Improvement in breast magnetic resonance imaging after a sentinel procedure for breast cancer with superparamagnetic tracers.

The superparamagnetic iron oxide tracer Sienna+® was introduced as an alternative to the radioisotope 99Tc Nanocoll to preoperatively mark sentinel lymph nodes in breast cancer. As previously reported, this tracer causes susceptibility artifacts on magnetic resonance imaging (MRI), potentially hampering the diagnostic performance of follow-up breast MRI. This short report illustrates the temporal development of these artifacts in a patient who was followed up at 6, 12, and 18 months after administration of Sienna+® with MRI systems of different magnetic field strengths (1.5 T and 3.0 T) and using an MRI protocol with sequences optimized for artifact reduction. Although the artifacts were severe and predominant at the higher magnetic strength in the early postoperative period, they diminished over time and the image quality could be further improved by adapting the sequences. These findings indicate the possible use of MRI even after administration of a superparamagnetic tracer for post-treatment monitoring in breast cancer.

Multimodal ultrasound tomography for breast imaging: a prospective study of clinical feasibility.

BACKGROUND: To describe the clinical set-up and evaluate the feasibility of multimodal ultrasound tomography (MUT) for breast imaging. METHODS: Thirty-two consecutive patients referred for breast imaging and 24 healthy volunteers underwent MUT. In the 32 patients, the examination discomfort was compared to that of mammography (n = 31), handheld ultrasound (HUS) (n = 27) and magnetic resonance imaging (MRI) (n = 4) on a scale from 1 (lowest discomfort) to 10 (highest discomfort). MUT investigation time was recorded. Findings automatically detected by MUT were correlated with conventional imaging and biopsy results. RESULTS: Breast MUT was well tolerated by all 56 participants; 55 bilateral exams were uneventful. During one exam, the digitalisation card failed and the exam was successfully repeated within three days. Mean examination discomfort was 1.6 (range = 1-5) for MUT, 1.5 (range = 1-5) for HUS, 5.3 (range = 3-7) for MRI, and 6.3 (range = 1-10) for mammography. MUT examination time was 38 ± 6 min (mean ± standard deviation). In the patients referred for breast imaging, MUT detected four lesions and indicated malignancy in three of these cases. These findings were confirmed by additional imaging and biopsy. CONCLUSION: MUT is feasible in a clinical context considering examination time and patient acceptance. These interesting initial diagnostic findings warrant further studies.

The Standard Model from LHC to future colliders.

This review summarizes the results of the activities which have taken place in 2014 within the Standard Model Working Group of the "What Next" Workshop organized by INFN, Italy. We present a framework, general questions, and some indications of possible answers on the main issue for Standard Model physics in the LHC era and in view of possible future accelerators.

Neutrophil to lymphocyte ratio (NLR) improves the risk assessment of ISS staging in newly diagnosed MM patients treated upfront with novel agents.

Recent reports identify the ratio between absolute neutrophil count (ANC) and absolute lymphocyte count (ALC), called neutrophil to lymphocyte ratio (NLR), as a predictor of progression-free survival (PFS) and overall survival (OS) in various malignancies. We retrospectively examined the NLR in a cohort of 309 newly diagnosed multiple myeloma (MM) patients treated upfront with novel agents. NLR was calculated using data obtained from the complete blood count (CBC) at diagnosis and subsequently correlated with PFS and OS. The median NLR was 1.9 (range 0.4-15.9). Higher NLR was independent of international staging system (ISS) stage, plasma cell infiltration or cytogenetics. The 5-year PFS and OS estimates were, respectively, 18.2 and 36.4 % for patients with NLR ≥ 2 versus 25.5 and 66.6 % in patients with NLR < 2. Among younger patients (age <65 years, N = 179), NLR ≥ 2 had a negative prognostic impact on both PFS and OS, in all ISS stages. By combining ISS stage and NLR in a model limited to young patients, we found that 19 % of the patients were classified as very low risk, 70 % standard risk and 11 % very high risk. The 5-year estimates were 39.3, 19.4 and 10.9 % for PFS and 95.8, 50.9 and 23.6 % for OS for very low, standard-risk and very high-risk groups. We found NLR to be a predictor of PFS and OS in MM patients treated upfront with novel agents. NLR can be combined with ISS staging system to identify patients with dismal outcome. However, larger cohorts and prospective studies are needed to use NLR as additional parameter to personalise MM therapy in the era of novel agents.

