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The World Health Organization classification of myelodysplastic syndromes (MDS) is based on morphological evaluation of marrow dysplasia. We performed a systematic review of cytological and histological data from 1150 patients with peripheral blood cytopenia. We analyzed the frequency and discriminant power of single morphological abnormalities. A score to define minimal morphological criteria associated to the presence of marrow dysplasia was developed. This score showed high sensitivity/specificity (>90%), acceptable reproducibility and was independently validated. The severity of granulocytic and megakaryocytic dysplasia significantly affected survival. A close association was found between ring sideroblasts and SF3B1 mutations, and between severe granulocytic dysplasia and mutation of ASXL1 , RUNX1 , TP53 and SRSF2 genes. In myeloid neoplasms with fibrosis, multilineage dysplasia, hypolobulated/multinucleated megakaryocytes and increased CD34+ progenitors in the absence of JAK2 , MPL and CALR gene mutations were significantly associated with a myelodysplastic phenotype. In myeloid disorders with marrow hypoplasia, granulocytic and/or megakaryocytic dysplasia, increased CD34+ progenitors and chromosomal abnormalities are consistent with a diagnosis of MDS. The proposed morphological score may be useful to evaluate the presence of dysplasia in cases without a clearly objective myelodysplastic phenotype. The integration of cytological and histological parameters improves the identification of MDS cases among myeloid disorders with fibrosis and hypocellularity.

Background. The purpose of our study was to evaluate the incidence and outcome of invasive fungal infection (IFI) among patients who underwent autologous or allogeneic hematopoietic stem cell transplantation (HSCT) at 11 Italian transplantation centers. Methods. This cohort-retrospective study, conducted during 1999–2003, involved HSCT patients admitted to 11 tertiary care centers or university hospitals in Italy, who developed IFIs (proven or probable). Results. Among 3228 patients who underwent HSCT (1249 allogeneic HSCT recipients and 1979 autologous HSCT recipients), IFI occurred in 121 patients (overall incidence, 3.7%). Ninety-one episodes (2.8% of all patients) were due to molds, and 30 (0.9%) were due to yeasts. Ninety-eight episodes (7.8%) occurred among the 1249 allogeneic HSCT recipients, and 23 (1.2%) occurred among the 1979 autologous HSCT recipients. The most frequent etiological agents were Aspergillus species (86 episodes) and Candida species (30 episodes). The overall mortality rate was 5.7% among allogeneic HSCT recipients and 0.4% among autologous HSCT recipients, whereas the attributable mortality rate registered in our population was 65.3% (72.4% for allogeneic HSCT recipients and 34.7% for autologous HSCT recipients). Etiology influenced the patients' outcomes: the attributable mortality rate for aspergillosis was 72.1% (77.2% and 14.3% for allogeneic and autologous HSCT recipients, respectively), and the rate for Candida IFI was 50% (57.1% and 43.8% for allogeneic and autologous HSCT recipients, respectively). Conclusions. IFI represents a common complication for allogeneic HSCT recipients. Aspergillus species is the most frequently detected agent in these patients, and aspergillosis is characterized by a high mortality rate. Conversely, autologous HSCT recipients rarely develop aspergillosis, and the attributable mortality rate is markedly lower. Candidemia was observed less often than aspergillosis among both allogeneic and autologous HSCT recipients; furthermore, there was no difference in either the incidence of or the attributable mortality rate for candidemia among recipients of the 2 transplant types.

