Physiological tremor is suppressed and force steadiness is enhanced with increased availability of serotonin regardless of muscle fatigue.

Although there is evidence that 5-HT acts as an excitatory neuromodulator to enhance maximal force generation, it is largely unknown how 5-HT activity influences the ability to sustain a constant force during steady-state contractions. A total of 22 healthy individuals participated in the study, where elbow flexion force was assessed during brief isometric contractions at 10% maximal voluntary contraction (MVC), 60% MVC, MVC, and during a sustained MVC. The selective serotonin reuptake inhibitor, paroxetine, suppressed physiological tremor and increased force steadiness when performing the isometric contractions. In particular, a main effect of drug was detected for peak power of force within the 8-12 Hz range (P = 0.004) and the coefficient of variation (CV) of force (P < 0.001). A second experiment was performed where intermittent isometric elbow flexions (20% MVC sustained for 2 min) were repeatedly performed so that serotonergic effects on physiological tremor and force steadiness could be assessed during the development of fatigue. Main effects of drug were once again detected for peak power of force in the 8-12 Hz range (P = 0.002) and CV of force (P = 0.003), where paroxetine suppressed physiological tremor and increased force steadiness when the elbow flexors were fatigued. The findings of this study suggest that enhanced availability of 5-HT in humans has a profound influence of maintaining constant force during steady-state contractions. The action of 5-HT appears to suppress fluctuations in force regardless of the fatigue state of the muscle.NEW & NOTEWORTHY Converging lines of research indicate that enhanced serotonin availability increases maximal force generation. However, it is largely unknown how serotonin influences the ability to sustain a constant force. We performed two experiments to assess physiological tremor and force steadiness in unfatigued and fatigued muscle when serotonin availability was enhanced in the central nervous system. Enhanced availability of serotonin reduced physiological tremor amplitude and improved steadiness regardless of muscle fatigue.

Postoperative complications of pulmonary resection.

Thoracic surgery has seen a resurgence in recent years with increasing numbers of cases taken on since the mid-2000s. There has been a paradigm shift in how we manage lung cancer with more emphasis on surgical resection, and this has been aided by minimally invasive video-assisted thoracic surgery (VATS) techniques. As a result, the prevalence of postoperative findings and complications is also increasing, and it is increasingly important for the general radiologist to recognise and diagnose these conditions as thoracic surgical patients may present acutely to non-thoracic surgical institutions. This review will cover both the early and late complications following a variety of lung resection surgeries.

Clinicopathologic characteristics associated with long-term survival in advanced epithelial ovarian cancer: an NRG Oncology/Gynecologic Oncology Group ancillary data study.

OBJECTIVE: To identify clinicopathologic factors associated with 10-year overall survival in epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC), and to develop a predictive model identifying long-term survivors. METHODS: Demographic, surgical, and clinicopathologic data were abstracted from GOG 182 records. The association between clinical variables and long-term survival (LTS) (>10years) was assessed using multivariable regression analysis. Bootstrap methods were used to develop predictive models from known prognostic clinical factors and predictive accuracy was quantified using optimism-adjusted area under the receiver operating characteristic curve (AUC). RESULTS: The analysis dataset included 3010 evaluable patients, of whom 195 survived greater than ten years. These patients were more likely to have better performance status, endometrioid histology, stage III (rather than stage IV) disease, absence of ascites, less extensive preoperative disease distribution, microscopic disease residual following cyoreduction (R0), and decreased complexity of surgery (p<0.01). Multivariable regression analysis revealed that lower CA-125 levels, absence of ascites, stage, and R0 were significant independent predictors of LTS. A predictive model created using these variables had an AUC=0.729, which outperformed any of the individual predictors. CONCLUSIONS: The absence of ascites, a low CA-125, stage, and R0 at the time of cytoreduction are factors associated with LTS when controlling for other confounders. An extensively annotated clinicopathologic prediction model for LTS fell short of clinical utility suggesting that prognostic molecular profiles are needed to better predict which patients are likely to be long-term survivors.

Radiation responses of stem cells: targeted and non-targeted effects.