Safety and efficacy of the combination acetaminophen-codeine in the treatment of pain of different origin.

BACKGROUND: Pain is the most common reason people see doctors in developed Countries and a very common cause of access in Emergency Department (ED). The combination acetaminophen/codeine represents the standard medication in the second step of the WHO analgesic scale and codeine is one of the most commonly used opioid analgesic for a variety of pain conditions. However, many aspects related to safety and efficacy are still undefined. AIM: To summarize and review the results of the most relevant studies on the efficacy and safety profile of acetaminophen/codeine combination in the treatment of pain of different origin. MATERIALS AND METHODS: We performed a literature search to identify and evaluate all relevant english-language randomized controlled trials (RCTs), meta-analyses and reviews about the codeine plus paracetamol combination in the treatment of pain from any source. RESULTS: Acetaminophen/codeine combination is effective in the treatment of moderate to severe pain in all setting analyzed in this study, which include headache, postoperative, osteoarticular and post-traumatic. The best results in terms of safety and efficacy have been obtained in postoperative pain. Efficacy of acetaminophen/codeine combination is not inferior to NSAIDs. CONCLUSIONS: Acetaminophen/codeine combination is effective in the treatment of pain, through a synergistic action of the two molecules, and is not inferior to NSAIDs. Side effects of acetaminophen/codeine are usually minor, differently from NSAIDs, which may induce some potentially life threatening conditions.

Intravenous injection of bortezomib, melphalan and dexamethasone in refractory and relapsed multiple myeloma.

BACKGROUND: A combination of bortezomib (1.3 mg/m(2)), melphalan (5 mg/m(2)), and dexamethasone (40 mg) (BMD), with all three drugs given as a contemporary intravenous administration, was retrospectively evaluated. PATIENTS AND METHODS: Fifty previously treated (median 2 previous lines) patients with myeloma (33 relapsed and 17 refractory) were assessed. The first 19 patients were treated with a twice-a-week (days 1, 4, 8, 11, 'base' schedule) administration while, in the remaining 31 patients, the three drugs were administered once a week (days 1, 8, 15, 22, 'weekly' schedule). RESULTS: Side-effects were predictable and manageable, with prominent haematological toxicity, and a better toxic profile in 'weekly' schedule (36% versus 66% in 'base' schedule). The overall response rate was 62%. After median follow-up of 24.5 months (range 2.7-50 months), the median progression-free survival (PFS) was 21.6 with no difference between the two schedules and the median overall survival (OS) was 33.8 months. Independently from the adopted schedule, we found that also in a cohort of relapsed/refractory patients achieving at least partial remission improved PFS (35.2 versus 9 months) and OS (unreached median versus 18 months). CONCLUSION: Taken together, our observations suggest that BMD is an effective regimen in advanced myeloma patients with acceptable toxicity.

Analysis of the combined action of miR-143 and miR-145 on oncogenic pathways in colorectal cancer cells reveals a coordinate program of gene repression.

MicroRNAs (miRNAs) from the gene cluster miR-143-145 are diminished in cells of colorectal tumor origin when compared with normal colon epithelia. Until now, no report has addressed the coordinate action of these miRNAs in colorectal cancer (CRC). In this study, we performed a comprehensive molecular and functional analysis of the miRNA cluster regulatory network. First, we evaluated proliferation, migration, anchorage-independent growth and chemoresistance in the colon tumor cell lines after miR-143 and miR-145 restoration. Then, we assessed the contribution of single genes targeted by miR-143 and miR-145 by reinforcing their expression and checking functional recovery. Restoring miR-143 and miR-145 in colon cancer cells decreases proliferation, migration and chemoresistance. We identified cluster of differentiation 44 (CD44), Kruppel-like factor 5 (KLF5), Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) as proteins targeted by miR-143 and miR-145. Their re-expression can partially revert a decrease in transformation properties caused by the overexpression of miR-143 and miR-145. In addition, we determined a set of mRNAs that are diminished after reinforcing miR-143 and miR-145 expression. The whole transcriptome analysis ascertained that downregulated transcripts are enriched in predicted target genes in a statistically significant manner. A number of additional genes, whose expression decreases as a direct or indirect consequence of miR-143 and miR-145, reveals a complex regulatory network that affects cell signaling pathways involved in transformation. In conclusion, we identified a coordinated program of gene repression by miR-143 and miR-145, in CRC, where either of the two miRNAs share a target transcript, or where the target transcripts share a common signaling pathway. Major mediators of the oncosuppression by miR-143 and miR-145 are genes belonging to the growth factor receptor-mitogen-activated protein kinase network and to the p53 signaling pathway.

