The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia

Cytarabine (ara-C) is the most effective agent for the treatment of acute myeloid leukaemia (AML). Aberrant expression of enzymes involved in the transport/metabolism of ara-C could explain drug resistance. We determined mRNA expression of these factors using quantitative-real-time-PCR in leukemic blasts from children diagnosed with de novo AML. Expression of the inactivating enzyme pyrimidine nucleotidase-I (PN-I) was 1.8-fold lower in FAB-M5 as compared to FAB-M1/2 (P=0.007). In vitro sensitivity to deoxynucleoside analogues was determined using the MTT-assay. Human equilibrative nucleoside transporter-1 (hENT1) mRNA expression and ara-C sensitivity were significantly correlated (rp=−0.46; P=0.001), with three-fold lower hENT1 mRNA levels in resistant patients (P=0.003). hENT1 mRNA expression also seemed to correlate inversely with the LC50 values of cladribine (rp=−0.30; P=0.04), decitabine (rp=−0.29; P=0.04) and gemcitabine (rp=−0.33; P=0.02). Deoxycytidine kinase (dCK) and cytidine deaminase (CDA) mRNA expression seemed to correlate with in vitro sensitivity to gemcitabine (rp=−0.31; P=0.03) and decitabine (rp=0.33; P=0.03), respectively. The dCK/PN-I ratio correlated inversely with LC50 values for gemcitabine (rp=−0.45, P=0.001) and the dCK/CDA ratio seemed to correlate with LC50 values for decitabine (rp=−0.29; 0.04). In conclusion, decreased expression of hENT1, which transports ara-C across the cell membrane, appears to be a major factor in ara-C resistance in childhood AML

COPD in patients with stable heart failure in the primary care setting

Mark J Valk,1 Berna D Broekhuizen,1 Arend Mosterd,1,2 Nicolaas P Zuithoff,1 Arno W Hoes,1 Frans H Rutten1 1Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 2Department of Cardiology, Meander Medical Center, Amersfoort, the Netherlands Background: Presence of chronic obstructive pulmonary disease (COPD) in heart failure (HF) has prognostic and therapeutic implications. Exact prevalence estimates are lacking because most previous studies estimated the prevalence of COPD among HF patients while unstable and in the presence of pulmonary congestion.Methods: Community-dwelling patients with an established diagnosis of HF and in a stable phase of their disease were invited for spirometry. COPD was defined according to the Global initiative for chronic Obstructive Lung Disease (GOLD) classification and considered present if the ratio of the post-bronchodilator forced expiratory volume in 1 second and forced vital capacity was below 0.7.Results: Thirty of the 106 patients with HF (mean age 76 [standard deviation] 11.9 years, 57% male) had COPD (prevalence 28.3% [95% confidence interval (CI) 19.7%–36.9%]), with similar rates among those with HF and a reduced ejection fraction (18 individuals; prevalence 28.6% [95% CI 20.0%–37.2%]) and HF with preserved ejection fraction (12 individuals; prevalence 27.9% [95% CI 19.4–36.4]). Twenty-one (70%) of the 30 participants were newly detected cases of COPD.Conclusion: More than a quarter of the patients with HF concomitantly have COPD, with the large majority being previously unrecognized. Coexistence of COPD should be considered more often in these patients. Keywords: heart failure, COPD, prevalence, comorbidity, spirometry, diagnosis, primary care&nbsp

Interpretability of the European Heart Failure Self-care Behaviour scale

Kim P Wagenaar,1 Berna DL Broekhuizen,1 Frans H Rutten,1 Anna Strömberg,2 Henk F van Stel,1 Arno W Hoes,1 Tiny Jaarsma2 1Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, the Netherlands; 2Department of Social and Welfare Studies, Linköping University, Linköping, Sweden Objective: The European Heart Failure Self-care Behaviour scale (EHFScBs) is a valid patient-reported questionnaire to measure self-care behavior of heart failure (HF) patients. We assessed the interpretability of the EHFScBs.Methods: We used data of 1,023 HF patients. Interpretability refers to the clinical meaning of the score and its changes over time. We operationalized interpretability by evaluating distributions of EHFScBs scores across relevant HF subgroups by eyeballing, by testing the risk on hospitalizations and mortality of a plausible threshold, and by determining a clinically relevant minimal important change (MIC). The scale score ranged from 0 to 100, with a higher score meaning better self-care. A threshold of ≥70 was defined as adequate and <70 as inadequate self-care.Results: The EHFScBs scores were similarly normally distributed among the subgroups with a mean between 57.8 (SD 19.4) and 72.0 (SD 18.0). The 464 HF patients with adequate self-care had significantly less all-cause hospitalizations than the 559 patients with inadequate self-care.Conclusion: The degree of self-care showed to be independent of relevant HF subgroups. A single threshold of 70 accurately discriminated between patients with adequate and inadequate self-care.Practice implications: The threshold of 70 can be used in designing studies and informing health policy makers. Keywords: heart failure, self-care, interpretability, patient-reported outcome, threshold and minimal important chang

Prediction of chronic heart failure and chronic obstructive pulmonary disease in a general population: the Tromsø study

