The effects of maintenance schedules following pulmonary rehabilitation in patients with chronic obstructive pulmonary disease: a randomised controlled trial.

OBJECTIVES: Pulmonary rehabilitation (PR) provides benefit for patients with chronic obstructive pulmonary disease (COPD) in terms of quality of life (QoL) and exercise capacity; however, the effects diminish over time. Our aim was to evaluate a maintenance programme for patients who had completed PR. SETTING: Primary and secondary care PR programmes in Norfolk. PARTICIPANTS: 148 patients with COPD who had completed at least 60% of a standard PR programme were randomised and data are available for 110 patients. Patients had greater than 20 pack year smoking history and less than 80% predicted forced expiratory volume in 1 s but no other significant disease or recent respiratory tract infection. INTERVENTIONS: Patients were randomised to receive a maintenance programme or standard care. The maintenance programme consisted of 2 h (1 h individually tailored exercise training and 1 h education programme) every 3 months for 1 year. PRIMARY AND SECONDARY OUTCOME MEASURES: The Chronic Respiratory Questionnaire (CRQ) (primary outcome), endurance shuttle walk test (ESWT), EuroQol (EQ5D), hospital anxiety and depression score (HADS), body mass index (BMI), body fat, activity levels (overall score and activity diary) and exacerbations were assessed before and after 12 months. RESULTS: There was no statistically significant difference between the groups for the change in CRQ dyspnoea score (primary end point) at 12 months which amounted to 0.19 (-0.26 to 0.64) units or other domains of the CRQ. There was no difference in the ESWT duration (-10.06 (-191.16 to 171.03) seconds), BMI, body fat, EQ5D, MET-minutes, activity rating, HADS, exacerbations or admissions. CONCLUSIONS: A maintenance programme of three monthly 2 h sessions does not improve outcomes in patients with COPD after 12 months. We do not recommend that our maintenance programme is adopted. Other methods of sustaining the benefits of PR are required. TRIAL REGISTRATION NUMBER: NCT00925171.This paper presents independent research funded by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfPB) Programme (Grant Reference Number PB-PG-0408-16225). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.This is the final published version. It first appeared at http://bmjopen.bmj.com/content/5/3/e005921.full?g=w_thorax_open_tab

A Sensitive and Quantitative Polymerase Chain Reaction-Based Cell Free In Vitro Non-Homologous End Joining Assay for Hematopoietic Stem Cells

Hematopoietic stem cells (HSCs) are responsible for sustaining hematopoietic homeostasis and regeneration after injury for the entire lifespan of an organism. Maintenance of genomic stability is crucial for the preservation of HSCs, which depends on their efficient repair of DNA damage, particularly DNA double strand breaks (DSBs). Because of the paucity of HSCs and lack of sensitive assays, directly measuring the ability of HSCs to repair DSBs has been difficult. Therefore, we developed a sensitive and quantitative cell free in vitro non-homologous end joining (NHEJ) assay using linearized plasmids as the substrates and quantitative polymerase chain reaction (qPCR) technique. This assay can sensitively detect DSB repair via NHEJ in less than 1 µg 293T cell nuclear proteins or nuclear extracts from about 5,000 to 10,000 human BM CD34+ hematopoietic cells. Using this assay, we confirmed that human bone marrow HSCs (CD34+CD38− cells) are less proficient in the repair of DSBs by NHEJ than HPCs (CD34+CD38+ cells). In contrast, mouse quiescent HSCs (Pyronin-Ylow LKS+ cells) and cycling HSCs (Pyronin-Yhi LKS+ cells) repaired the damage more efficiently than HPCs (LKS− cells). The difference in the abilities of human and mouse HSCs and HPCs to repair DSBs through NHEJ is likely attributed to their differential expression of key NHEJ DNA damage repair genes such as LIG4. These findings suggest that the qPCR-based cell free in vitro NHEJ assay can be used to sensitively measure the ability of human and mouse HSCs to repair DSBs

To bite or not to bite! A questionnaire-based survey assessing why some people are bitten more than others by midges

