Resuscitating preterm infants with 100% oxygen is associated with higher oxidative stress than room air.

AIM: The starting fraction of inspired oxygen for preterm resuscitation is a matter of debate, and the use of room air in full-term asphyxiated infants reduces oxidative stress. This study compared oxidative stress in preterm infants randomised for resuscitation with either 100% oxygen or room air titrated to internationally recommended levels of preductal oxygen saturations. METHODS: Blood was collected at birth, two and 12 hours of age from 119 infants <32 weeks of gestation randomised to resuscitation with either 100% oxygen (n = 60) or room air (n = 59). Oxidative stress markers, including advanced oxidative protein products (AOPP) and isoprostanes (IsoP), were measured with high-performance liquid chromatography and mass spectrometry. RESULTS: Significantly higher levels of AOPP were found at 12 hours in the 100% oxygen group (p < 0.05). Increases between two- and 12-hour AOPP (p = 0.004) and IsoP (p = 0.032) concentrations were significantly higher in the 100% oxygen group. CONCLUSION: Initial resuscitation with room air versus 100% oxygen was associated with lower protein oxidation at 12 hour and a lower magnitude of increase in AOPP and IsoP levels between two and 12 hours of life. Correlations with clinical outcomes will be vital to optimise the use of oxygen in preterm resuscitation.

Variable post-zygotic isolation in Drosophila melanogaster/D. simulans hybrids.

The study of hybrid inviability reveals cryptic divergence between the genetic interactions that maintain stable phenotypes in the pure species. We characterized the effects of natural variation on the penetrance of hybrid inviability phenotypes in crosses between Drosophila melanogaster and two species of the D. simulans subcomplex, D. simulans and D. sechellia. Using a panel of wild-caught lines, we studied the levels of genetic variance present in D. simulans and D. sechellia affecting prezygotic and post-zygotic isolation in hybridizations with D. melanogaster females. We observed extensive variability in the viability of hybrid individuals, dependent on the genotype of the parents, suggesting that intraspecific natural variation manifests directly in hybrid phenotypes. Furthermore, we found that genetic background significantly affects the penetrance of a well-studied determinant of hybrid inviability: the interaction between Hmrmel-Lhrsim. Our results suggest that hybrid inviability--and reproductive isolation generally--can be modified by polymorphisms at multiple loci segregating within the parental species. Just as the penetrance of most mutant phenotypes can be modified by the genetic background within the pure species, the penetrance of hybrid inviability phenotypes is highly influenced by the parental genotypes.

A meta-analysis of endovascular versus surgical reconstruction of femoropopliteal arterial disease.

BACKGROUND: Controversy exists as to the relative merits of surgical and endovascular treatment of femoropoliteal arterial disease. METHODS: A systematic review of the literature was undertaken to identify studies comparing open surgical and percutaneous transluminal methods for the treatment of femoropopliteal arterial disease. Outcome data were pooled and combined overall effect sizes were calculated using fixed or random effects models. RESULTS: Four randomized controlled trials and six observational studies reporting on a total of 2817 patients (1387 open, 1430 endovascular) were included. Endovascular treatment was accompanied by lower 30-day morbidity (odds ratio [OR], 2.93; 95% confidence interval [CI], 1.34-6.41) and higher technical failure (OR, 0.10; 95% CI, 0.05-0.22) than bypass surgery, whereas no differences in 30-day mortality between the two groups were identified (OR, 0.92; 95% CI, 0.55-1.51). Higher primary patency in the surgical treatment arm was found at 1 (OR, 2.42; 95% CI, 1.37-4.28), 2 (OR, 2.03; 95% CI, 1.20-3.45), and 3 (OR, 1.48; 95% CI, 1.12-1.97) years of intervention. Progression to amputation was found to occur more commonly in the endovascular group at the end of the second (OR, 0.60; 95% CI, 0.42-0.86) and third (OR, 0.55; 95% CI, 0.39-0.77) year of intervention. Higher amputation-free and overall survival rates were found in the bypass group at 4 years (OR, 1.31; 95% CI, 1.07-1.61 and OR, 1.29; 95% CI, 1.04-1.61, respectively). CONCLUSIONS: High-level evidence demonstrating the superiority of one method over the other is lacking. An endovascular-first approach may be advisable in patients with significant comorbidity, whereas for fit patients with a longer-term perspective a bypass procedure may be offered as a first-line interventional treatment.