Stem cells are fundamental to the development of any tissue or organism via their ability to self-renew, which is aided by their unlimited proliferative capacity and their ability to produce fully differentiated offspring, often from multiple lineages. Stems cells are long lived and have the potential to accumulate mutations, including in response to radiation exposure. It is thought that stem cells have the potential to be induced into a cancer stem cell phenotype and that these may play an important role in resistance to radiotherapy. For radiation-induced carcinogenesis, the role of targeted and non-targeted effects is unclear with tissue or origin being important. Studies of genomic instability and bystander responses have shown consistent effects in haematopoietic models. Several models of radiation have predicted that stem cells play an important role in tumour initiation and that bystander responses could play a role in proliferation and self-renewal.

Detection and characterization of extended-spectrum beta-lactamase-producing Enterobacteriaceae in high-risk patients in an Irish tertiary care hospital.

BACKGROUND: Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) are Gram-negative, multi-drug-resistant organisms that are of major clinical significance among immunocompromised patients in high-risk areas in hospital settings. In Ireland, the number of ESBL-E bloodstream infections is increasing. AIMS: To conduct a prevalence study of ESBL-E among immunocompromised patients in high-risk areas [intensive care unit (ICU), liver transplantation and haematology/oncology wards], characterize any ESBL genes detected by polymerase chain reaction (PCR), and perform epidemiological typing using pulsed-field gel electrophoresis (PFGE). METHODS: In total, 317 non-duplicate rectal swabs from patients in high-risk wards were screened anonymously for ESBL-E carriage. Positive isolates were characterized using PCR to detect blaCTX-M, blaTEM, blaOXA-1 and blaSHV ESBL-E genes. Clonal relationships of these isolates were investigated using PFGE. FINDINGS: Fifty (15.8%) high-risk patients were found to harbour ESBL-E. Prevalence rates of 21.9% (N = 28), 14.3% (N = 15) and 8.3% (N = 7) of ESBL-E were isolated from patients on the liver transplantation, ICU and haematology/oncology wards, respectively. Seventy percent of ESBL-E isolates carried more than one resistance gene. Of the 25 ESBL-producing Escherichia coli isolates typed by PFGE, two pairs of two isolates demonstrated >80% homology, and four of the five ESBL-producing Enterobacter cloacae isolates typed by PFGE demonstrated >80% homology, suggesting clonal relatedness and potential cross-transmission from individual patients. CONCLUSION: A significant proportion of the patients screened were found to be colonized with ESBL-E. Typing revealed three incidents of potential cross-infection. Therefore, timely detection of ESBL-E among patients in high-risk wards is critical for treatment and infection control.

Phyllodes tumours of the breast: radiological presentation, management and follow-up.

OBJECTIVE: Phyllodes tumours (PTs) are rare neoplasms accounting for <1% of breast lesions. With increased breast awareness and screening programmes, smaller PTs are being detected. The purpose of this study was to determine the clinical, radiological and pathological presentation of PTs and to evaluate the role of imaging follow-up, for which there are no specific guidelines. METHODS: A retrospective study of all patients diagnosed with PT in a symptomatic unit between January 2006 and March 2013 was carried out. Patients were identified using breast care and electronic patient record databases. RESULTS: 53 patients with 54 lesions were diagnosed as having a PT. The median age was 27.5, 35.0 and 38.5 years for benign, borderline and malignant PT, respectively. Borderline and malignant PTs were larger than benign PTs, with mean sizes of 33 and 42 mm compared with 29 mm. 38% of PTs were labelled by the reporting radiologist as fibroadenomas, including two borderline PTs and one malignant PT. In 24% of cases, the radiologist raised the possibility of PT in the report. 17 patients (40%) developed a new fibroepithelial breast lesion during follow-up of which 4 were recurrent PTs. CONCLUSION: Despite adequate surgical management, the development of further fibroepithelial lesions in the ipsilateral breast is common. 3-year clinical surveillance, with the addition of 6-monthly ultrasound is advised for females with initial borderline or malignant PT histology. ADVANCES IN KNOWLEDGE: We propose a follow-up protocol with ultrasound based on the grade of the PT diagnosed for 3 years to detect recurrence.

Using process data to understand outcomes in sexual health promotion: an example from a review of school-based programmes to prevent sexually transmitted infections.