Microdialysis was used to study the acute and chronic effects of escitalopram (S‐citalopram; ESCIT) and chronic citalopram (CIT), together with the 5‐HT1A receptor antagonist WAY100,635 (N‐[2‐[methoxyphenyl)‐1‐piperazinyl]ethyl]‐N‐(2‐pyridinyl) cyclohexane carboxamide trihydrochloride) and the 5‐HT1A receptor agonist 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT), on extracellular 5‐hydroxytryptamine (5‐HT) levels in the rat prefrontal cortex. Extracellular 5‐HT rose to 234 and 298% of basal values after subcutaneous (s.c.) acute doses of 0.15 and 0.63 mg kg−1 ESCIT. No further increase was observed at 2.5 mg kg−1 ESCIT (290%). The effect of 13‐day s.c. infusion of 10 mg kg−1day−1 ESCIT on extracellular 5‐HT (422% of baseline) was greater than after 2 days (257% of baseline), whereas exposure to ESCIT was similar. In contrast, the increase in extracellular 5‐HT induced by the infusion of CIT for 2 (306%) and 13 days (302%) was similar. However, brain and plasma levels of S‐citalopram in rats infused with CIT for 13 days were lower than after 2 days. Acute treatment with 2.5 mg kg−1 ESCIT or 5 mg kg−1 CIT raised extracellular 5‐HT by 243 and 276%, respectively, in rats given chronic vehicle but had no effect in rats given ESCIT (10 mg kg−1 day−1) or CIT (20 mg kg−1 day−1) for 2 or 13 days, suggesting that the infused doses had maximally increased extracellular 5‐HT. WAY100,635 (0.1 mg kg−1 s.c.) increased extracellular 5‐HT levels by 168, 174 and 169% of prechallenge values in rats infused with vehicle or ESCIT for 2 or 13 days, respectively. WAY100,635 enhanced extracellular 5‐HT levels to 226, 153 and 164% of prechallenge values in rats infused with vehicle or CIT for 2 and 13 days, respectively. 8‐OH‐DPAT (0.025 mg kg−1) reduced extracellular 5‐HT by 54% in control rats, but had no effect in those given ESCIT and CIT for 13 days. This series of experiments led to the conclusion that chronic treatment with ESCIT desensitizes the 5‐HT1A receptors, regulating the release of 5‐HT in the prefrontal cortex and enhances the effect of the drug on extracellular 5‐HT. They also indicate that chronic treatment with ESCIT and CIT did not prevent WAY100,635 from raising extracellular 5‐HT. British Journal of Pharmacology (2004) 142, 469–478. doi:10.1038/sj.bjp.0705800

The purpose of this study was to develop a flow cytometric approach to the evaluation of marrow dysplasia in myelodysplastic syndromes (MDS). We first studied a cohort of 103 MDS patients as well as 46 pathological and healthy controls. Flow cytometry data were expressed as percentage of positive cells. Analysis of erythroid cells showed higher proportions of immature cells ( P <0.001) and decreased levels of CD71 expression on nucleated red cells ( P =0.02) in MDS. Analysis of myeloid cells showed lower proportions of CD10+ and higher proportions of CD56+ granulocytes ( P <0.001), and increased ratios of immature to mature cells ( P =0.007). Since no single immunophenotype could accurately differentiate MDS from other conditions, we used discriminant analysis for generating erythroid and myeloid classification functions using combinations of immunophenotypic parameters. These functions were prospectively validated in a testing cohort of 69 MDS patients and 46 pathological controls. A diagnosis of MDS was obtained in 60/69 cases (87%). No false-positive results were noticed among controls. Significant correlations between values of these functions and both degree of morphological dysplasia and the International Prognostic Scoring System were found. These findings indicate that flow cytometry evaluation of marrow dysplasia is feasible and may be useful in the work-up of individual MDS patients.

Circulating endothelial cells (CECs) are associated with neoangiogenesis in various malignant disorders. Using flow cytometry, we studied CECs in 128 patients with myelodysplastic syndrome (MDS). MDS patients had higher CEC levels than controls ( P <0.001), and an inverse relationship was found between CECs and international prognostic scoring system risk ( r =−0.55, P <0.001). There was a positive correlation between marrow microvessel density and CECs, low-risk patients showing the strongest association ( r =0.62, P <0.001). We calculated a progenitor-to-mature CEC ratio, which was higher in MDS patients than in healthy subjects ( P <0.001), the highest values were found at diagnosis. CECs assessed by flow cytometry positively correlated with the ability to produce endothelial colony-forming cells in vitro (ECFCs; r =0.57, P =0.021), which was significantly higher in MDS patients than in controls ( P =0.011). Fluorescence in situ hybridization analysis showed that a variable proportion of CECs (from 40 to 84%) carried the same chromosomal aberration as the neoplastic clone, while endothelial cells isolated from in vitro assays were negative. This study suggests that CECs reflect the abnormal angiogenesis found in MDS, especially in the early stages of the disease. The increased number of functional endothelial progenitor cells in MDS strengthens the rationale for therapeutic interventions aimed at restoring a normal interaction between hematopoietic progenitors and marrow microenvironment.

