bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapy-related acute leukaemia with Mitoxantrone: what is the risk and can we minimise it?
Authors: Ellis R , Boggild M 
Published: February 2009

Background Therapy-related acute leukaemia (TRAL) is a concern for neurologists and patients when considering treatment with Mitoxantrone for multiple sclerosis (MS). The timing of this complication, risk, mortality and relationship to exposure remain uncertain. Methods We searched literature for publications relating to Mitoxantrone in MS, reviewed publication references and handsearched abstract lists to identify case-series reporting follow-up and complications of treatment with Mitoxantrone. We combined this with our local database of 250 cases treated since 1997. We also identified all reported individual cases of TRAL and extracted data reporting exposure (dose or mg/m2), timing and outcome of TRAL. Results Case-series including 5472 patients were identified; mean dose of Mitoxantrone was 74.2 mg/m2 (range:12–120 mg/m2). TRAL was diagnosed in 0.30% (1 in 333). In 34 TRAL cases, sufficient data was available to inform analysis of exposure. Onset was a median of 18.5 months following Mitoxantrone treatment (range:4–60). Acute Myelocytic Leukaemia and Acute Promyelocytic Leukaemia represented 46.4% each of the leukaemia subtypes. Six of 25 TRAL patients, where outcome was reported, died (24%). Over 80% of cases occurred in patients exposed to >60 mg/m2, with a relative risk of 1.44 (CI95%:1.18–1.70) when comparing total dose >60 mg/m2 against <60 mg/m2 strongly suggesting a relationship between risk of TRAL and total dose.
Defective homing and impaired induction of cytotoxic T cells by BCR/ABL-expressing dendritic cells
Authors: Mumprecht Sabine , Claus Christina , Schürch Christian , Pavelic Viktor , Matter Matthias S. , Ochsenbein Adrian F. 
Published: February 2009

Abstract
Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease arising from a hematopoietic stem cell expressing the BCR/ABL fusion protein. Leukemic and dendritic cells (DCs) develop from the same transformed hematopoietic progenitors. How BCR/ABL interferes with the immunoregulatory function of DCs in vivo is unknown. We analyzed the function of BCR/ABL-expressing DCs in a retroviral-induced murine CML model using the glycoprotein of lymphocytic choriomeningitis virus as a model leukemia antigen. BCR/ABL-expressing DCs were found in bone marrow, thymus, spleen, lymph nodes, and blood of CML mice. They were characterized by a low maturation status and induced only limited expansion of naive and memory cytotoxic T lymphocytes (CTLs). In addition, immunization with in vitro–generated BCR/ABL-expressing DCs induced lower frequencies of specific CTLs than immunization with control DCs. BCR/ABL-expressing DCs preferentially homed to the thymus, whereas only few BCR/ABL-expressing DCs reached the spleen. Our results indicate that BCR/ABL-expressing DCs do not efficiently induce CML-specific T-cell responses resulting from low DC maturation and impaired homing to secondary lymphoid organs. In addition, BCR/ABL-expressing DCs in the thymus may contribute to CML-specific tolerance induction of specific CTLs.
Tumor suppressor microRNAs are underrepresented in primary effusion lymphoma and Kaposi sarcoma
Authors: O'Hara Andrea J. , Wang Ling , Dezube Bruce J. , Harrington William J. , Damania Blossom , Dittmer Dirk P. 
Published: February 2009

Abstract
The presence of tumor-specific microRNAs reflects tissue of origin and tumor stage. We show that the absence of miRNAs likewise can be used to determine tumor origin (miR-155) and proliferation state because tumor suppressor miRNAs (miR-222/221, let-7 family) were significantly down-regulated in primary effusion lymphoma (PEL) and in Kaposi sarcoma (KS), an endothelial cell tumor. PEL and KS are associated with KS-associated herpesvirus infection. We identified 15 virally regulated miRNAs in latently infected, nontumorigenic endothelial cells. MiR-143/145 were elevated only in KS tumors, not virally infected endothelial cells. Thus, they represent tumor-specific, rather than virus-specific, miRNAs. Because many tumor suppressor proteins are wild-type in KS and PEL, down-regulation of multiple tumor suppressor miRNAs provides a novel, alternative mechanism of transformation.
Dissociation of airway inflammation and hyperresponsiveness by cyclooxygenase inhibition in allergen challenged mice
Authors: Swedin L. , Neimert-Andersson T. , Hjoberg J. , Jonasson S. , van Hage M. , Adner M. , Ryrfeldt Å. , Dahlén S-E. 
Published: February 2009