This article discusses how process indicators can complement outcomes as part of a comprehensive explanatory evaluation framework, using the example of skills-based behavioural interventions to prevent sexually transmitted infections and promote sexual health among young people in schools. A systematic review was conducted, yielding 12 eligible outcome evaluations, 9 of which included a process evaluation. There were few statistically significant effects in terms of changes in sexual behaviour outcomes, but statistically significant effects were more common for knowledge and self-efficacy. Synthesis of the findings of the process evaluations identified a range of factors that might explain outcomes, and these were organized into two overarching categories: the implementation of interventions, and student engagement and intervention acceptability. Factors which supported implementation and engagement and acceptability included good quality teacher training, involvement and motivation of key school stakeholders and relevance and appeal to young people. Factors which had a negative impact included teachers' failure to comprehend the theoretical basis for behaviour change, school logistical problems and omission of topics that young people considered important. It is recommended that process indicators such as these be assessed in future evaluations of school-based sexual health behavioural interventions, as part of a logic model.

In situ production of human ß defensin-3 in lager yeasts provides bactericidal activity against beer-spoiling bacteria under fermentation conditions.

AIMS: To examine the use of a natural antimicrobial peptide, human ß-defensin-3 (HBD3), as a means of preventing spoilage from bacterial contamination in brewery fermentations and in bottled beer. METHODS AND RESULTS: A chemically synthesised HBD3 peptide was tested for bactericidal activity against common Gram-positive and Gram-negative beer-spoiling bacteria, including species of Lactobacillus, Pediococcus and Pectinatus. The peptide was effective at the µmol l(-1) range in vitro, reducing bacterial counts by 95%. A gene construct encoding a secretable form of HBD3 was integrated into the genome of the lager yeast Saccharomyces pastorianus strain CMBS-33. The integrated gene was expressed under fermentation conditions and was secreted from the cell into the medium, but a significant amount remains associated with yeast cell surface. We demonstrate that under pilot-scale fermentation conditions, secreted HBD3 possesses bactericidal activity against beer-spoiling bacteria. Furthermore, when added to bottled beer, a synthetic form of HBD3 reduces the growth of beer-spoiling bacteria. CONCLUSIONS: Defensins provide prophylactic protection against beer-spoiling bacteria under brewing conditions and also in bottled beer. SIGNIFICANCE AND IMPACT OF THE STUDY: The results have direct application to the brewing industry where beer spoilage due to bacterial contamination continues to be a major problem in breweries around the world.

Imaging features of extrapulmonary small cell carcinoma.

Small cell carcinoma accounts for approximately 20% of lung cancers; however, it rarely occurs at other sites. Extrapulmonary small cell carcinoma (EPSCC) is notoriously aggressive with a strong propensity for both regional and distant spread. The majority of the literature on these uncommon tumours is from a clinicopathological viewpoint with a relative paucity of detail regarding the radiological findings. This review will focus on the imaging features of EPSCC in its predominant sites of origin: the gastrointestinal tract, genitourinary tract, head, neck, and breast. We will also discuss the role of positron-emission tomography (PET)/computed tomography (CT) in the staging of EPSCC.

Antiproton induced DNA damage: proton like in flight, carbon-ion like near rest.

Biological validation of new radiotherapy modalities is essential to understand their therapeutic potential. Antiprotons have been proposed for cancer therapy due to enhanced dose deposition provided by antiproton-nucleon annihilation. We assessed cellular DNA damage and relative biological effectiveness (RBE) of a clinically relevant antiproton beam. Despite a modest LET (~19 keV/µm), antiproton spread out Bragg peak (SOBP) irradiation caused significant residual γ-H2AX foci compared to X-ray, proton and antiproton plateau irradiation. RBE of ~1.48 in the SOBP and ~1 in the plateau were measured and used for a qualitative effective dose curve comparison with proton and carbon-ions. Foci in the antiproton SOBP were larger and more structured compared to X-rays, protons and carbon-ions. This is likely due to overlapping particle tracks near the annihilation vertex, creating spatially correlated DNA lesions. No biological effects were observed at 28-42 mm away from the primary beam suggesting minimal risk from long-range secondary particles.

Recurrence patterns and prognosis of endometrial stromal sarcoma and the potential of tyrosine kinase-inhibiting therapy.

