Management of polycythaemia vera: a critical review of current data

Polycythaemia vera (PV) is a chronic blood cancer; its clinical features are dominated by myeloproliferation (erythrocytosis, often leucocytosis and/or thrombocytosis) and a tendency for thrombosis and transformation to myelofibrosis or acute myeloid leukaemia. In the past 10 years the pathophysiology of this condition has been defined as JAK/STAT pathway activation, almost always due to mutations in JAK2 exons 12 or 14 (JAK2 V617F). In the same time period our understanding of the optimal management of PV has expanded, most recently culminating in the approval of JAK inhibitors for the treatment of PV patients who are resistant or intolerant to therapy with hydroxycarbamide. It has also been demonstrated that life expectancy for many patients with PV is not normal, nor is their quality of life. We critically explore these findings and discuss their impact. In addition, we highlight persisting gaps in our current management strategy; for example, what is the optimal first line cytoreductive therapy and, indeed, which patients need cytoreductive drugs.

Plasma levels of intermedin (adrenomedullin-2) in healthy human volunteers and patients with heart failure

Intermedin/adrenomedullin-2 (IMD) is a member of the adrenomedullin/CGRP peptide family. Less is known about the distribution of IMD than for other family members within the mammalian cardiovascular system, particularly in humans. The aim was to evaluate plasma IMD levels in healthy subjects and patients with chronic heart failure. IMD and its precursor fragments, preproIMD25–56 and preproIMD57–92, were measured by radioimmunoassay in 75 healthy subjects and levels of IMD were also compared to those of adrenomedullin (AM) and mid-region proadrenomedullin45–92 (MRproAM45–92) in 19 patients with systolic heart failure (LVEF < 45%). In healthy subjects, plasma levels (mean + SE) of IMD (6.3 + 0.6 pg ml−1) were lower than, but correlated with those of AM (25.8 + 1.8 pg ml−1; r = 0.49, p < 0.001). Plasma preproIMD25–56 (39.6 + 3.1 pg ml−1), preproIMD57–92 (25.9 + 3.8 pg ml−1) and MRproAM45–92 (200.2 + 6.7 pg ml−1) were greater than their respective bioactive peptides. IMD levels correlated positively with BMI but not age, and were elevated in heart failure (9.8 + 1.3 pg ml−1, p < 0.05), similarly to MRproAM45–92 (329.5 + 41.9 pg ml−1, p < 0.001) and AM (56.8 + 10.9 pg ml−1, p < 0.01). IMD levels were greater in heart failure patients with concomitant renal impairment (11.3 + 1.8 pg ml−1) than those without (6.5 + 1.0 pg ml−1; p < 0.05). IMD and AM were greater in patients receiving submaximal compared with maximal heart failure drug therapy and were decreased after 6 months of cardiac resynchronization therapy. In conclusion, IMD is present in the plasma of healthy subjects less abundantly than AM, but is similarly correlated weakly with BMI. IMD levels are elevated in heart failure, especially with concomitant renal impairment, and tend to be reduced by high intensity drug or pacing therapy.

Higher plasma levels of complement C3a, C4a and C5a increase the risk of subretinal fibrosis in neovascular age-related macular degeneration.

Background: The aim of this study was to investigate the plasma levels of complement C3a, C4a, and C5a in different types of neovascular age-related macular degeneration (nAMD) and whether the levels were related to patients’ responsiveness to anti-VEGF therapy.

Results: Ninety-six nAMD patients (including 61 with choroidal neovascularisation (CNV), 17 with retinal angiomatous proliferation (RAP), 14 with polypoidal choroidal vasculopathy (PCV) and 4 unclassified patients) and 43 controls were recruited to this case–control study. Subretinal fibrosis was observed in 45 nAMD patients and was absent in 51 nAMD patients. In addition, the responsiveness to anti-VEGF (Lucentis) therapy was also evaluated in nAMD patients. Forty-four patients were complete responders, 48 were partially responders, and only 4 patients did not respond to the therapy. The plasma levels of C3a, C4a and C5a were significantly higher in nAMD patients compared to
controls. Further analysis of nAMD subgroups showed that the levels of C3a, C4a and C5a were significantly increased in patients with CNV but not RAP and PCV. Significantly increased levels of C3a, C4a and C5a were also observed in nAMD patients with subretinal fibrosis but not in those without subretinal fibrosis. Higher levels of C3a were observed in nAMD patients who responded partially to anti-VEGF therapy.