BACKGROUND: The Scottish biting midge, Culicoides impunctatus, responsible for more than 90% of biting attacks on human beings in Scotland, is known to demonstrate a preference for certain human hosts over others. METHODS: In this study we used a questionnaire-based survey to assess the association between people's perception of how badly they get bitten by midges and their demographic, lifestyle and health related characteristics. RESULTS: Most people (85.8%) reported being bitten sometimes, often or always with only 14.2% reporting never being bitten by midges when in Scotland. There was no association between level of bites received and age, smoking, diet, exercise, medication, eating strongly flavoured foods or alcohol consumption. However, there was a strong association between the probability of being bitten and increasing height (in men) and BMI (in women). A large proportion of participants (33.8%) reported experiencing a bad/severe reaction to midge bites while 53.1% reported a minor reaction and 13.1% no reaction at all. Also, women tend to react more than men to midge bites. Additionally, the results indicated that the susceptibility to being bitten by midges is hereditary. CONCLUSIONS: This study suggests that midges prefer to bite men that are tall and women that have a large BMI, and that the tendency for a child to be bitten or not could be inherited from their parent. The study is questionnaire-based; therefore, the interpretation of the results may be limited by the subjectivity of the answers given by the respondents. Although the results are relevant only to the Scottish biting midge, the approach used here could be useful for investigating human-insect interactions for other insects, particularly those which transmit pathogens that cause disease

Are isomeric alkenes used in species recognition among neo-tropical stingless bees (Melipona spp)

The majority of our understanding of the role of cuticular hydrocarbons (CHC) in recognition is based largely on temperate ant species and honey bees. The stingless bees remain relatively poorly studied, despite being the largest group of eusocial bees, comprising more than 400 species in some 60 genera. The Meliponini and Apini diverged between 80-130 Myr B.P. so the evolutionary trajectories that shaped the chemical communication systems in ants, honeybees and stingless bees may be very different. Therefore, the main aim of this study was to study if a unique species CHC signal existed in Neotropical stingless bees, as shown for many temperate species, and if so what compounds are involved. This was achieved by collecting CHC data from 24 colonies belonging to six species of Melipona from North-eastern Brazil and comparing this new data with all previously published CHC studies on Melipona. We found that each of the eleven Melipona species studied so far each produced a unique species CHC signal based around their alkene isomer production. A remarkable number of alkene isomers, up to 25 in M. asilvai, indicated the diversification of alkene positional isomers among the stingless bees. The only other group to have really diversified in alkene isomer production are the primitively eusocial Bumblebees (Bombus spp), which are the sister group of the stingless bees. Furthermore, among the eleven Neotropical Melipona species we could detect no effect of the environment on the proportion of alkane production as has been suggested for some other species

A Novel Checkpoint and RPA Inhibitory Pathway Regulated by Rif1

Cells accumulate single-stranded DNA (ssDNA) when telomere capping, DNA replication, or DNA repair is impeded. This accumulation leads to cell cycle arrest through activating the DNA–damage checkpoints involved in cancer protection. Hence, ssDNA accumulation could be an anti-cancer mechanism. However, ssDNA has to accumulate above a certain threshold to activate checkpoints. What determines this checkpoint-activation threshold is an important, yet unanswered question. Here we identify Rif1 (Rap1-Interacting Factor 1) as a threshold-setter. Following telomere uncapping, we show that budding yeast Rif1 has unprecedented effects for a protein, inhibiting the recruitment of checkpoint proteins and RPA (Replication Protein A) to damaged chromosome regions, without significantly affecting the accumulation of ssDNA at those regions. Using chromatin immuno-precipitation, we provide evidence that Rif1 acts as a molecular “band-aid” for ssDNA lesions, associating with DNA damage independently of Rap1. In consequence, small or incipient lesions are protected from RPA and checkpoint proteins. When longer stretches of ssDNA are generated, they extend beyond the junction-proximal Rif1-protected regions. In consequence, the damage is detected and checkpoint signals are fired, resulting in cell cycle arrest. However, increased Rif1 expression raises the checkpoint-activation threshold to the point it simulates a checkpoint knockout and can also terminate a checkpoint arrest, despite persistent telomere deficiency. Our work has important implications for understanding the checkpoint and RPA–dependent DNA–damage responses in eukaryotic cells

The role of TNF genetic variants and the interaction with cigarette smoking for gastric cancer risk: a nested case-control study

