Management of Septated Malignant Pleural Effusions

Purpose of Review: We review recent studies of patients with septated malignant pleural effusions, to understand what the clinical implications for patients are and what evidence-based methods should be used to manage these effusions. Recent Findings: Fibrinolytics improve effusion size assessed radiologically in patients with a chest drain inserted for septated malignant pleural effusions but this does not translate into an improvement in breathlessness relief or pleurodesis success. Fibrinolytics have also been used in patients with septated effusions associated with indwelling pleural catheters, but dyspnoea relief has not been assessed in this population. Patients with septated effusions or extensive adhesions appear to have a worse prognosis. Summary: Patients with septated malignant pleural effusions have a poor prognosis and do not gain clinical benefit from fibrinolytics via chest drain. The role of fibrinolytics for septated effusions associated with indwelling pleural catheters requires further study

Randomized controlled trial comparing four strategies for delivering e-curriculum to health care professionals [ISRCTN88148532]

BACKGROUND: Internet education is increasingly provided to health professionals, but little is known about the most effective strategies for delivering the content. The purpose of this study is to compare four strategies for delivering an Internet-based (e-) curriculum on clinicians' knowledge (K), confidence (CONF), and communication (COMM) about herbs and other dietary supplements (HDS). METHODS: This national randomized 2 × 2 factorial trial included physicians, pharmacists, nurses, nutritionists and trainees in these fields. Participants were randomly assigned to one of four curriculum delivery strategies for 40 brief modules about HDS: a) delivering four (4) modules weekly over ten (10) weeks by email (drip-push); b) modules accessible on web site with 4 reminders weekly for 10 weeks (drip-pull); c) 40 modules delivered within 4 days by email (bolus-push); and d) 40 modules available on the Internet with one email informing participants of availability (bolus-pull). RESULTS: Of the 1,267 enrollees, 25% were male; the average age was 40 years. The completion rate was 62%, without significant differences between delivery groups. There were statistically significant improvements in K, CONF and COMM scores after the course (P<0.001 for all), although the difference in COMM was small. There were no significant differences in any of the three outcomes by delivery strategy, but outcomes were better for those who paid for continuing education credit. CONCLUSION: All delivery strategies tested similarly improved K, CONF, COMM scores about HDS. Educators can use the strategy that is most convenient without diminishing effectiveness. Additional curricula may be necessary to make substantial changes in clinicians' communication practices

Neonatal umbilical cord blood transplantation halts skeletal disease progression in the murine model of MPS-I

Umbilical cord blood (UCB) is a promising source of stem cells to use in early haematopoietic stem cell transplantation (HSCT) approaches for several genetic diseases that can be diagnosed at birth. Mucopolysaccharidosis type I (MPS-I) is a progressive multi-system disorder caused by deficiency of lysosomal enzyme α-L-iduronidase, and patients treated with allogeneic HSCT at the onset have improved outcome, suggesting to administer such therapy as early as possible. Given that the best characterized MPS-I murine model is an immunocompetent mouse, we here developed a transplantation system based on murine UCB. With the final aim of testing the therapeutic efficacy of UCB in MPS-I mice transplanted at birth, we first defined the features of murine UCB cells and demonstrated that they are capable of multi-lineage haematopoietic repopulation of myeloablated adult mice similarly to bone marrow cells. We then assessed the effectiveness of murine UCB cells transplantation in busulfan-conditioned newborn MPS-I mice. Twenty weeks after treatment, iduronidase activity was increased in visceral organs of MPS-I animals, glycosaminoglycans storage was reduced, and skeletal phenotype was ameliorated. This study explores a potential therapy for MPS-I at a very early stage in life and represents a novel model to test UCB-based transplantation approaches for various diseases

Validation of the SCID-hu Thy/Liv mouse model with four classes of licensed antiretrovirals.

BackgroundThe SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclinical evaluation of antiviral efficacy in vivo. We performed this study to validate the model with representatives of all four classes of licensed antiretrovirals.Methodology/principal findingsEndpoint analyses for quantification of Thy/Liv implant viral load included ELISA for cell-associated p24, branched DNA assay for HIV-1 RNA, and detection of infected thymocytes by intracellular staining for Gag-p24. Antiviral protection from HIV-1-mediated thymocyte depletion was assessed by multicolor flow cytometric analysis of thymocyte subpopulations based on surface expression of CD3, CD4, and CD8. These mice can be productively infected with molecular clones of HIV-1 (e.g., the X4 clone NL4-3) as well as with primary R5 and R5X4 isolates. To determine whether results in this model are concordant with those found in humans, we performed direct comparisons of two drugs in the same class, each of which has known potency and dosing levels in humans. Here we show that second-generation antiretrovirals were, as expected, more potent than their first-generation predecessors: emtricitabine was more potent than lamivudine, efavirenz was more potent than nevirapine, and atazanavir was more potent than indinavir. After interspecies pharmacodynamic scaling, the dose ranges found to inhibit viral replication in the SCID-hu Thy/Liv mouse were similar to those used in humans. Moreover, HIV-1 replication in these mice was genetically stable; treatment of the mice with lamivudine did not result in the M184V substitution in reverse transcriptase, and the multidrug-resistant NY index case HIV-1 retained its drug-resistance substitutions.ConclusionGiven the fidelity of such comparisons, we conclude that this highly reproducible mouse model is likely to predict clinical antiviral efficacy in humans