Clinically relevant fatigue in recurrence-free prostate cancer survivors.

BACKGROUND: Little is known about the prevalence and associations of clinically relevant fatigue (CRF) in recurrence-free prostate cancer survivors. PATIENTS AND METHODS: Four hundred and sixteen recurrence-free prostate cancer survivors who were >1 year post-radiotherapy or radical prostatectomy were surveyed. The prevalence of CRF (defined as Brief Fatigue Inventory >3) was determined and compared with a noncancer control group. Other measures included the Hospital Anxiety and Depression Scale, International Prostate Symptom Score, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Relationships between these factors and CRF were explored in univariate and multivariate analyses. RESULTS: Analyzable data were obtained from 91% (377/416) of patients. The prevalence of CRF was 29% (108/377) versus 16% (10/63) in the controls (P=0.031). CRF was more common in post-radiotherapy than in post-prostatectomy 33% (79/240) versus 22% (29/133), P=0.024. However, when other factors (current depression, anxiety, urinary symptoms, medical comorbidities, pain and insomnia) were controlled for, previous treatment did not predict CRF. Current depression [Hospital Anxiety and Depression Scale≥8 was by far the strongest association [odds ratio 9.9, 95% confidence interval 4.2-23.5)]. CONCLUSIONS: Almost one-third of recurrence-free prostate cancer survivors report CRF. Depression, anxiety, urinary symptoms, pain and insomnia measured at outcome are more strongly associated than type of cancer treatment previously received.

Clinically relevant fatigue in men with hormone-sensitive prostate cancer on long-term androgen deprivation therapy.

BACKGROUND: The purpose of the study was to determine the prevalence and associations of clinically relevant fatigue (CRF) in men with biochemically controlled prostate cancer on long-term androgen deprivation therapy (ADT). PATIENTS AND METHODS: One hundred and ninety-eight men were surveyed and the prevalence of CRF (Brief Fatigue Inventory score >3) determined. Associations with other measures (Hospital Anxiety and Depression Scale; International Prostate Symptom Score; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; Brief Pain Inventory worst pain; clinical and demographic information) were explored in univariate and multivariate analyses. RESULTS: Eight-one per cent (160 of 198) of questionnaires were analysable. CRF prevalence was 43% (68 of 160). CRF associations included moderate/severe urinary symptoms, anxiety and medical co-morbidities; the strongest associations were depression [odds ratio (OR) 9.8, 95% confidence interval (CI) 4.3-22.8] and pain (OR 9.2, 95% CI 4.0-21.5). After controlling for other factors, the independent associations were depression (OR 4.7, 95% CI 1.6-14.0) and pain (OR 3.1, 95% CI 1.0-8.9). There was no association with age, disease burden or treatment duration. CONCLUSIONS: Two-fifths of men with biochemically controlled prostate cancer on long-term ADT report CRF that interferes with function. Management aimed at improving CRF should address depression and pain.

Percutaneous transluminal angioplasty and stenting in patients with proximal vertebral artery stenosis.

