Clinical and laboratory features of children with community-acquired pneumonia are associated with distinct radiographic presentations

Chest radiographs from children with community-acquired pneumonia (CAP) were categorized into three distinct presentations and each presentation was correlated to clinical and laboratory findings. Children < 59 months with CAP presenting to pediatric emergency rooms during two years were enrolled prospectively in eight centers across Europe. Clinical and laboratory data were documented and radiographs obtained from patients. Of the 1107 enrolled patients, radiographs were characterized as 74.9% alveolar CAP, 8.9% non-alveolar CAP, and 16.3% clinical CAP. Alveolar CAP patients had significantly higher rates of fever (90.7%), vomiting (27.6%), and abdominal pain (18.6%), while non-alveolar CAP patients presented more with cough (96.9%). A model using independent parameters that characterize alveolar, non-alveolar, and clinical CAP demonstrated that alveolar CAP patients were significantly older (OR = 1.02) and had significantly lower oxygen saturation than non-alveolar CAP patients (OR = 0.54). Alveolar CAP patients had significantly higher mean WBC (17,760 ± 8539.68 cells/mm3) and ANC (11.5 ± 7.5 cells/mm3) than patients categorized as non-alveolar CAP (WBC 15,160 ± 5996 cells/mm3, ANC 9.2 ± 5.1 cells/mm3) and clinical CAP (WBC 13,180 ± 5892, ANC 7.3 ± 4.7). CONCLUSION: Alveolar CAP, non-alveolar CAP, and clinical CAP are distinct entities differing not only by chest radiographic appearance but also in clinical and laboratory characteristics. Alveolar CAP has unique characteristics, which suggest association with bacterial etiology

Predictive factors for skeletal complications in hormone-refractory prostate cancer patients with metastatic bone disease

Factors predictive of skeletal-related events (SREs) in bone metastatic prostate cancer patients with hormone-refractory disease were investigated. We evaluated the frequency of SREs in 200 hormone-refractory patients consecutively observed at our Institution and followed until death or the last follow-up. Baseline parameters were evaluated in univariate and multivariate analysis as potential predictive factors of SREs. Skeletal-related events were observed in 86 patients (43.0%), 10 of which (5.0%) occurred before the onset of hormone-refractory disease. In univariate analysis, patient performance status (P=0.002), disease extent (DE) in bone (P=0.0001), bone pain (P=0.0001), serum alkaline phosphatase (P=0.0001) and urinary N-telopeptide of type one collagen (P=0.0001) directly correlated with a greater risk to develop SREs, whereas Gleason score at diagnosis, serum PSA, Hb, serum albumin, serum calcium, types of bone lesions and duration of androgen deprivation therapy did not. Both DE in bone (hazard ratio (HR): 1.16, 95% confidence interval (CI): 1.07–1.25, P=0.000) and pain score (HR: 1.13, 95% CI: 1.06–1.20, P=0.000) were independent variables predicting for the onset of SREs in multivariate analysis. In patients with heavy tumour load in bone and great bone pain, the percentage of SREs was almost twice as high as (26 vs 52%, P<0.02) and occurred significantly earlier (P=0.000) than SREs in patients with limited DE in bone and low pain. Bone pain and DE in bone independently predict the occurrence of SREs in bone metastatic prostate cancer patients with hormone-refractory disease. These findings could help physicians in tailoring the skeletal follow-up most appropriate to individual patients and may prove useful for stratifying patients enrolled in bisphosphonate clinical trials

EUCAARI ion spectrometer measurements at 12 European sites – analysis of new particle formation events

We present comprehensive results on continuous atmospheric cluster and particle measurements in the size range ~1–42 nm within the European Integrated project on Aerosol Cloud Climate and Air Quality interactions (EUCAARI) project. We focused on characterizing the spatial and temporal variation of new particle formation events and relevant particle formation parameters across Europe. Different types of air ion and cluster mobility spectrometers were deployed at 12 field sites across Europe from March 2008 to May 2009. The measurements were conducted in a wide variety of environments, including coastal and continental locations as well as sites at different altitudes (both in the boundary layer and the free troposphere). New particle formation events were detected at all of the 12 field sites during the year-long measurement period. From the data, nucleation and growth rates of newly formed particles were determined for each environment. In a case of parallel ion and neutral cluster measurements, we could also estimate the relative contribution of ion-induced and neutral nucleation to the total particle formation. The formation rates of charged particles at 2 nm accounted for 1–30% of the corresponding total particle formation rates. As a significant new result, we found out that the total particle formation rate varied much more between the different sites than the formation rate of charged particles. This work presents, so far, the most comprehensive effort to experimentally characterize nucleation and growth of atmospheric molecular clusters and nanoparticles at ground-based observation sites on a continental scale