This study investigated the effect of acute (2 days) and chronic (14 days) treatment with a selective inhibitor of noradrenaline uptake, reboxetine (10 mg kg−1 day−1) by osmotic pumps, on extracellular noradrenaline and the sensitivity of α2‐adrenoceptors in the prefrontal cortex of rats. The effect of continuous infusion of reboxetine for 14 days on cortical extracellular noradrenaline was significantly higher (599% of vehicle levels) than after 2 days (263% of vehicle levels). Brain concentrations of reboxetine after 2 and 14 days of infusion were 37.9±17.8 and 37.1±7.7 ng g−1, respectively. Reboxetine infused for 2 and 14 days significantly increased extracellular dopamine in the prefrontal cortex, to a similar extent (257 and 342% of vehicle levels, respectively), whereas extracellular 5‐HT was not modified by either treatment. Clonidine (10 and 30 μg kg−1 i.p.) reduced cortical extracellular noradrenaline similarly in animals treated with reboxetine or vehicle for 2 days whereas the effects in rats infused with reboxetine for 14 days were markedly less than in vehicle‐treated animals. Clonidine (0.05 and 0.2 μM), infused through the dialysis probe into the prefrontal cortex, reduced cortical extracellular noradrenaline much less in rats treated with reboxetine for 14 days than in vehicle‐treated animals. Reboxetine's effect on extracellular noradrenaline in the prefrontal cortex was greater after chronic treatment and could be associated with desensitization of terminal α2‐adrenoceptors that normally serve to inhibit noradrenaline release. British Journal of Pharmacology (2001) 132, 183–188; doi:10.1038/sj.bjp.0703821

We have evaluated bone marrow morphology, percentage of bone marrow CD34(+) cells, proliferative activity of bone marrow precursors, clonogenic assay (BFU-E and CFU-GM) in short-term bone marrow cultures, and bone marrow cell apoptosis, together with serum TNF-alpha and IL-6, in 16 chronic, refractory RA patients, as well as in five healthy controls. Of 16 RA patients (68.7%), 11 showed a reduced bone marrow cellularity, while it was normal in all the controls. In RA patients, the median percentage of CD34(+) bone marrow cells, the median percentage of proliferating bone marrow myeloid precursors, and the median number of both BFU-E and CFU-GM colonies were significantly lower than observed in the controls. As far as TNF-alpha and IL-6 titers is concerned, the latter did not significantly differ from controls' values, while TNF-alpha titers were significantly lower in healthy controls. Finally, the median apoptotic index of early bone marrow myeloid cells of RA patients was significantly higher compared with controls. These observations may identify the biological risk factors for impaired mobilization and/or engraftment when RA patients are candidates for autologous hematopoietic stem cell grafting.