Changes in cerebrospinal fluid magnesium levels in patients undergoing spinal anaesthesia for hip arthroplasty: does intravenous infusion of magnesium sulphate make any difference? A prospective, randomized, controlled study.

BACKGROUND: Most investigators have attributed the reduced postoperative pain or anaesthetic drug requirements in patients receiving i.v. magnesium sulphate (MgSO(4)) infusion during spinal or general anaesthesia to central N-methyl-d-aspartate (NMDA) receptor magnesium (Mg) activity. In this study, we investigated how cerebrospinal fluid (CSF) Mg concentrations change after spinal anaesthesia, and whether peripherally infusing MgSO(4) influences central Mg levels. METHODS: Forty-five patients undergoing continuous spinal anaesthesia for hip arthroplasty were randomly assigned to receive either i.v. MgSO(4) at a dose of 50 mg kg(-1) diluted in 100 ml 0.9% saline solution followed by 15 mg kg(-1) h(-1) for 6 h or saline at the same volume [mean (sd) 64 (10) ml]. The changes in CSF and serum total and ionized Mg concentrations were assessed at six time points before and after spinal anaesthesia. Secondary outcome variables included serum and CSF electrolytes and proteins. RESULTS: Thirty-five patients completed the study. We found that spinal anaesthesia reduced total and ionized Mg concentrations in CSF by about 10%. Increasing serum Mg concentration over 80% of the baseline value left CSF Mg levels unchanged. CONCLUSIONS: Spinal anaesthesia unexpectedly reduced CSF total and ionized Mg concentrations in patients undergoing hip arthroplasty, although the mechanism is unclear. The dose used for peripheral MgSO(4) infusion in this study had no influence on central Mg concentrations in neurologically healthy patients undergoing spinal anaesthesia. If CSF Mg concentration is a reliable marker of Mg brain bioavailability, peripherally infused MgSO(4) during spinal anaesthesia is unlikely to influence central NMDA receptor activity.

miRò: a miRNA knowledge base.

miRò is a web-based knowledge base that provides users with miRNA-phenotype associations in humans. It integrates data from various online sources, such as databases of miRNAs, ontologies, diseases and targets, into a unified database equipped with an intuitive and flexible query interface and data mining facilities. The main goal of miRò is the establishment of a knowledge base which allows non-trivial analysis through sophisticated mining techniques and the introduction of a new layer of associations between genes and phenotypes inferred based on miRNAs annotations. Furthermore, a specificity function applied to validated data highlights the most significant associations. The miRò web site is available at: http://ferrolab.dmi.unict.it/miro.Database URL:http://ferrolab.dmi.unict.it/miro.

Pulmonary masses in a patient with blue-gray cutaneous hyperpigmentation.

Authors describe a case of pulmonary masses and estensive skin pigmentation: "blue-gray syndrome" occurred in a patient in amiodarone therapy who presented with progressive dyspnea, cough, and fever. The diagnosis was suspected by detection of a high attenuation of the pulmonary masses on the nonenhanced chest computed tomography (CT) and lots of foamy macrophages in the bronchoalveolar lavage fluid. Relief of respiratory symptoms and radiological improvement was achieved when amiodarone treatment was stopped.

The l2 minor capsid protein of low-risk human papillomavirus type 11 interacts with host nuclear import receptors and viral DNA.