OBJECTIVE: Endometrial stromal sarcoma (ESS) is a rare uterine malignancy. The current treatment approaches yield unsatisfactory results, and potential therapeutic targets need exploration. METHODS: We reviewed the electronic medical records of 74 patients with low-grade ESS who had been evaluated at the University of Texas MD Anderson Cancer Center between 1995 and 2006. Using immunohistochemistry, we tested the expression of targets in paraffin-embedded tissue samples taken from 13 of the patients. RESULTS: Forty-seven patients (64%) had a recurrence, and 16 (22%) had died of their disease at last follow-up. The 10-year progression-free survival (PFS) rate was 43% (median PFS duration, 108months), and the overall survival (OS) rate was 85% (median OS, 288months). Patients who received hormonal therapy had an overall response rate of 27%; another 53% had stable disease, with a median time to progression of 24months. No complete response or partial response was observed among patients who received radiotherapy or chemotherapy. In the paraffin-embedded specimens we tested, c-abl was expressed universally. Expression of PDGF-α, PDGF-ß, VEGF, and c-Kit was detected in 33%, 36%, 54%, and 8%, of specimens, respectively. EGFR and HER-2 were not detectable in any specimens. CONCLUSIONS: Our study suggests that ESS is a hormone-dependent malignancy, with hormonal therapy having activity in recurrent disease. Targeted therapy, specifically targeting c-abl may be a potential treatment for this disease.

Design development of an electrocoagulation reactor for molasses process wastewater treatment.

The impact of electrode corrosion behaviour, reactor geometry and current density on electrocoagulation efficiency were investigated for the treatment of molasses process wastewater. Two laboratory-scale vertical plate electrocoagulation reactors were used for this investigation: the first being a low aspect ratio bath reactor with a low specific electrode area, while the other was a high aspect ratio column reactor with a high specific electrode area. Anomalous anodic dissolution and cathodic corrosion of the aluminium electrodes both contributed significantly to overall metal consumption. Increasing specific electrode area and aspect ratio each led to improved treatment efficiency, whereas the impact of current density was more complicated involving the combined influences of several competing effects. The space-time yields of coagulant and bubbles (both functions of specific electrode area, current density and current efficiency) were found to influence mixing within the reactor and thus treatment efficiency.

Reverse engineering the kidney: modelling calcium oxalate monohydrate crystallization in the nephron.

Crystallization of calcium oxalate monohydrate in a section of a single kidney nephron (distal convoluted tubule) is simulated using a model adapted from industrial crystallization. The nephron fluid dynamics is represented as a crystallizer/separator series with changing volume to allow for water removal along the tubule. The model integrates crystallization kinetics and crystal size distribution and allows the prediction of the calcium oxalate concentration profile and the nucleation and growth rates. The critical supersaturation ratio for the nucleation of calcium oxalate crystals has been estimated as 2 and the mean crystal size as 1 mum. The crystal growth order, determined as 2.2, indicates a surface integration mechanism of crystal growth and crystal growth dispersion. The model allows the exploration of the effect of varying the input calcium oxalate concentration and the rate of water extraction, simulating real life stressors for stone formation such as dietary loading and dehydration.

The effectiveness and cost-effectiveness of behavioural interventions for the prevention of sexually transmitted infections in young people aged 13-19: a systematic review and economic evaluation.

