoma architecture. Collectively, the findings implicate accumulation of pY654-ß-catenin specifically complexed to HIF1α and Src kinase as critically involved in HIF1α signaling and tumor invasion. The findings also suggest that targeting ROS-dependent aspects of the pY654-ß-catenin/ HIF1α pathway may attenuate untoward biological effects of anti-angiogenic agents and tumor hypoxia.

Nuclear factor kappa B and matrix metalloproteinase induced receptor cleavage in the spontaneously hypertensive rat.

Recent evidence suggests that inflammation in the spontaneously hypertensive rat (SHR) is associated with an uncontrolled matrix metalloproteinase (MMP) activity. We hypothesize that the transcription factor nuclear factor kappa B (NFκB) is overexpressed in the SHR, enhancing its MMP activity and enzymatic cleavage of the ß2 adrenergic receptor (ß2AR), thereby diminishing catecholamine-mediated arteriolar vasodilation. NFκB expression level and translocation were compared between Wistar Kyoto rat and SHR kidney, heart, and brain. The animals were treated with NFκB inhibitor, pyrrolidine dithiocarbamate, for 10 weeks and correlations between NFκB and MMP activity were determined. Immunohistochemistry showed that NFκB expression is increased in untreated SHR kidney (≈ 14%) and brain hypothalamus (≈ 22%) compared to that in Wistar Kyoto rats (P < 0.05), but not in myocardium and cerebral cortex. After pyrrolidine dithiocarbamate treatment, the SHR systolic blood pressure was reduced to close to Wistar Kyoto rat levels. NFκB expression level in treated SHR was also decreased in kidney and hypothalamus compared to nontreated animals (P < 0.05). Furthermore, MMP-2 and MMP-9 activities in SHR plasma were significantly reduced (≈ 41%) by pyrrolidine dithiocarbamate treatment. Additionally, zymographic analyses and in situ zymography showed decreased MMP-2 activity in kidney homogenates and decreased MMP-1 and MMP-9 activities in brain. The level of the ß2AR extracellular, but not intracellular, domain density was found to be reduced in kidney, showing a receptor cleavage process that can be blocked by pyrrolidine dithiocarbamate treatment. These results suggest NFκB is an important transcription factor in the SHR and may be involved in the enhanced MMP activity and, consequently, receptor cleavage.

Synaptic development in the crayfish opener muscle.

Nerve terminal regions in walking leg opener muscles of several crayfish of different ages (0 to 245 days after hatching) were examined by means of electron microscopy. This muscle is innervated by two axons (excitatory and inhibitory) and at maturity contains three classes of synapse: excitatory and inhibitory neuromuscular synapses, and inhibitory axo-axonal synapses. The muscle itself is initially a syncytium, which gradually becomes subdivided into distinct "muscle fibers" as the animal matures. Innervation was not found in the opener muscle just before or just after hatching, but was present in restricted locations on the inner side of the muscle within a few days of hatching. As the muscle enlarged and became subdivided, innervation appeared in various other locations. Synaptic contacts were located in young stages soon after hatching, and in later stages. Morphological differences characteristic of excitatory nerve terminals could be found even at the earliest stages of innervation. Both excitatory and inhibitory synapses, but particularly the former, showed evidence of progressive enlargement to a final size within the first two months, and no evidence for further enlargement of existing synapses thereafter. Synaptic maturation also involved the appearance of presynaptic "dense bodies" though to be regions at which transmitter substance is preferentially released. Nerve terminals at different levels of maturation were observed in opener muscles of young crayfish. Clear evidence for differential maturation of the three types of synapse present in this muscle was obtained. The inhibitory neuromuscular synapses attained their final average size and developed their dense bodies sooner than the excitatory neuromuscular synapses. The inhibitory axo-axonal synapses were the last to appear and to mature.