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to investigate the role of <it>TNF </it>genetic variants and the combined effect between <it>TNF </it>gene and cigarette smoking in the development of gastric cancer in the Korean population.</p> <p>Methods</p> <p>We selected 84 incident gastric cancer cases and 336 matched controls nested within the Korean Multi-Center Cancer Cohort. Six SNPs on the <it>TNF </it>gene, <it>TNF</it>-α-238 G/A, -308 G/A, -857 C/T, -863 C/A, -1031 T/C, and <it>TNF</it>-β 252 A/G were genotyped. The ORs (95% CIs) were calculated using unconditional logistic regression model to detect each SNP and haplotype-pair effects for gastric cancer. The combined effects between the <it>TNF </it>gene and smoking on gastric cancer risk were also evaluated. Multi dimensionality reduction (MDR) analyses were performed to explore the potential <it>TNF </it>gene-gene interactions.</p> <p>Results</p> <p><it>TNF</it>-α-857 C/T containing the T allele was significantly associated with an increased risk of gastric cancer and a linear trend effect was observed in the additive model (OR = 1.6, 95% CI 1.0–2.5 for CT genotype; OR = 2.6, 95% CI 1.0–6.4 for TT genotype). All haplotype-pairs that contained TCT or CCC of <it>TNF</it>-α-1031 T/C, <it>TNF</it>-α-863 C/A, and <it>TNF</it>-α-857 C/T were associated with a significantly higher risk for gastric cancer only among smokers. In the MDR analysis, regardless of smoking status, <it>TNF</it>-α-857 C/T was included in the first list of SNPs with a significant main effect.</p> <p>Conclusion</p> <p><it>TNF</it>-α-857 C/T polymorphism may play an independent role in gastric carcinogenesis and the risk for gastric cancer by <it>TNF </it>genetic effect is pronounced by cigarette smoking.</p

Gender differences in first episode psychotic mania

Background : The aim of this paper was to delineate the impact of gender on premorbid history, onset, and 18 month outcomes of first episode psychotic mania (FEPM) patients. Methods : Medical file audit assessment of 118 (male = 71; female = 47) patients with FEPM aged 15 to 29 years was undertaken on clinical and functional measures. Results : Males with FEPM had increased likelihood of substance use (OR = 13.41, p &lt; .001) and forensic issues (OR = 4.71, p = .008), whereas females were more likely to have history of sexual abuse trauma (OR = 7.12, p = .001). At service entry, males were more likely to be using substances, especially cannabis (OR = 2.15, p = .047), had more severe illness (OR = 1.72, p = .037), and poorer functioning (OR = 0.96, p = .045). During treatment males were more likely to decrease substance use (OR = 5.34, p = .008) and were more likely to be living with family (OR = 4.30, p = .009). There were no gender differences in age of onset, psychopathology or functioning at discharge. Conclusions : Clinically meaningful gender differences in FEPM were driven by risk factors possibly associated with poor outcome. For males, substance use might be associated with poorer clinical presentation and functioning. In females with FEPM, the impact of sexual trauma on illness course warrants further consideration

Eucapnic Voluntary Hyperpnea: Gold Standard for Diagnosing Exercise-Induced Bronchoconstriction in Athletes?

In athletes, a secure diagnos is of exercise-induced bronchoconstriction (EIB) is dependent on objective testing. Evaluating spirometric indices of airflow before and following an exercise bout is intuitively the optimal means for the diagnosis; however, this approach is recognized as having several key limitations. Accordingly, alternative indirect bronchoprovocation tests have been recommended as surrogate means for obtaining a diagnosis of EIB. Of these tests, it is often argued that the eucapnic voluntary hyperpnea (EVH) challenge represents the ‘gold standard’. This article provides a state-of-the-art review of EVH, including an overview of the test methodology and its interpretation. We also address the performance of EVH against the other functional and clinical approaches commonly adopted for the diagnosis of EIB. The published evidence supports a key role for EVH in the diagnostic algorithm for EIB testing in athletes. However, its wide sensitivity and specificity and poor repeatability preclude EVH from being termed a ‘gold standard’ test for EIB

Rif1 Supports the Function of the CST Complex in Yeast Telomere Capping

Telomere integrity in budding yeast depends on the CST (Cdc13-Stn1-Ten1) and shelterin-like (Rap1-Rif1-Rif2) complexes, which are thought to act independently from each other. Here we show that a specific functional interaction indeed exists among components of the two complexes. In particular, unlike RIF2 deletion, the lack of Rif1 is lethal for stn1ΔC cells and causes a dramatic reduction in viability of cdc13-1 and cdc13-5 mutants. This synthetic interaction between Rif1 and the CST complex occurs independently of rif1Δ-induced alterations in telomere length. Both cdc13-1 rif1Δ and cdc13-5 rif1Δ cells display very high amounts of telomeric single-stranded DNA and DNA damage checkpoint activation, indicating that severe defects in telomere integrity cause their loss of viability. In agreement with this hypothesis, both DNA damage checkpoint activation and lethality in cdc13 rif1Δ cells are partially counteracted by the lack of the Exo1 nuclease, which is involved in telomeric single-stranded DNA generation. The functional interaction between Rif1 and the CST complex is specific, because RIF1 deletion does not enhance checkpoint activation in case of CST-independent telomere capping deficiencies, such as those caused by the absence of Yku or telomerase. Thus, these data highlight a novel role for Rif1 in assisting the essential telomere protection function of the CST complex