CD4 recovery following antiretroviral treatment interruptions in children and adolescents with HIV infection in Europe and Thailand

Objectives: The aim of the study was to explore factors associated with CD4 percentage (CD4%) reconstitution following treatment interruptions (TIs) of antiretroviral therapy (ART). Methods: Data from paediatric HIV-infected cohorts across 17 countries in Europe and Thailand were pooled. Children on combination ART (cART; at least three drugs from at least two classes) for > 6 months before TI of ≥ 30 days while aged < 18 years were included. CD4% at restart of ART (r-ART) and in the long term (up to 24 months after r-ART) following the first TI was modelled using asymptotic regression. Results: In 779 children with at least one TI, the median age at first TI was 10.1 [interquartile range (IQR) 6.4, 13.6] years and the mean CD4% was 27.3% [standard deviation (SD) 11.0%]; the median TI duration was 9.0 (IQR 3.5, 22.5) months. In regression analysis, the mean CD4% was 19.2% [95% confidence interval (CI) 18.3, 20.1%] at r-ART, and 27.1% (26.2, 27.9%) in the long term, with half this increase in the first 6 months. r-ART and long-term CD4% values were highest in female patients and in children aged < 3 years at the start of TI. Long-term CD4% was highest in those with a TI lasting 1 to <3 months, those with r-ART after year 2000 and those with a CD4% nadir ≥ 25% (all P < 0.001). The effect of CD4% nadir during the TI differed significantly (P = 0.038) by viral suppression at the start of the TI; in children with CD4% nadir < 15% during TI, recovery was better in those virally suppressed prior to the TI; viral suppression was not associated with recovery in children with CD4% nadir ≥ 25%. Conclusions: After restart of ART following TI, most children reconstituted well immunologically. Nevertheless, several factors predicted better immunological reconstitution, including younger age and higher nadir CD4% during TI

Quantitative Analysis of Histone Modifications: Formaldehyde Is a Source of Pathological N6-Formyllysine That Is Refractory to Histone Deacetylases

Aberrant protein modifications play an important role in the pathophysiology of many human diseases, in terms of both dysfunction of physiological modifications and the formation of pathological modifications by reaction of proteins with endogenous electrophiles. Recent studies have identified a chemical homolog of lysine acetylation, N[superscript 6]-formyllysine, as an abundant modification of histone and chromatin proteins, one possible source of which is the reaction of lysine with 3′-formylphosphate residues from DNA oxidation. Using a new liquid chromatography-coupled to tandem mass spectrometry method to quantify all N[superscript 6]-methyl-, -acetyl- and -formyl-lysine modifications, we now report that endogenous formaldehyde is a major source of N[superscript 6]-formyllysine and that this adduct is widespread among cellular proteins in all compartments. N[superscript 6]-formyllysine was evenly distributed among different classes of histone proteins from human TK6 cells at 1–4 modifications per 10[superscript 4] lysines, which contrasted strongly with lysine acetylation and mono-, di-, and tri-methylation levels of 1.5-380, 5-870, 0-1400, and 0-390 per 10[superscript 4] lysines, respectively. While isotope labeling studies revealed that lysine demethylation is not a source of N[superscript 6]-formyllysine in histones, formaldehyde exposure was observed to cause a dose-dependent increase in N[superscript 6]-formyllysine, with use of [[superscript 13]C,[superscript 2]H[subscript 2]]-formaldehyde revealing unchanged levels of adducts derived from endogenous sources. Inhibitors of class I and class II histone deacetylases did not affect the levels of N[superscript 6]-formyllysine in TK6 cells, and the class III histone deacetylase, SIRT1, had minimal activity (<10%) with a peptide substrate containing the formyl adduct. These data suggest that N[superscript 6]-formyllysine is refractory to removal by histone deacetylases, which supports the idea that this abundant protein modification could interfere with normal regulation of gene expression if it arises at conserved sites of physiological protein secondary modification

Early hCG addition to rFSH for ovarian stimulation in IVF provides better results and the cDNA copies of the hCG receptor may be an indicator of successful stimulation