BACKGROUND: Atherosclerotic occlusive disease of the proximal vertebral artery is an important cause of cerebrovascular ischemic events with a significant associated morbidity and mortality. Endovascular treatment has emerged as a promising tool of the therapeutic armamentarium, along with medical therapy and surgical reconstruction. Our objective was to systemically review the pertinent evidence on the endovascular management of proximal vertebral artery disease and perform an analysis of the published outcomes. METHODS: A systematic review of the literature identified all studies reporting percutaneous transluminal angioplasty or stenting, or both, for proximal vertebral artery stenosis. Web-based search engines were searched using the Medical Subject Headings terms "vertebral artery," "angioplasty," and "stents" in all possible combinations. Studies comprising a series of at least five patients were considered for analysis. Periprocedural transient ischemic attack and stroke and death from any cause ≤30 days of treatment were defined as the primary outcome end points. RESULTS: One randomized controlled trial comparing angioplasty and stenting of the proximal vertebral artery and medical therapy was identified. No comparative studies of endovascular treatment and open surgical repair were found. Forty-two selected studies reported endovascular treatment (angioplasty or stenting, or both) of 1117 vertebral arteries in 1099 patients. The weighted mean technical success rate was 97% (range, 36%-100%). Periprocedural transient ischemic attack occurred in 17 patients (1.5%). The combined stroke and death rate was 1.1%. Recurrent symptoms of vertebrobasilar insufficiency developed in 65 of 967 patients (8%) within a reported follow-up of 6 to 54 months. Restenosis developed in 183 of 789 patients (23%) who underwent follow-up imaging (range, 0%-58%). Reintervention for recurrent disease during follow-up occurred in 86 patients (9%; range, 0%-35%). CONCLUSIONS: There is limited comparative evidence on the efficacy of medical, surgical, and endovascular treatment of proximal vertebral artery disease. Percutaneous transluminal angioplasty and stenting has low periprocedural neurologic adverse events and mortality.

Delayed carotid surgery: what are the causes in the north west of England?

INTRODUCTION: Carotid endarterectomy (CEA) should be performed within two weeks of symptoms for patients with carotid stenosis >50%. Whether these standards are being achieved and causes of delay between symptoms and CEA were investigated. DESIGN: An analysis of prospectively collected multi-centre data. MATERIALS: Consecutive data for patients undergoing CEA between January-2006 and September-2010 were collected. Asymptomatic patients and those with no details on the timing of cerebral symptoms were excluded. METHODS: 'Delay' from symptom to CEA was defined as more than two weeks and 'prolonged-delay' more than eight weeks. Univariable and multivariable analyses were used to identify factors associated with these delays. RESULTS: Of 2147 patients with symptoms of cerebral ischaemia, 1522(70.9%) experienced 'delay' and 920(42.9%) experienced 'prolonged delay'. Patients with ischaemic heart disease were more likely to experience 'delay' (OR = 1.56; 95% CI 1.11-2.19, p = 0.011), whereas patients with stroke (OR = 0.77; 95%CI 0.63-0.94, p = 0.011) and those treated at hospitals with a stroke-prevention clinic (OR = 0.57; 95%CI 0.46-0.71, p < 0.001) were less likely to experience 'delay'. Patients treated after the publication of National Institute for Health and Clinical Excellence (NICE) guidelines were less likely to experience 'prolonged delay' (OR = 0.77; 95%CI 0.65-0.91, p = 0.003) but not 'delay'. CONCLUSION: Few patients achieved CEA within two weeks of symptoms. Introducing stroke-prevention clinics with one-stop carotid imaging appears important.

Multilayer stent in the treatment of popliteal artery aneurysms.

Endovascular repair of popliteal artery aneurysms is an emerging treatment in high risk surgical patients. The location in a functionally demanding anatomical area creates limitations in terms of endograft patency. Technological advancements have been conscripted in an effort to circumvent such constraints. The multilayer stent technology effects through haemodynamic modulation. We used the multilayer stent to treat 6 asymptomatic popliteal artery aneurysms in 3 patients. All procedures were successfully accomplished without any complications. Over a mean follow up period of 9 months, thrombosis occurred in two limbs, and blood flow was restored with thrombolysis, achieving a primary and secondary patency rate at 6 months of 67 % and 100 %, respectively. Partial or complete thrombosis of the aneurysm sac was achieved in all aneurysms. Even though the use of the multilayer stent in popliteal artery aneurysms was safe in the short term, our experience showed that close surveillance is required.