OBJECTIVES: To assess the effectiveness and cost-effectiveness of schools-based skills-building behavioural interventions to encourage young people to adopt and maintain safer sexual behaviour and to prevent them from acquiring sexually transmitted infections (STIs). DATA SOURCES: Electronic bibliographic databases (e.g. MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, CINAHL, PsycINFO, CCRCT, NHS EED and DARE) were searched for the period 1985 to March 2008. Bibliographies of systematic reviews and related papers were screened and experts contacted to identify additional published and unpublished references. REVIEW METHODS: A systematic review of effectiveness and economic evaluation of cost-effectiveness were carried out. A descriptive map of studies that met inclusion criteria was produced, and keywords were developed and systematically applied to these studies to identify a policy-relevant subset of studies for the systematic review. Outcome data for variables including sexual behaviour were extracted. An economic model was developed to compare the costs and consequences of the behavioural interventions. A Bernoulli statistical model was constructed to describe the probability of STI infection. RESULTS: There were few significant differences between the interventions and comparators in terms of changes in sexual behaviour outcomes, although there were some significant differences for knowledge and some measures of self-efficacy. The studies included in this review conducted relatively short follow-up assessments at a time when many young people were becoming sexually active. It is therefore possible that favourable behaviour change may have occurred, and become more cost-effective, with time, as sexual activity becomes more routine in young people's lives. The quality of the intervention provider influenced whether or not young people found the interventions to be acceptable and engaging; enthusiasm and considerable expertise were important for effective class management and delivery of skills-building activities, and a supportive school culture was also helpful. Recognition of young people's individual needs in relation to sexual health was another important factor. No conclusions could be drawn on the impact of the interventions on sexual health inequalities due to a lack of relevant data on socioeconomic status, gender and ethnicity. The results of the economic evaluation were considered to be illustrative, mainly due to the uncertainty of the effect of intervention on behavioural outcomes. The results were most sensitive to changes in parameter values for the intervention effect, the transmission probability of STIs and the number of sexual partners. The costs of teacher-led and peer-led behavioural interventions, based on the resources estimated from the relevant randomised controlled trials in our systematic review, were 4.30 pounds and 15 pounds per pupil, respectively. Teacher-led interventions were more cost-effective than peer-led interventions due to the less frequent need for training. The incremental cost-effectiveness of the teacher-led and peer-led interventions was 20,223 pounds and 80,782 pounds per quality-adjusted life-year gained, respectively. An analysis of individual parameters revealed that future research funding should focus on assessing the intervention effect for condom use from a school-based intervention. CONCLUSIONS: School-based behavioural interventions for the prevention of STIs in young people can bring about improvements in knowledge and increased self-efficacy, but the interventions did not significantly influence sexual risk-taking behaviour or infection rates. Future investigation should include long-term follow-up to assess the extent to which safer sexual behaviour is adopted and maintained into adulthood, and prospective cohort studies are needed to look at the parameters that describe the transmission of STIs between partners. Funding should focus on the effectiveness of the interventions on influencing behaviour.

What is the benefit of bevacizumab combined with chemotherapy in patients with recurrent ovarian, fallopian tube or primary peritoneal malignancies?

The aim of this retrospective analysis was to investigate the efficacy and adverse effects of the monoclonal antivascular endothelial growth factor antibody bevacizumab (Avastin(R)) combined with chemotherapeutic agents in non-protocol patients with recurrent ovarian, fallopian tube, or primary peritoneal malignancies. Using our databases, we identified patients treated with bevacizumab combination therapy since June 2005. Responses were evaluated with Response evaluation Criteria in Solid tumors and serum CA125 Rustin criteria. Toxicity was assessed according to the Common toxicity Criteria (CTC) v.3.0. Data from 64 patients were included. The median patient age was 58 years, and they had undergone a median of 4.5 (range, 1-10) prior cytotoxic chemotherapy regimens. The median length of follow-up was 8 months (range, 2-29). The most commonly used combinations were bevacizumab plus taxanes (26.6%) and plus cyclophosphamide (26.6%). A median of 4 cycles of therapy with a median bevacizumab dose of 3,600 mg (range, 500-18,240) were administered. An overall response rate of 21.3% was observed in 13 patients with partial response, and another 42.6% of patients had stable disease. Among the patients with elevated pretreatment serum CA125 concentration, an overall response rate of 46.3% (25/54) was observed according to modification of the Rustin criteria. Fifteen (23.4%) patients had grades 3 or 4 adverse events. Gastrointestinal perforations occurred in 2 (3.1%) patients. Seventeen (26.6%) patients had improved performance status scores. Bevacizumab combined with chemotherapy showed promising clinical benefits, with significant response of serum CA125 concentration and moderate adverse effects.

Phase 3 randomised study of canfosfamide (Telcyta, TLK286) versus pegylated liposomal doxorubicin or topotecan as third-line therapy in patients with platinum-refractory or -resistant ovarian cancer.