Conclusions: Our results suggest increased systemic complement activation in nAMD patients with CNV but not RAP and PCV. Our results also suggest that higher levels of systemic complement activation may increase the risk of subretinal fibrosis in nAMD patients

mRNA Levels of BACE1 and its interacting proteins, RTN3 and PPIL2, correlate in human post mortem brain tissue

β-Site amyloid precursor protein cleaving enzyme (BACE1) is the rate-limiting enzyme for production of Aβ peptides, proposed to drive the pathological changes found in Alzheimer’s disease (AD). Reticulon 3 (RTN3) is a negative modulator of BACE1 (β-secretase) proteolytic activity, while peptidylprolyl isomerase (cyclophilin)-like 2 (PPIL2) positively regulated BACE1 gene expression in a cell-based assay. This study aimed to analyze RTN3 and PPIL2 mRNA levels in four brain regions from individuals with AD and controls. BACE1 mRNA had been previously quantified in the samples, as had glial fibrillary acidic protein (GFAP) and neuron-specific enolase (NSE), to track changing cell populations in the tissue. mRNA levels in the human post mortem brain tissue were assayed using quantitative real-time polymerase chain reaction (qPCR) and qbasePLUS, employing validated stably expressed reference genes. No differences in RTN3 or PPIL2 mRNA levels were found in individuals with AD, compared to controls. Both RTN3 and PPIL2 mRNA levels correlated significantly with BACE1 mRNA and all three showed similar disease stage-dependent changes with respect to NSE and GFAP. These findings indicated that the in vitro data demonstrating an effect of PPIL2 on BACE1 expression have functional relevance in vivo. Further research into BACE1-interacting proteins could provide a fruitful approach to the modulation of this protease and consequently Aβ production.

Effective collision strengths for forbidden transitions among the 3s23p3 fine-structure levels of Cl III

Effective collision strengths for the 10 astrophysically important fine-structure forbidden transitions among the ⁴S^o, ²D^o and ²P^o levels in the 3s²3p³ configuration of Cl III are presented. The calculation employs the multichannel R-matrix method to compute the electron-impact excitation collision strengths in a close-coupling expansion, which incorporates the lowest 23 LS target eigenstates of Cl III. These states are formed from the 3s²3p³, 3s3p⁴, 3s²3p²3d and 3s²3p²4s configurations. The Maxwellian-averaged effective collision strengths are presented graphically for all 10 fine-structure transitions over a wide range of electron temperatures appropriate for astrophysical applications [log T(K) = 3.3 - log T(K) = 5.9]. Comparisons are made with the earlier seven-state close-coupling calculation of Butler & Zeippen, and in general excellent agreement is found in the low-temperature region where a comparison is possible [log T(K) = 3.3 - log T(K) = 4.7]. However, discrepancies of up to 30 per cent are found to occur for the forbidden transitions which involve the ⁴S^o ground state level, particularly for the lowest temperatures considered. At the higher temperatures, the present data are the only reliable results currently available.

Effective collision strengths for fine-structure forbidden transitions among the 2s22p3 levels of S x

Effective collision strengths for electron-impact excitation of the N-like ion S x are calculated in the close-coupling approximation using the multichannel R-matrix method. Specific attention is given to the 10 astrophysically important fine-structure forbidden transitions among the ⁴S^O, ²D^o and ²P^o levels in the 2s²2p³ ground configuration. The total (e^- + ion) wavefunction is expanded in terms of the 11 lowest LS eigenstates of S x, and each eigenstate is represented by extensive configuration-interaction wavefunctions. The collision strengths obtained are thermally averaged over a Maxwellian distribution of velocities, for all 10 fine-structure transitions, over the range of electron temperatures log T(K) = 4.6-6.7 (the range appropriate for astrophysical applications). The present effective collision strengths are the only results currently available for these fine-structure transition rates.

Effective collision strengths for fine-structure forbidden transitions among the 2s22p3 levels of Ne IV

Effective collision strengths for electron-impact excitation of the N-like ion NeIV are calculated in the close-coupling approximation using the multichannel R-matrix method. Specific attention is given to the 10 astrophysically important fine-structure forbidden transitions among the ⁴S^o, ²D^o and ²P^o levels in the 2s²2p³ ground-state configuration. The expansion of the total wavefunction incorporates the lowest 11 LS eigenstates of NeIV, consisting of eight n = 2 terms with configurations 2s²2p³, 2s2p⁴ and 2p⁵, together with three n = 3 states of configuration 2s²2p²3s. We present in graphical form the effective collision strengths obtained by thermally averaging the collision strengths over a Maxwellian distribution of velocities, for all 10 fine-structure transitions, over the range of electron temperatures log T(K) = 3.6 to log T(K) = 6.1 (the range appropriate for astrophysical applications). Comparisons are made with the earlier, less sophisticated close-coupling calculation of Giles, and excellent agreement is found in the limited temperature region where a comparison is possible [log T(K) = 3.7 to log 7(K) = 4.3]. At higher temperatures the present data are the only reliable results currently available.