Aims Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are main causes of dyspnoea, and echocardiography and spirometry are essential investigations for these diagnoses. Our aim was to determine the prevalence of HF and COPD in a general population, also how the diseases may be identified, and to what extent their clinical characteristics differ. Methods and results In the seventh survey of Tromsø study (2015–16), subjects aged 40 years or more were examined with echocardiography, spirometry, lung sound recordings, questionnaires, including the modified Medical Research Council (mMRC) questionnaire on dyspnoea, and N‐terminal pro‐brain natriuretic peptide analysis. A diagnosis of HF (HF with reduced ejection fraction, HF with mid‐range ejection fraction, or HF with preserved ejection fraction) or COPD was established according to current guidelines. Predictors of HF and COPD were evaluated by logistic regression and receiver operating characteristic curve analysis. A total of 7110 participants could be evaluated for COPD, 1624 for HF, and 1538 for both diseases. Age‐standardized prevalence of HF was 6.8% for women and 6.1% for men; the respective figures for COPD were 5.2% and 5.1%. Among the 1538 evaluated for both diseases, 139 subjects fulfilled the HF criteria, but only 17.1% reported to have the disease. Of those fulfilling the COPD criteria, 31.6% reported to have the disease. Shortness of breath at exertion was a frequent finding in HF; 59% of those with mMRC ≥2 had HF, while such shortness of breath was found in 24% among those with COPD. Reporting mMRC ≥2 had an odds ratio for HF of 19.5 (95% confidence interval 11.3–33.7), whereas the odds ratio for COPD was 6.3 (95% confidence interval 3.5–11.6). Current smoking was the strongest predictor of COPD but did not predict HF. Basal inspiratory crackles were significant predictors of HF in multivariable analysis. Among the subtypes of HF, an age <70 years was most frequently found in HF with reduced ejection fraction, in 51.7%. Clinical scores based on the predictive value in multivariable analysis of history, symptoms, and signs predicted HF and COPD with areas under the curve of 0.833 and 0.829, respectively. Conclusions Study participants with HF and COPD were in most cases not aware of their condition. In general practice, when an elderly patient present with shortness of breath, both diseases should be considered. Previous cardiovascular disease points at HF, while a history of smoking points at COPD. The threshold should be low for ordering echocardiography or spirometry for verifying the suspected cause of dyspnoea

Illness perception and related behaviour in lower respiratory tract infections-a European study.

BACKGROUND: Lower respiratory tract infection (LRTI) is a common presentation in primary care, but little is known about associated patients' illness perception and related behaviour. OBJECTIVE: To describe illness perceptions and related behaviour in patients with LRTI visiting their general practitioner (GP) and identify differences between European regions and types of health care system. METHODS: Adult patients presenting with acute cough were included. GPs recorded co morbidities and clinical findings. Patients filled out a diary for up to 4 weeks on their symptoms, illness perception and related behaviour. The chi-square test was used to compare proportions between groups and the Mann-Whitney U or Kruskal Wallis tests were used to compare means. RESULTS: Three thousand one hundred six patients from 12 European countries were included. Eighty-one per cent (n = 2530) of the patients completed the diary. Patients were feeling unwell for a mean of 9 (SD 8) days prior to consulting. More than half experienced impairment of normal or social activities for at least 1 week and were absent from work/school for a mean of 4 (SD 5) days. On average patients felt recovered 2 weeks after visiting their GP, but 21% (n = 539) of the patients did not feel recovered after 4 weeks. Twenty-seven per cent (n = 691) reported feeling anxious or depressed, and 28% (n = 702) re-consulted their GP at some point during the illness episode. Reported illness duration and days absent from work/school differed between countries and regions (North-West versus South-East), but there was little difference in reported illness course and related behaviour between health care systems (direct access versus gate-keeping). CONCLUSION: Illness course, perception and related behaviour in LRTI differ considerably between countries. These finding should be taken into account when developing International guidelines for LRTI and interventions for setting realistic expectations about illness course

Illness perception and related behaviour in lower respiratory tract infections-a European study.

BACKGROUND: Lower respiratory tract infection (LRTI) is a common presentation in primary care, but little is known about associated patients' illness perception and related behaviour. OBJECTIVE: To describe illness perceptions and related behaviour in patients with LRTI visiting their general practitioner (GP) and identify differences between European regions and types of health care system. METHODS: Adult patients presenting with acute cough were included. GPs recorded co morbidities and clinical findings. Patients filled out a diary for up to 4 weeks on their symptoms, illness perception and related behaviour. The chi-square test was used to compare proportions between groups and the Mann-Whitney U or Kruskal Wallis tests were used to compare means. RESULTS: Three thousand one hundred six patients from 12 European countries were included. Eighty-one per cent (n = 2530) of the patients completed the diary. Patients were feeling unwell for a mean of 9 (SD 8) days prior to consulting. More than half experienced impairment of normal or social activities for at least 1 week and were absent from work/school for a mean of 4 (SD 5) days. On average patients felt recovered 2 weeks after visiting their GP, but 21% (n = 539) of the patients did not feel recovered after 4 weeks. Twenty-seven per cent (n = 691) reported feeling anxious or depressed, and 28% (n = 702) re-consulted their GP at some point during the illness episode. Reported illness duration and days absent from work/school differed between countries and regions (North-West versus South-East), but there was little difference in reported illness course and related behaviour between health care systems (direct access versus gate-keeping). CONCLUSION: Illness course, perception and related behaviour in LRTI differ considerably between countries. These finding should be taken into account when developing International guidelines for LRTI and interventions for setting realistic expectations about illness course