Analysis of the interactions of low-risk human papillomavirus type 11 (HPV11) L2 with karyopherin beta (Kap beta) nuclear import receptors revealed that L2 interacted with Kap beta 1, Kap beta 2, and Kap beta 3 and formed a complex with the Kap alpha 2 beta 1 heterodimer. HPV11 L2 contains two nuclear localization signals (NLSs)-in the N terminus and the C terminus-that could mediate its nuclear import via a classical pathway. Each NLS was functional in vivo, and deletion of both of them abolished L2 nuclear localization. Both NLSs interacted with the viral DNA. Thus, HPV11 L2 can interact with several karyopherins and the viral DNA and may enter the nucleus via multiple pathways.

N-Acetylcysteine counteracts erythrocyte alterations occurring in chronic obstructive pulmonary disease.

A key role has been proposed for reactive oxygen species (ROS) in chronic obstructive pulmonary disease (COPD). Aim of the present work was to evaluate possible implications of ROS in the integrity and function of the cell type mainly involved in oxygen uptake and delivery to the peripheral tissues: the erythrocyte. Red blood cells (RBCs) were thus collected from blood samples from COPD patients. Furthermore, blood samples from the same patients treated with the antioxidizing drug of widespread use in such disease i.e., N-acetylcysteine (NAC), were also considered. Morphometric and analytical cytology studies were then conducted. We report herein that: (i) alterations of RBC ultrastructure were detectable in RBCs from COPD patients, that (ii) relevant changes of spectrin cytoskeleton and glycophorin expression were also found and that (iii) NAC treatment was capable of significantly counteracting these changes. These results are consistent with a reappraisal of the role of RBCs in this disease.

Ventilatory and metabolic adaptations to walking and cycling in patients with COPD.

To test the hypothesis that in chronic obstructive pulmonary disease (COPD) patients the ventilatory and metabolic requirements during cycling and walking exercise are different, paralleling the level of breathlessness, we studied nine patients with moderate to severe, stable COPD. Each subject underwent two exercise protocols: a 1-min incremental cycle ergometer exercise (C) and a "shuttle" walking test (W). Oxygen uptake (VO(2)), CO(2) output (VCO(2)), minute ventilation (VE), and heart rate (HR) were measured with a portable telemetric system. Venous blood lactates were monitored. Measurements of arterial blood gases and pH were obtained in seven patients. Physiological dead space-tidal volume ratio (VD/VT) was computed. At peak exercise, W vs. C VO(2), VE, and HR values were similar, whereas VCO(2) (848 +/- 69 vs. 1,225 +/- 45 ml/min; P < 0. 001) and lactate (1.5 +/- 0.2 vs. 4.1 +/- 0.2 meq/l; P < 0.001) were lower, DeltaVE/DeltaVCO(2) (35.7 +/- 1.7 vs. 25.9 +/- 1.3; P < 0. 001) and DeltaHR/DeltaVO(2) values (51 +/- 3 vs. 40 +/- 4; P < 0.05) were significantly higher. Analyses of arterial blood gases at peak exercise revealed higher VD/VT and lower arterial partial pressure of oxygen values for W compared with C. In COPD, reduced walking capacity is associated with an excessively high ventilatory demand. Decreased pulmonary gas exchange efficiency and arterial hypoxemia are likely to be responsible for the observed findings.

Attenuation of human immunodeficiency virus type 1 cytopathic effects by replacing a 424-bp region of envelope from a noncytopathic biological clone.

We analyzed the env genes of cytopathic and noncytopathic biological clones derived from two HIV-1-infected children with discordant clinical courses. Chimeric viruses were constructed by switching env regions from V2 through V3 of the biological clones with the corresponding region from the molecular clone NL4-3. These HIV-1 chimeric viruses exhibited similar replication kinetics as well as syncytium-inducing abilities. The chimeric virus containing the env region of noncytopathic biological clone, GC6 8-4, was noncytopathic in an in vitro cell-killing assay, while the chimeric virus containing the env region of cytopathic biological clone, HC4, was cytopathic in the in vitro cell-killing assay. These studies suggest the presence of a cytopathicity determinant that maps to the envelope sequences contained within the downstream region of V2 and within the V3 region (nucleotide position 6822 to nucleotide position 7250, based on NL4-3 sequence).