The aim of the current study was to define how cyclooxygenase (COX)-activity affects airway hyperresponsiveness (AHR) and inflammation using interventions with COX inhibitors at different time points during allergen challenge and/or prior to measurement of AHR in an eosinophil-driven allergic mouse model. Inflammatory cells were assessed in bronchioalveolar lavage (BAL) and AHR was evaluated as the total lung resistance to methacholine (MCh) challenge.Administration of FR122047 (COX-1 inhibitor) during ovalbumin (OVA) challenge and prior to MCh challenge enhanced AHR without affecting the inflammatory cell response. In contrast, administration of lumiracoxib (COX-2 inhibitor) during the same time period had no effect on AHR but reduced the inflammatory cells in BAL. Nonselective COX inhibition with diclofenac both enhanced the AHR and reduced the inflammatory cells.Administration of diclofenac only during OVA challenge reduced the cells in BAL without any changes in AHR, whereas administration of diclofenac only prior to MCh challenge enhanced AHR but did not affect the cells in BAL.The present study implicates distinct roles of prostanoids generated along the COX-1 and COX-2 pathways and, furthermore, that inflammatory cells in BAL do not change in parallel with AHR. These findings support the fact that AHR and the inflammatory response are distinct and, at least in part, uncoupled events.
An evaluation of the completeness of reporting of childhood tuberculosis: Table 1—
Authors: Teo S. S. S. , Alfaham M. , Evans M. R. , Watson J. M. , Riordan A. , Sonnenberg P. , Clark J. , Hayward A. , Sharland M. , Moore-Gillon J. , Novelli V. , Quinn D. , Shingadia D. 
Published: February 2009

The sensitivity of the Enhanced Tuberculosis Surveillance (ETS) scheme for monitoring tuberculosis in children is unknown.We used the British Paediatric Surveillance Unit (BPSU) reporting scheme to conduct a prospective observational study of tuberculosis in children aged <16 yrs in the UK. Reported cases were then matched with records from the ETS database.A total of 320 cases were reported to the BPSU between January and December 2004. We estimated that there were 557 paediatric cases in England, Wales and Northern Ireland in 2004: 222 (40%) cases reported to both BPSU and ETS, 98 (18%) reported to BPSU but not ETS and 237 (42%) reported to ETS but not BPSU. Children aged <5 yrs were significantly less likely to be reported to ETS compared with older children (p<0.01).There is substantial under-reporting of childhood tuberculosis, especially of children aged <5 yrs. ETS provides a representative picture of the demographics but may miss ∼20% of cases. This should be taken into account when planning training and resource requirements for tuberculosis. Increased efforts are needed to ensure that all paediatric cases are reported to ETS.
Clinical relevance of constant power exercise duration changes in COPD
Authors: Puente-Maestu L. , Villar F. , de Miguel J. , Stringer W. W. , Sanz P. , Sanz M. L. , García de Pedro J. , Martínez-Abad Y. 
Published: February 2009

The endurance time during constant high work-rate exercise (tLIM) is used to assess exercise capacity in patients with chronic obstructive pulmonary disease and as an outcome measure for pulmonary rehabilitation. Our study was designed to establish the minimum clinically important difference for thetLIM.tLIMwas measured in 105 patients (86 males) before and after an 8-week outpatient pulmonary rehabilitation programme. Subjects were asked to identify, from a five-point Likert scale, the perceived change in their exercise performance immediately upon completion of the exercise tests. The scale ranged from “better” to “worse”.The mean±sdage was 64±5 yrs, forced expiratory volume in 1 s (FEV1) 47±10% and FEV1/forced vital capacity 54.7±16.3%. BaselinetLIMat 75% of the peak work rate was 397±184 s, which increased by 62±63% after rehabilitation. In subjects who felt their exercise tolerance was “slightly better”, the mean improvement was 34% in the relative improvement over the baseline value (95% CI 29–39)% or 101 (86–116) s compared with 121 (109–134)% in those who reported that their exercise tolerance was “better” and 8 (2–14)% in those who felt their exercise tolerance was “about the same”.Minimum clinically important improvement fortLIMaveraged ∼33% of baseline. Patients were able to distinguish at least one further additional level of benefit at 120% of baseline.
Vehicle exhaust outside the home and onset of asthma among adults
Authors: Modig L. , Torén K. , Janson C. , Jarvholm B. , Forsberg B. 
Published: February 2009