A simple, safe and cost-effective treatment protocol in ovarian stimulation is of great importance in IVF practice, especially in the case of previous unsuccessful attempts. hCG has been used as a substitute of LH because of the degree of homology between the two hormones. The main aim of this prospective randomized study was to determine, for the first time, whether low dose hCG added to rFSH for ovarian stimulation could produce better results compared to the addition of rLH in women entering IVF-ET, especially in those women that had previous IVF failures. An additional aim was to find an indicator that would allow us to follow-up ovarian stimulation and, possibly, modify it in order to achieve a better IVF outcome; and that indicator may be the cDNA copies of the LH/hCG receptor. Group A patients (n = 58) were administered hCG and Group B rLH (n = 56) in addition to rFSH in the first days of ovarian stimulation. The number of follicles and oocytes and, most importantly, implantation and pregnancy rates were shown to be statistically significantly higher in the hCG group. This study has also determined, for the first time to our best knowledge, m-RNA for LH/hCG receptors in the lymphocytes of peripheral blood 40 h before ovum pick-up. cDNA levels of the hCG receptor after ovarian stimulation were significantly higher among women receiving hCG compared to those receiving LH. In addition, higher levels were encountered among women with pregnancy compared to those without, although this was not statistically significant due to the small number of pregnancies. It seems that hCG permits a highly effective and more stable occupancy of rLH/hCG receptors and gives more follicles and more oocytes. The determination of cDNA copies could be, in the future, a marker during ovulation induction protocols and of course a predictor for the outcome of ART in the special subgroup of patients with previous failures

A tool for examining the role of the zinc finger myelin transcription factor 1 (Myt1) in neural development: Myt1 knock-in mice

The Myt1 family of transcription factors is unique among the many classes of zinc finger proteins in how the zinc-stabilized fingers contact the DNA helix. To examine the function of Myt1 in the developing nervous system, we generated mice in which Myt1 expression was replaced by an enhanced Green Fluorescent Protein fused to a Codon-improved Cre recombinase as a protein reporter. Myt1 knock-in mice die at birth, apparently due to improper innervation of their lungs. Elimination of Myt1 did not significantly affect the number or distribution of neural precursor cells that normally express Myt1 in the embryonic spinal cord. Nor was the general pattern of differentiated neurons altered in the embryonic spinal cord. The Myt1 knock-in mice should provide an important tool for identifying the in vivo targets of Myt1 action and unraveling the role of this structurally distinct zinc finger protein in neural development

PF-05280014 (a trastuzumab biosimilar) plus paclitaxel compared with reference trastuzumab plus paclitaxel for HER2-positive metastatic breast cancer: a randomised, double-blind study

BACKGROUND: This randomised, double-blind study compared PF-05280014 (a trastuzumab biosimilar) with reference trastuzumab (Herceptin®) sourced from the European Union (trastuzumab-EU), when each was given with paclitaxel as first-line treatment for HER2-positive metastatic breast cancer. METHODS: Between 4 April 2014 and 22 January 2016, 707 participants were randomised 1:1 to receive intravenous PF-05280014 plus paclitaxel (PF-05280014 group; n = 352) or trastuzumab-EU plus paclitaxel (trastuzumab-EU group; n = 355). PF-05280014 or trastuzumab-EU was administered weekly (first dose 4 mg/kg, subsequent doses 2 mg/kg), with the option to change to a 3-weekly regimen (6 mg/kg) from Week 33. Treatment with PF-05280014 or trastuzumab-EU could continue until disease progression. Paclitaxel (starting dose 80 mg/m2 ) was administered on Days 1, 8 and 15 of 28-day cycles for at least six cycles or until maximal benefit of response. The primary endpoint was objective response rate (ORR), evaluating responses achieved by Week 25 and confirmed by Week 33, based on blinded central radiology review. RESULTS: The risk ratio for ORR was 0.940 (95% CI: 0.842–1.049). The 95% CI fell within the pre-specified equivalence margin of 0.80–1.25. ORR was 62.5% (95% CI: 57.2–67.6%) in the PF-05280014 group and 66.5% (95% CI: 61.3–71.4%) in the trastuzumab-EU group. As of data cut-off on 11 January 2017 (using data up to 378 days post-randomisation), there were no notable differences between groups in progression-free survival (median: 12.16 months in the PF-05280014 group vs. 12.06 months in the trastuzumab-EU group; 1-year rate: 54% vs. 51%) or overall survival (median: not reached in either group; 1-year rate: 89.31% vs. 87.36%). Safety outcomes and immunogenicity were similar between the treatment groups. CONCLUSION: When given as first-line treatment for HER2-positive metastatic breast cancer, PF-05280014 plus paclitaxel demonstrated equivalence to trastuzumab-EU plus paclitaxel in terms of ORR. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT0198967