Pulmonary gas exchange and exercise capacity in patients with systemic lupus erythematosus.

OBJECTIVE: Exercise tolerance is often reduced in patients with systemic lupus erythematosus (SLE). Mechanisms have been proposed but the underlying causes have not yet been elucidated. The study of pulmonary gas exchange during exercise may be helpful in revealing circulatory, ventilatory, and metabolic abnormalities. We hypothesized that in SLE, exercise aerobic capacity would be reduced due to chronic inactivity and poor muscle energetics. METHODS: Thirteen women with SLE and low disease activity were studied; 5 age matched subjects served as controls. Clinical examination, chest radiography, electrocardiogram, and pulmonary function test were all normal. Subjects underwent 1 min incremental cycle ergometer exercise to exhaustion. Oxygen uptake (VO2), CO2 output (VCO2), minute ventilation (VE), heart rate (HR), and arterial O2 saturation were monitored. Anaerobic threshold (AT), VO2/HR, deltaVO2/deltaWatt, respiratory rate (RR), Ti/Ttot, VE/VCO2, and breathing reserve (BR) were computed. RESULTS: At rest, patients exhibited high VE, respiratory alkalosis, and a wide alveolar-arterial O2 gradient [(A - a)O2] during 50% O2 breathing. Other indexes of respiratory function were within the normal range. In the 6 patients with SLE where pulmonary artery systolic pressure at Doppler echocardiography was measurable, mean level was in the upper limits of normal. During exercise, maximal aerobic capacity was reduced in all patients (VO2 peak, 1098+/-74 vs. 2150+/-160 ml/min, p<0.01; AT, 36 +/-3 vs. 48+/-3% predicted VO2 max, p<0.05). Ventilation adjusted for the metabolic demand (VE/VCO2 at AT) was increased (31+/-1 vs. 24+/-1; p<0.05). A normal breathing pattern was observed during all tests. No patient stopped exercising because of ventilatory limitation (i.e., they had normal breathing reserve). CONCLUSION: Reduced muscle aerobic capacity is common in SLE and is most likely because of peripheral muscle deconditioning. Increased ventilatory demand, secondary to diffuse interstitial lung disease, is not a significant contributor to the reduction in exercise tolerance.

Effect of reduced body weight on muscle aerobic capacity in patients with COPD.

BACKGROUND: Reduced muscle aerobic capacity in COPD patients has been demonstrated in several laboratories by phosphorus magnetic resonance spectroscopy and by analysis of oxygen uptake (VO2) kinetics. COPD patients are usually elderly, hypoxemic, poorly active with muscle atrophy, and often malnourished. Under these conditions there is usually reduction of O2 delivery to the tissues (bulk O2 flow), redistribution of fiber type within the muscle, capillary rarefaction, and decreased mitochondrial function, alterations all capable of reducing muscle aerobic capacity. In COPD, the effect of reduced body mass on muscle aerobic capacity has not been investigated (to our knowledge). METHODS: We studied 24 patients with stable COPD with moderate-to-severe airway obstruction (68+/-5 [SD] years; FEV1, 39+/-12% predicted; PaO2, 66+/-8 mm Hg; PaCO2, 41+/-3 mm Hg) with poor to normal nutritional status, as indicated by a low-normal percent of ideal body weight (IBW). Each subject first underwent 1-min maximal incremental cycle ergometer exercise for determination of VO2 peak and lactate threshold (LT). Subsequently, they performed a 10-min moderate (80% of LT-VO2) constant load exercise for determination of oxygen deficit (O2DEF) and mean response time VO2 (MRT). VO2, CO2 output (VCO2), and minute ventilation were measured breath by breath. RESULTS: Patients displayed low VO2 peak (1,094+/-47 [SE] mL/min), LT-VO2 (35+/-3% predicted O2 max), and higher MRT-VO2 (67+/-4 s). Univariate regression analysis showed that percent of IBW correlated with indexes of maximal and submaximal aerobic capacity: vs VO2 peak, R=0.53 (p<0.01); vs MRT R=-0.77 (p<0.001). Using stepwise regression analysis, MRT correlated (R2=-0.70) with percent of IBW (p<0.01) and with PaO2 (p<0.05). CONCLUSIONS: Reduced body mass has an independent negative effect on muscle aerobic capacity in COPD patients: this effect may explain the variability in exercise tolerance among patients with comparable ventilatory limitation.