Few studies have investigated the relationship between vehicle exhaust and the new onset of asthma among adults. The aim of the present prospective cohort study was to investigate the relationship between the cumulative incidence of asthma and onset of asthma among adults and vehicle exhaust concentrations at home.Participants from three Swedish cities included in the Respiratory Health in Northern Europe cohort constituted the study population. Exposure at each participant’s home was calculated using dispersion models. We also used <50 m distance to nearest major road as a more simple indicator of exposure. The adjusted model included 3,609 participants, of which 107 were classified as onset cases and 55 as true incident cases of asthma.There was a positive association between asthma onset (odds ratio (OR) per 10 μg·m−31.46, 95% confidence interval (CI) 1.07–1.99) and incident asthma (OR per 10 μg·m−31.54, 95% CI 1.00–2.36) and the levels of nitrogen dioxide (NO2), which remained statistically significant after adjusting for potential confounders. The relationship between asthma and NO2was not significantly modified by sex, hay fever or wheeze. The risk of developing asthma was also significantly related to living close to a major road.The current study suggests that elevated levels of vehicle exhaust outside the home increase the risk of onset and incident asthma among adults.
l-Arginine deficiency causes airway hyperresponsiveness after the late asthmatic reaction
Authors: Maarsingh H. , Bossenga B. E. , Bos I. S. T. , Volders H. H. , Zaagsma J. , Meurs H. 
Published: February 2009

Peroxynitrite has been shown to be crucially involved in airway hyperresponsiveness (AHR) after the late asthmatic reaction (LAR). Peroxynitrite production may result from simultaneous synthesis of nitric oxide (NO) and superoxide by inducible NO-synthase (iNOS) at lowl-arginine concentrations.l-Arginine availability to iNOS is regulated by its cellular uptake, which can be inhibited by eosinophil-derived polycations and by arginase, which competes with iNOS for the common substrate.Using a guinea pig model of allergic asthma, we investigated whether aberrantl-arginine homeostasis could underlie peroxynitrite-mediated AHR after the LAR.After the LAR, arginase activity in the airways and eosinophil peroxidase release from bronchoalveolar lavage cells were increased. These changes were associated with a 2.0-fold AHR to methacholine as measured in isolated perfused tracheal preparations. AHR was reduced by exogenousl-arginine administration. Moreover, both the arginase inhibitorNω-hydroxy-nor-l-arginine (nor-NOHA) and the polycation antagonist heparin normalised airway responsiveness. These effects were reversed by the nitric oxide synthase inhibitorNω-nitro-l-arginine methyl ester (l-NAME), indicating that both agents reduced AHR by restoring bronchodilating NO production.In conclusion, in allergen-challenged guinea pigs, the AHR after the LAR is caused by arginase- and polycation-induced attenuation ofl-arginine availability to iNOS, which may switch the enzyme to simultaneous production of superoxide and NO, and, consequently, peroxynitrite.
Sex-specific effect of body weight gain on systemic inflammation in subjects with COPD: results from the SAPALDIA cohort study 2
Authors: Bridevaux P-O. , Gerbase M. W. , Schindler C. , Felber Dietrich D. , Curjuric I. , Dratva J. , Ackermann-Liebrich U. , Probst-Hensch N. M. , Gaspoz J-M. , Rochat T. 
Published: February 2009

Systemic inflammation may mediate the association between chronic obstructive pulmonary disease (COPD) and extrapulmonary comorbidities. We measured high-sensitivity C-reactive protein (hs-CRP) in COPD and quantified the effect modification by body weight change and sex.Using data from the Swiss study on Air Pollution and Lung Diseases in Adults (SAPALDIA; n = 5,479) with measurements of forced expiratory volume in 1 s (FEV1), body weight and hs-CRP, we examined the association of hs-CRP and categories of body weight change (lost weight and weight gained 0–5%, 5–9%, 9–14% and >14%) with fast FEV1decline.hs-CRP was elevated both in association with fast FEV1decline and body weight gain. Subjects with fast FEV1decline and weight gain (>14%) had higher hs-CRP (2.0 mg·L−1for femalesversus1.6 mg·L−1for males). After adjustment for age, smoking, physical activity, hormonal therapy and diabetes, elevated hs-CRP (>3 mg) was found to be more likely in subjects with fast FEV1decline (ORmales1.38, ORfemales1.42) and in those with weight gain >14% (ORmales2.04, ORfemales4.51).The association of weight gain and fast FEV1decline predicts a higher level of systemic inflammation. Since the effect of weight gain on systemic inflammation is larger in females than in males, weight gain may be a risk factor for extrapulmonary comorbidities in females with COPD.
Diaphragm pacing restores olfaction in tetraplegia
Authors: Adler D. , Gonzalez-Bermejo J. , Duguet A. , Demoule A. , Le Pimpec-Barthes F. , Hurbault A. , Morélot-Panzini C. , Similowski T. 
Published: February 2009