We examined the association between serum ferritin (SF) levels and patient-reported functional aspects and symptoms, as measured by the EORTC QLQ-C30, in newly diagnosed patients with myelodysplastic syndromes (MDS). Analysis was conducted on 497 MDS patients who were classified in two groups based on the SF value of 1000 ng/mL. Clinically relevant differences of patient-reported functional and symptom scales were evaluated and classified as small, medium and large, based on established thresholds. Multivariable linear regression analysis was performed to account for potential confounding factors. Patients with SF of ≥ 1000 ng/mL reported statistically significant and clinically relevant worse outcomes across various health domains. Dyspnea was the symptom indicating the largest difference and mean scores of patients with higher and lower SF levels were 40 and 24.3, respectively (p = 0.005), indicating a large clinically relevant difference (Δ = 15.7). Further research is needed to better understand the relationship between SF levels and specific health-related quality of life domains.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease of unknown aetiology. There is growing evidence that the lung microbiota may play a role in IPF. However, no study has investigated the functional impact of the short-chain fatty acids (SCFAs) on primary bronchial epithelial cells (PBECs) and disease pathogenesis. Therefore, we investigated the influence of acetate, propionate, and butyrate on PBECs from healthy controls and subjects with IPF.Subjects diagnosed with IPF (n=201) and healthy controls (n=40) were prospectively recruited and underwent bronchoalveolar lavage. Bacterial DNA was isolated and 16S rRNA gene sequencing undertaken to characterise bacterial communities. Untargeted 1H nuclear magnetic resonance spectroscopy-based metabolomics and targeted gas chromatography-mass spectrometry captured the metabolic profile of these samples. PBECs from healthy controls and subjects with IPF were differentiated at air-liquid interface (ALI) and either left untreated or exposed to the SCFAs.The IPF microbiota was less diverse (P<0.01) and had increased proportions of Firmicutes (P<0.01) compared to healthy controls. Streptococcus and Staphylococcus were more abundant in IPF cases than controls (P<0.05). Metabolomics analysis revealed distinct differences between the cohorts. Relative concentrations of the SCFAs were increased in IPF compared to healthy controls, and in IPF, propionate positively correlated with bacterial burden (rho=0.47, P=8 × 10-5). Exposure of healthy and IPF PBECs cultured at ALI to 1 mM of the SCFAs did not impact cell viability. Treatment of PBECs from IPF subjects but not healthy controls with the SCFAs led to morphological changes, a dose-dependent release of pro-inflammatory mediators in the cell supernatant, and a decrease in transepithelial electrical resistance (TEER) over time. Specifically, compared to baseline, exposure of IPF PBECs to 1 mM of propionate led to a 40% reduction in TEER and a 2-fold increase in the secretion of IL-6.Subjects with IPF display an altered microbiome which is associated with a distinct metabolic signature in the lower airways. Differences in specific bacterial genera and an increased bacterial burden in IPF results in changes in the SCFAs in the airways. In vitro work demonstrates the potential of these SCFAs to shape immunological responses in the lung, mediating the pathogenesis of fibrosis.

1. This study investigated the effect of acute (2 days) and chronic (14 days) treatment with a selective inhibitor of noradrenaline uptake, reboxetine (10 mg kg(-1) day(-1)) by osmotic pumps, on extracellular noradrenaline and the sensitivity of alpha(2)-adrenoceptors in the prefrontal cortex of rats. 2. The effect of continuous infusion of reboxetine for 14 days on cortical extracellular noradrenaline was significantly higher (599% of vehicle levels) than after 2 days (263% of vehicle levels). 3. Brain concentrations of reboxetine after 2 and 14 days of infusion were 37.9+/-17.8 and 37.1+/-7.7 ng g(-1), respectively. 4. Reboxetine infused for 2 and 14 days significantly increased extracellular dopamine in the prefrontal cortex, to a similar extent (257 and 342% of vehicle levels, respectively), whereas extracellular 5-HT was not modified by either treatment. 5. Clonidine (10 and 30 microg kg(-1) i.p.) reduced cortical extracellular noradrenaline similarly in animals treated with reboxetine or vehicle for 2 days whereas the effects in rats infused with reboxetine for 14 days were markedly less than in vehicle-treated animals. 6. Clonidine (0.05 and 0.2 microM), infused through the dialysis probe into the prefrontal cortex, reduced cortical extracellular noradrenaline much less in rats treated with reboxetine for 14 days than in vehicle-treated animals. 7. Reboxetine's effect on extracellular noradrenaline in the prefrontal cortex was greater after chronic treatment and could be associated with desensitization of terminal alpha(2)-adrenoceptors that normally serve to inhibit noradrenaline release.