Microleakage of super-EBA with and without finishing as determined by the fluid filtration method.

Super-EBA (SEBA) has been used as a root-end filling material because of its superior sealing properties and clinical success. The purpose of this study was to evaluate whether finishing SEBA after it had set would affect the apical seal. Sixty-five extracted maxillary anterior teeth were instrumented and obturated with a single gutta-percha master cone. The root end was resected, and a 3 mm deep root-end preparation was made using ultrasonic tips. Teeth were randomly divided into three groups. Group 1 received SEBA and was finished with a 30-flute high-speed finishing bur. Group 2 received SEBA, which was cold-burnished with a ball burnisher. Temporary Endodontic Restorative Material was used as the negative control in group 3. Microleakage (microliter/min) was measured under 10 psi using the fluid filtration method at days 1, 7, 30, 90, and 180. SEBA/finished exhibited significant microleakage at day 1 when compared with the burnished group. The differences in leakage were not significant at any other time period.

In vitro characterization of HIV type 1 biological clones from asymptomatic and symptomatic pediatric patients.

To investigate the mechanisms of HIV-1 cytopathogenicity, functional biological HIV-1 clones were isolated from two infected children with high viral loads in vivo. Clone HC4 was isolated from a symptomatic child and clone GC6 8-4 was isolated from an asymptomatic child. These clones were characterized for their ability to induce syncytia, and to replicate and induce single-cell death in peripheral blood-derived normal CD4 T cell cultures containing anti-CD4 antibody. Despite similar viral loads as determined by p24 antigen production or viral RNA expression, GC6 8-4 was noncytopathogenic and HC4 was cytopathogenic. Since we had demonstrated that mitochondrial dysfunction correlated with HIV-1-induced cell death, we determined whether the cytopathogenic HC4 clone decreased mitochondrial viability using a mitochondrial-specific dye, rhodamine-123. Following infection, mitochondrial viability decreased in cells infected with HC4 by day 4 and continued to decline through day 7 when compared to uninfected cells. By day 7 postinfection, greater than 80% of the cells in culture were dead. Similar analyses on CD4 T cells infected with the noncytopathogenic GC6 8-4 demonstrated that mitochondria remained functionally viable and > 90% of the cells excluded trypan blue. These studies describe a cell culture system to study single-cell death in the absence of syncytia and secondary infection. Results with two patient-derived HIV-1 biological clones suggest that loss of mitochondrial viability may play a role in HIV-1-induced cytopathogenicity.

Nutritional state and exercise tolerance in patients with COPD.

We hypothesized that in patients with COPD, poor nutritional status adversely influences exercise tolerance by limiting aerobic capacity of exercising muscles. In 28 patients with stable COPD, we correlated nutritional status with gas exchange indexes obtained during maximal incremental cycle ergometer exercise and with respiratory function parameters. On the basis of percent of ideal body weight (%IBW), patients were divided into three groups (GP): GP1 (n = 8, %IBW < 90); GP2 (n = 13, %IBW > or = 90 < 110); and GP3 (n = 7, %IBW > or = 110). When compared with normally nourished individuals (GPs 2 and 3), malnourished GP1 patients showed greater reduction in maximal workload and in peak O2 uptake (VO2 peak), with earlier onset of metabolic acidosis (anaerobic threshold [AT]); in addition, indexes reflecting O2 cost of ventilation were higher in GP1. Nutritional status could be correlated with exercise tolerance (VO2 peak, r = 0.82, p < 0.0001), with onset of metabolic acidosis (AT, r = 0.69, p < 0.0001) and with dead space/tidal volume ratio (VD/VT, r = -0.59, p < 0.001). Body weight was inversely correlated with indexes that are likely to reflect the increase in O2 cost of ventilation. We conclude that in patients with stable COPD, (1) malnutrition significantly affects muscle aerobic capacity and exercise tolerance, and (2) high wasted ventilation and O2 cost of ventilation may be responsible for the weight loss.