High cervical spinal cord injuries induce extreme handicap and tactile isolation. Tracheotomised tetraplegic patients are also bound to be olfaction deprived. By restoring negative pressure inspiration, diaphragm pacing (DP) should improve olfaction.We tested olfaction in 10 consecutive tetraplegics during positive pressure mechanical ventilation and DP, using the University of Pennsylvania Smell Identification Test (UPSIT). Quality of life was assessed using the Satisfaction with Life Scale (SWLS). Self-perceived benefits of DP were studied using an in-house questionnaire.Olfaction was very poor during positive pressure mechanical ventilation (UPSIT, mean±sd17.1±6.4, anosmia or severe microsmia). It improved during DP (35.2±1.9, normosmia or mild microsmia; p<0.0001) and SWLS was 18.5±4.2. Nine patients stated that DP had improved their quality of life. This was driven by better mobility (ranked first), improved self-image and relationships with others (ranked second), improved olfaction and better feeling of security (both ranked third).Improved olfaction is among the benefits of DP and should be mentioned to patients considered for this therapy. Furthermore, attention to olfaction is warranted in tracheotomised ventilator-dependent patients, as a putative path towards improvement of quality of life.
T-SPOT.TBresponses during treatment of pulmonary tuberculosis
Authors: Ribeiro Samantha , Dooley Kelly , Hackman Judith , Loredo Carla , Efron Anne , Chaisson Richard E , Conde Marcus B , Boechat Neio , Dorman Susan E 
Published: February 2009

Abstract

Background
Immune responses to Mycobacterium tuberculosis antigens could serve as surrogate markers of treatment response.

Methods
Using the T-SPOT.TB assay and frozen peripheral blood mononuclear cells, we enumerated ESAT-6- and CFP-10-specific IFN-γ-producing T cells over time in pulmonary TB patients receiving directly observed treatment. T cell responses (measured as "spot forming cells" or "SFCs") were assessed prior to treatment and at 16 and 24 weeks of treatment.

Results
58 patients were evaluated, of whom 57 were HIV seronegative. Mean (SD) ESAT-6, CFP-10, and summed RD1 specific SFCs declined from 42.7 (72.7), 41.2 (66.4), and 83.8 (105.7) at baseline to 23.3 (39.4, p = 0.01), 23.2 (29.4, p = 0.18), and 46.5 (59.5, p = 0.02) at completion of 24 weeks of treatment, respectively. Only 10% of individuals with a baseline reactive test reverted to negative at treatment week 24. For the group that was culture positive at completion of 8 weeks of treatment compared to the culture negative group, the incidence rate ratio (IRR) of ESAT-6, CFP-10, and summed RD1 specific SFC counts were, respectively, 2.23 (p = 0.048), 1.51 (p = 0.20), and 1.83 (p = 0.047). Patients with cavitary disease had mean ESAT-6 specific SFC counts that were higher than those without cavitary disease (IRR 2.08, p = 0.034).

Conclusion
IFN-γ-producing RD1-specific T cells, as measured in the T-SPOT.TB assay, may be directly related to bacterial load in patients undergoing treatment for pulmonary TB. However, high inter-subject variability in quantitative results coupled with failure of reversion to negative of qualitative results in most subjects at treatment completion may limit the utility of this assay as a surrogate marker for treatment efficacy.
Methylation of homeobox genes is a frequent and early epigenetic event in breast cancer
Authors: Tommasi Stella , Karm Deborah L , Wu Xiwei , Yen Yun , Pfeifer Gerd P 
Published: February 2009

Abstract
Introduction
Aberrant methylation of CpG islands is a hallmark of cancer and occurs at an early stage in breast tumorigenesis. However, its impact on tumor development is not fully determined, and its potential as a diagnostic biomarker remains to be validated. Methylation profiling of invasive breast carcinoma has been largely explored. Conversely, very little and sparse information is available on early-stage breast cancer. To gain insight into the epigenetic switches that may promote and/or contribute to the initial neoplastic events during breast carcinogenesis, we have analyzed the DNA methylation profile of ductal carcinoma in situ, a premalignant breast lesion with a great potential to progress toward invasive carcinoma.