Mortality of one-week-old chickens during naturally occurring Marek's disease virus infection.

Marek's disease (MD) is a disease of chickens that occurs worldwide and has serious economic consequences. MD can present as one of several forms, with the most commonly occurring forms being the lymphoproliferative diseases. Under experimental conditions, an early mortality syndrome has been recognized following infection by some but not all strains of MD virus (MDV). This is the first report of a confirmed case of mortality due to naturally occurring MDV infection in 1-week-old, nonvaccinated, chickens. Necrotizing lesions were observed in the bursa of Fabricius, lung, duodenum, jejunum, and proventriculus, and large intranuclear inclusion bodies were a striking feature in tissues with lesions in all birds. Immunohistochemical staining for the pp38 protein of MDV revealed abundant pp38 antigen in the affected tissues, confirming the presence of MDV within the lesions. PCR yielded an amplicon with 97% homology to the meq gene of MDV. No evidence of co-infection by either of the immunosuppressive agents chicken anemia virus and infectious bursal disease virus was detected.

Investigator-initiated trials of targeted oncology agents: why independent research is at risk?

BACKGROUND: Drug development traditionally has relied upon the complementary contributions of clinicians and scientists at academic institutions and at pharmaceutical companies. Greater regulatory burdens, increased bureaucratic requirements, restricted reimbursement, and spiralling research and development costs are exerting pressure on the drug development pipeline. The result is a de-emphasis of exploratory research, particularly independent academic research, despite its proven value in identifying new drug targets and developing innovative cancer therapies. DESIGN: An expert panel assembled by the Biotherapy Development Association-a nonprofit international forum for academic and industry researchers, patients, and government regulatory and postregulatory agencies-examined the growing schism between academia and industry and identified several causes of declining academic research. RESULTS: The authors propose solutions to sustain investigator-initiated research and provide a new model whereby expert organisations provide a forum for academia and industry to plan studies within a regulatory framework to support licensure/authorisation and reimbursement for new molecularly targeted agents and biomarkers. CONCLUSIONS: Investigator-initiated trials have led to the discovery and development of innovative, safe, and effective cancer treatments. To ensure that such research continues, action will be required on the parts of legislative and regulatory bodies, industry, universities, patient advocacy organisations, and preclinical and clinical academic scientists.

A comparative study of carotid atherosclerotic plaque microvessel density and angiogenic growth factor expression in symptomatic versus asymptomatic patients.

OBJECTIVE: A challenge facing clinicians is identifying patients with asymptomatic carotid disease at risk of plaque instability. We hypothesise that locally released angiogenic growth factors contribute to plaque instability. METHODS: Carotid endarterectomy specimens from eight symptomatic and eight asymptomatic patients were interrogated for microvessel density and angiogenic growth factor expression histologically using immunofluorescence, and biochemically using quantitative real-time polymerase chain reaction (q-RT-PCR). Bio-Plex suspension array was used to assess circulating biomarkers in venous blood from the same patients and six healthy age-matched controls. RESULTS: Immunofluorescence demonstrated significantly greater neovessel density in symptomatic plaques (P=0.010) with elevated expression of hepatocyte growth factor (HGF) (P=0.001) and its receptor MET (P=0.011) than in asymptomatic plaques. The q-RT-PCR demonstrated up-regulation of Endoglin (CD105), HGF (P=0.001) and MET (P=0.011) in the plaques of symptomatic versus asymptomatic patients. Bio-Plex suspension array demonstrated elevated HGF (P=0.002) serum levels in symptomatic versus asymptomatic patients and healthy controls, and decreased platelet-derived growth factor (PDGF) (P=0.036) serum levels in symptomatic versus asymptomatic patients. CONCLUSION: Plaque instability may be mediated by HGF-induced formation of new microvessels, and decreased vessel stability resulting from decreased PDGF. Suspension array technology has the potential to identify circulating biomarkers that correlate with plaque rupture risk.