RATIONALE: Canfosfamide HCl (CAN) is a glutathione analogue prodrug that is activated by glutathione S-transferase P1-1 and induces apoptosis. CAN is synergistic in vitro with carboplatin, paclitaxel and anthracyclines. METHODS: Patients with platinum-refractory or -resistant ovarian cancer (OC) who had progressed on second-line therapy with pegylated liposomal doxorubicin (PLD) or topotecan (TOPO), were randomised between CAN 1000 mg/m(2) IV q 3 weeks or to either PLD 50mg/m(2) IV q 4 weeks or TOPO 1.5mg/m(2) IV d1-5 q 3 weeks. RESULTS: About 461 patients were randomised after stratification for ECOG performance status, prior therapy, and bulky (>5 cm) disease. Groups were well balanced. In the control arm 58% and 42% were treated with PLD and TOPO, respectively. CAN was well tolerated with the most common grade 3-4 toxicities of 5% anaemia, 4% neutropaenia (no febrile neutropaenia), 4% thrombocytopaenia, and 7% vomiting. Progression-free survival (PFS) and overall survival (OS) were significantly higher in the control arm (p<0.001 and p<0.01, respectively). In a subgroup analysis PFS and OS tended to be higher with PLD than with TOPO. CONCLUSION: CAN was well tolerated. This is the first randomised study showing an increased OS with third-line therapy. This might have important consequences for other recurrent OC trials.

Ovarian endometriosis associated with carcinoma and sarcoma: case report.

Endometriosis is a common clinical disorder that shares certain characteristics, metastasis and recurrence, with malignant neoplasms. Most malignant ovarian tumors arising from endometriosis are clear cell carcinoma or endometrioid adenocarcinoma. Few reports exist of sarcoma associated with endometriosis, and even fewer exist of multiple types of malignancies occurring simultaneously. Here, we report the case of a 32-year-old woman who presented with infertility and a pelvic mass. She underwent exploratory laparotomy and bilateral salpingo-oophorectomy. She was then referred to our institution for treatment recommendation. The pathologic findings revealed bilateral endometrioid adenofibroma of low malignant potential, which was associated with endometrioid intraepithelial carcinoma in the left ovary and high-grade sarcoma in the right ovary. Both tumors seemed to have arisen from endometriosis. She was treated with 75 mg/m2 of doxorubicin and 10 g/m2 of ifosfamide every three weeks for eight courses. She was later found to have bilateral brain metastases, which were resected and treated by whole-brain irradiation. She was again treated with doxorubicin and ifosfamide. The optimal treatment for endometriosis-associated ovarian cancer depends on the type of malignancy; simultaneously occurring multiple tumor types should be treated individually.

Chemotherapy for gynecological malignancies in organ transplantation patients: report of two cases.

Long-term risk of gynecological malignancies in organ transplantation patients has increased compared with that of the general population owing to the use of immunosuppressive agents. Treatment, especially chemotherapy, in these patients should take into consideration their renal function and the effects of immunosuppressive agents. We here present two case reports of patients with chemotherapy-treated gynecological malignancies who had previously received organ transplantation. The first case, a rare occurrence of simultaneous carcinomas of the uterine corpus and ovary, is the first such report in the English literature describing chemotherapy for concurrent serous papillary ovarian carcinoma and endometrioid endometrial carcinoma in a renal transplant patient. The second case report, describing chemotherapy for cervical cancer following two organ transplantation, also rare, is the first such report in the English literature and the first report of cervical cancer after heart-kidney transplantation.

Erosive osteoarthritis during treatment with bevacizumab and paclitaxel in a patient with recurrent papillary serous carcinoma of the ovary.

Bevacizumab (BVC) is currently used in recurrent ovarian cancer and as part of the initial treatment for ovarian cancer. The most serious toxicities associated with BVC include gastrointestinal perforations, delayed wound healing, and hemorrhage. Arthritis had never been addressed in patients who received BVC treatment. This is the first case report of arthritis emergence linked to BVC administration. A 59-year-old female with recurrent ovarian cancer received multiple hormonal and cytotoxic regimens for 5 years and then developed erosive osteoarthritis of the hands secondary to BVC and paclitaxel. This effect was confirmed by a significant improvement in her symptoms and signs, after treatment was discontinued.