The quasar feedback survey: discovering hidden Radio-AGN and their connection to the host galaxy ionized gas

We present the first results from the Quasar Feedback Survey, a sample of 42 z 1042.1 ergs s−1) with moderate radio luminosities (i.e. L1.4GHz > 1023.4 W Hz−1; median L1.4GHz = 5.9 × 1023 W Hz−1). Using high spatial resolution (∼0.3–1 arcsec), 1.5–6 GHz radio images from the Very Large Array, we find that 67 per cent of the sample have spatially extended radio features on ∼1–60 kpc scales. The radio sizes and morphologies suggest that these may be lower radio luminosity versions of compact, radio-loud AGNs. By combining the radio-to-infrared excess parameter, spectral index, radio morphology, and brightness temperature, we find radio emission in at least 57 per cent of the sample that is associated with AGN-related processes (e.g. jets, quasar-driven winds, or coronal emission). This is despite only 9.5–21 per cent being classified as radio-loud using traditional criteria. The origin of the radio emission in the remainder of the sample is unclear. We find that both the established anticorrelation between radio size and the width of the [O III] line, and the known trend for the most [O III] luminous AGNs to be associated with spatially extended radio emission, also hold for our sample of moderate radio luminosity quasars. These observations add to the growing evidence of a connection between the radio emission and ionized gas in quasar host galaxies. This work lays the foundation for deeper investigations into the drivers and impact of feedback in this unique sample

Involvement of Noradrenergic Neurotransmission in the Stress- but not Cocaine-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Role for β-2 Adrenergic Receptors

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20–25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, i.p.) or BRL44408 (5, 10 mg/kg, i.p.). To investigate the role of ARs, mice were administered the nonselective β-AR antagonist, propranolol (5, 10 mg/kg, i.p.), the α-1 AR antagonist, prazosin (1, 2 mg/kg, i.p.), or the α-2 AR agonist, clonidine (0.03, 0.3 mg/kg, i.p.) before reinstatement testing. Clonidine, prazosin, and propranolol failed to block cocaine-induced reinstatement. The low (0.03 mg/kg) but not high (0.3 mg/kg) clonidine dose fully blocked FS-induced reinstatement but not reinstatement by yohimbine. Propranolol, but not prazosin, blocked reinstatement by both yohimbine and FS, suggesting the involvement of β-ARs. The β-2 AR antagonist ICI-118551 (1 mg/kg, i.p.), but not the β-1 AR antagonist betaxolol (10 mg/kg, i.p.), also blocked FS-induced reinstatement. These findings suggest that stress-induced reinstatement requires noradrenergic signaling through β-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate

Antarctic ice sheet discharge driven by atmosphere-ocean feedbacks at the Last Glacial Termination.

Reconstructing the dynamic response of the Antarctic ice sheets to warming during the Last Glacial Termination (LGT; 18,000-11,650 yrs ago) allows us to disentangle ice-climate feedbacks that are key to improving future projections. Whilst the sequence of events during this period is reasonably well-known, relatively poor chronological control has precluded precise alignment of ice, atmospheric and marine records, making it difficult to assess relationships between Antarctic ice-sheet (AIS) dynamics, climate change and sea level. Here we present results from a highly-resolved 'horizontal ice core' from the Weddell Sea Embayment, which records millennial-scale AIS dynamics across this extensive region. Counterintuitively, we find AIS mass-loss across the full duration of the Antarctic Cold Reversal (ACR; 14,600-12,700 yrs ago), with stabilisation during the subsequent millennia of atmospheric warming. Earth-system and ice-sheet modelling suggests these contrasting trends were likely Antarctic-wide, sustained by feedbacks amplified by the delivery of Circumpolar Deep Water onto the continental shelf. Given the anti-phase relationship between inter-hemispheric climate trends across the LGT our findings demonstrate that Southern Ocean-AIS feedbacks were controlled by global atmospheric teleconnections. With increasing stratification of the Southern Ocean and intensification of mid-latitude westerly winds today, such teleconnections could amplify AIS mass loss and accelerate global sea-level rise