Macroscopic quantum effects in nanometer-scale magnets.

Quantum tunneling, the passage of a microscopic system from one state to another by way of a classically forbidden path, is theoretically possible in the macroscopic world. One can now make direct observations of such macroscopic quantum tunneling in very small magnetic structures. This is possible because of significant advances both in the ability to obtain magnetic systems of almost any desirable size, shape, and composition and in the development of superconducting instrumentation for the detection of extremely weak magnetic signals. As an example, measurements on magnetic horse spleen ferritin proteins with the predictions of quantum tunneling theory are discussed and shown.

Inflammatory abdominal aortic aneurysms (IAAA): past and present.

AIM: The aim of the study is to determine whether presentation and outcomes of inflammatory abdominal aortic aneurysms (IAAA) have changed over the last five decades. METHODS: Comparison of current outcomes (January 2001 to December 2007) with results of the earliest report from our unit in 1972. RESULTS: In contemporary series, 421 patients underwent AAA repair; 38 (9%) were IAAA. In 58% patients, IAAA was an incidental finding, whereas 42% patients were symptomatic with abdominal or back pain. Of those, 32% were ruptured IAAA. Male-to-female ratio was 12:1. Thirty-day mortality was 13%; elective 11.5%; emergency 17%. Comparison with 1972 study showed no change in the incidence and gender predilection. Presentation as an incidental finding and rupture increased 4- and 2-folds, respectively. CONCLUSION: The incidence and gender predilection of IAAA have remained unchanged. The 4-fold increase in the presentation as an incidental finding reflects current trends in patient evaluation.

A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer.

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is an important regulator of the chronic inflammation contributing to tumour progression. Infliximab, an anti-TNF-alpha monoclonal antibody was investigated in this trial of patients with advanced cancer. The primary objectives were to determine the safety profile and biological response of infliximab in a cancer population. Clinical response was a secondary objective. PATIENTS AND METHODS: Forty-one patients received infliximab at 5 mg/kg (n = 21) or 10 mg/kg (n = 20) i.v. at 0 and 2 weeks and then every 4 weeks. Post-treatment samples were measured for changes in plasma and serum TNF-alpha, CCL2, IL-6 and C-reactive protein (CRP). RESULTS: Infliximab was well tolerated with no dose-limiting toxic effects. At both doses of infliximab, neutralisation of serum TNF-alpha was observed after 1 h while plasma CCL2, IL-6 and serum CRP were decreased 24 and 48 h following infliximab administration. Seven patients experienced disease stablisation (range 10-50+ weeks). There was no evidence of disease acceleration in any patient. CONCLUSIONS: Infliximab treatment was safe and well tolerated in patients with advanced cancer. There was evidence of biological activity with baseline TNF-alpha and CCL2 being correlated with infliximab response.

Terminology: the historical perspective, evolution and current usage--room for confusion?

Modern palliative care started with St Christopher's Hospice in 1967 and was initially regarded as 'terminal care'. This served as a template for a developing model of multidisciplinary clinical care, teaching and research. A decade later, several hospital Palliative Care Teams were established and different terms were used to describe them. An evidence base developed slowly and a medical subspeciality was established, known as Palliative Medicine. Over the last two decades we have seen an expansion in non-hospice palliative care. The terms used to describe this care have been variable and inconsistent. Our challenges in progress involve establishing clear terminology and an evolving improved evidence base, along with a realisation that there are large gaps in patient care.

Polymorphisms spanning the 0N exon and promoter of the estrogen receptor-beta (ERbeta) gene ESR2 are associated with venous ulceration.