Methods
We have utilized a comprehensive and sensitive array-based DNA mapping technique, the methylated-CpG island recovery assay, to profile the DNA methylation pattern in ductal carcinoma in situ. Differential methylation of CpG islands was compared genome-wide in tumor DNA versus normal DNA utilizing a statistical linear model in the LIMMA software package.

Results
Using this approach, we have identified 108 significant CpG islands that undergo aberrant DNA methylation in ductal carcinoma in situ and stage I breast tumors, with methylation frequencies greater than or comparable with those of more advanced invasive carcinoma (50% to 93%). A substantial fraction of these hypermethylated CpG islands (32% of the annotated CpG islands) is associated with several homeobox genes, such as the TLX1, HOXB13, and HNF1B genes. Fifty-three percent of the genes hypermethylated in early-stage breast cancer overlap with known Polycomb targets and include homeobox genes and other developmental transcription factors.

Conclusions
We have identified a series of new potential methylation biomarkers that may help elucidate the underlying mechanisms of breast tumorigenesis. More specifically, our results are suggestive of a critical role of homeobox gene methylation in the insurgence and/or progression of breast cancer.
The burden of sepsis-associated mortality in the United States from 1999 to 2005: an analysis of multiple-cause-of-death data
Authors: Melamed Alexander , Sorvillo Frank J 
Published: February 2009

Abstract
Introduction
Sepsis is the 10th leading cause of death in the United States. The National Center for Health Statistics' multiple-cause-of-death (MCOD) dataset is a large, publicly available, population-based source of information on disease burden in the United States. We have analysed MCOD data from 1999 to 2005 to investigate trends, assess disparities and provide population-based estimates of sepsis-associated mortality during this period.

Methods
Sepsis-associated deaths occurring in the United States from 1999 to 2005 were identified in MCOD data using International Classification of Disease, 10th Revision (ICD-10) codes. Population-based mortality rates were calculated using bridged-race population estimates from the National Center for Health Statistics. Comparisons across age, sex and racial/ethnic groups were achieved by calculating mortality rate ratios.

Results
From 1999 to 2005 there were 16,948,482 deaths in the United States. Of these, 1,017,616 were associated with sepsis (6.0% of all deaths). The age-adjusted rate of sepsis-associated mortality was 50.37 deaths per 100,000 (95% confidence interval (CI) = 50.28 to 50.47). There were significant disparities in sepsis-associated mortality in race/ethnicity and sex groups (P < 0.0001). After controlling for age, Asians were less likely than whites to experience sepsis-related death (rate ratio (RR) = 0.78, 95% CI = 0.77 to 0.78), while Blacks (RR = 2.24, 95% CI = 2.23 to 2.24), American Indians/Alaska Natives (RR = 1.24, 95% CI = 1.24 to 1.25) and Hispanics (RR = 1.14, 95% CI = 1.13 to 1.14) were more likely than whites to experience sepsis-related death. Men were at increased risk for sepsis-associated death in all race/ethnicity categories (RR = 1.27, 95% CI = 1.27 to 1.28), but the degree of increased susceptibility associated with being male differed among racial/ethnic groups (P < 0.0001). Although crude sepsis-associated mortality increased by 0.67% per year during the study period (P < 0.0001), the age-adjusted mortality rate decreased by 0.18% per year (P < 0.01).

Conclusions
The rapid rise in sepsis mortality seen in previous decades has slowed, but population ageing continues to drive the growth of sepsis-associated mortality in the United States. Disparities in sepsis-associated mortality mirror those previously reported for sepsis incidence. Sepsis in Asians, Hispanics and American Indian/Alaska Natives should be studied separately because aggregate measures may obscure important differences among these groups.
A CBT-based approach to medically unexplained symptoms
Authors: Kent Catriona , McMillan Graham 
Published: February 2009

SummaryThis article discusses a cognitive–behavioural therapy (CBT) approach to the treatment of medically unexplained symptoms that is based on the ‘five areas’ model of CBT. We describe a typical course of therapy and some of the common problems encountered during treatment. Emphasis is placed on the practical management of these conditions, and the focus is on symptoms as opposed to cause. We believe that this approach is widely applicable and could be used in a large range of settings to tackle these debilitating conditions. In writing this article we intended to provide an overview of patients with medically unexplained symptoms. The article would be of interest to staff within liaison psychiatry departments looking to set up a medically unexplained symptoms service and general psychiatry teams who may have contact with patients presenting with somatic symptoms. Psychiatric teams without access to a liaison department may also find this article interesting.