Venous ulcers are characterized by excessive inflammation and raised levels of proinflammatory cytokines. Estrogen has been shown to accelerate the rate of wound healing in elderly subjects by dampening the inflammatory response. The estrogen receptor (ER) proteins, ER-alpha (ERalpha) and ER-beta (ERbeta) mediate the actions of estrogen during wound repair through the activation or repression of target gene transcription. Recent evidence implicates the chromosomal region harboring the ERbeta gene with venous ulceration in a British Caucasian population, highlighting the need to conduct further genetic interrogation. To address this, we conducted a case-control study to investigate whether single nucleotide polymorphisms in the ERbeta gene are associated with venous ulceration in elderly (age >50 years) subjects. We recruited a case group (n = 124, 56 males and 68 females) consisting of patients with an active venous ulcer and a control group consisting of individuals from the general population with no evidence of venous disease or history of venous ulceration (n = 380, 189 males and 191 females). Polymorphisms in close proximity to upstream regulatory regions of the ERbeta gene, including the 0N exon and promoter transcribed in inflammatory cells, were significantly (p < 0.05) associated with venous ulceration. A major susceptibility haplotype carried by 23% (26/112) of cases compared with only 10% (27/276) of controls (odds ratio = 2.8, 95% confidence interval = 1.6-5.0) was significantly (p < 0.01) associated with elevated serum levels of tumor necrosis factor-alpha. In conclusion, common variation in the regulatory regions of the ERbeta gene may pre-dispose to venous ulceration in a British Caucasian population.

Sequence comparison of pigeon circoviruses.

The genome sequences of eight pigeon circoviruses (PiCV) were determined and compared with four previously published sequences. The viruses compared were from the USA, five European countries, China and Australia and included PiCVs from racing, feral, ornamental and meat pigeons and a Senegal dove (Streptopelia senegalensis). The 12 PiCV genomes, ranging from 2032 to 2040 nucleotides in length, displayed similar organizations. Pairwise comparisons showed that the genome nucleotide sequence identities ranged from 85.1% to 97.8% and that the amino acid identities of the putative replication associated (Rep) and putative capsid (Cap) proteins displayed ranges of 91.5-99.1% and 73.0-99.3%, respectively. Comparative analyses identified conserved nucleotide sequences within the Rep gene and 3' intergenic regions, which would be suitable for diagnostic PCR primers, and variable amino acid sequences within the capsid proteins, which should be considered when selecting virus isolates for vaccine development.

Fatal necrotising fasciitis and myositis in a cat associated with Streptococcus canis.

Necrotising fasciitis and necrotising myositis are rare but serious life threatening conditions reported mainly in human beings and dogs. Most cases to date have been caused by beta-haemolytic streptococci of Lancefield groups A, B, C or G. Necrotising fasciitis has been reported only twice in cats and necrotising myositis has never been described. This paper describes a fatal case of necrotising fasciitis and myositis with pneumonia and septicaemia in a nine-year-old cat. The cat had been undergoing treatment for a suspected tear of the cranial cruciate ligament, but on the seventh day of treatment it suddenly deteriorated and died. On postmortem examination, there was an area of hair loss from its left hindlimb and discoloration of the underlying fascia and biceps femoris muscle. Severe necrotising fasciitis and myositis, with numerous intralesional Gram-positive coccoid bacteria, was diagnosed histologically. Other findings included necrotising pneumonia, pleuritis, focal encephalitis, myocarditis and nephritis. Culture of the affected tissues yielded a pure, heavy growth of Streptococcus canis.

The use of real-world data in cancer drug development.

Excitement about the dramatic increase in potential successful anticancer medicines in recent years is hampered by the high costs involved as well as the length of time traditional pathways take for regulatory approval. The translation of experimental clinical data into real-world evidence is also problematic. While the randomised controlled trial remains the gold standard for assessing efficacy and safety, there is increasing interest in the use of observational data to enable more rapid, informed and widespread availability and access to important anticancer medicines. Taking real-world evidence into account in regulatory and health technology assessment in a thoughtful and balanced fashion will enrich and justify sound decision-making.