Effective collision strengths for fine-structure forbidden transitions among the 3s 23p 3 levels of Ar IV

The multichannel R-matrix method is used to compute electron impact excitation collision strengths in Ar IV for all fine-structure transitions among the ⁴S°, ²D° and ²P° levels in the 3s ²3p ³ ground configuration. Included in the expansion of the total wavefunction are the lowest 13 LS target eigenstates of Ar iv formed from the 3s ²3p ³, 3s3p ⁴ and 3s ²3p ²3d configurations. The effective collision strengths, obtained by averaging the electron collision strengths over a Maxwellian distribution of electron velocities, are presented for all 10 fine-structure transitions over a wide range of electron temperatures of astrophysical interest (T _e = 2000-100 000 K). Comparisons are made with an earlier 7-state close-coupling calculation by Zeippen, Butler & Le Bourlot, and significant differences are found to occur for many of the forbidden transitions considered, in particular those involving the ⁴S° ground state, where discrepancies of up to a factor of 3 are found in the low-temperature region. © 1997 RAS.

Remonstrance of the citizens of Beaufort District, S.C. against any further increase of the duties on imports, December 31, 1827

This document contains a remonstrance, which was written by the citizens of Beaufort district of South Carolina, in connection with tariff increases. It was presented to the Senate and House of Representatives of the United States.

Three-level energy decoupling : energy decoupling at the primary, final and useful levels of energy use

Tese de doutoramento, Sistemas Sustentáveis de Energia, Universidade de Lisboa, Faculdade de Ciências, 2015

The determinants of retail productivity: a critical review of the evidence

This paper discusses the literature on the established determinants of productivity in the retail sector. It also draws attention to some neglected strands of research which provide useful insights into strategies that could allow productivity enhancements in this area of the economy. To date, very few attempts have been made to integrate different specialisms in order to explain what drives productivity in retail. Here this paper rectifies this omission by putting together studies from economics, geography, knowledge management and employment studies. It is the authors' view that quantitative studies of retail productivity should focus on total factor productivity in retailing as the result of competition/composition effects, planning regulations, information and communications technology, the multinational operation element and workforce skills. Further, the fact that retail firms possess advantages that are transferable between locations suggests that investment in strategies enhancing the transfer of explicit and tacit knowledge between and within businesses are crucial to achieve productivity gains.

The sound of a breaking string: critical environmental law and ontological vulnerability

This is a thought-provoking contribution on the space of ontological vulnerability as the awareness of being existentially exposed. This space, conceptualised as a space of ‘the middle’ (as opposed, emphatically, to ‘the centre’) offers an opportunity to think away from the sterile debate on eco/anthropocentricity and from such limiting hierarchies as animal/human, human/environmental, natural/artificial. This new, vulnerable position of the middle allows the reconfiguration of ecological processes, and more specifically the position of environmental law in relation to them. Environmental law now finds itself amidst a new, moving, ‘open ecology’ of social, biological and ecological processes. This is a new, radical conceptualisation of what the author has called ‘critical environmental law,’ based upon an epistemology of observation and an ontology of being part of this open ecology. Environmental law, in this light, is simultaneously reformulated as an invitation to disciplinary and ontological openness and yet a call to remain immanent within existing legal structures. This finds expression in four critical environmental positions that set the stage for the further elaboration of a critical environmental law.

Diversity in levels of intracellular total creatine and triglycerides in human skeletal muscles observed by 1H-MRS

We used1H-magnetic resonance spectroscopy to noninvasively determine total creatine (TCr), choline-containing compounds (Cho), and intracellular (IT) and extracellular (between-muscle fibers) triglycerides (ET) in three human skeletal muscles. Subjects' (n = 15 men) TCr concentrations in soleus [Sol; 100.2 ± 8.3 (SE) mmol/kg dry wt] were lower (P < 0.05) than those in gastrocnemius (Gast; 125.3 ± 9.2 mmol/kg dry wt) and tibialis anterior (TA; 123.7 ± 8.8 mmol/kg dry wt). The Cho levels in Sol (35.8 ± 3.6 mmol/kg dry wt) and Gast (28.5 ± 3.5 mmol/kg dry wt) were higher (P < 0.001 andP < 0.01, respectively) compared with TA (13.6 ± 2.4 mmol/kg dry wt). The IT values were found to be 44.8 ± 4.6 and 36.5 ± 4.2 mmol/kg dry wt in Sol and Gast, respectively. The IT values of TA (24.5 ± 4.5 mmol/kg dry wt) were lower than those of Sol (P < 0.01) and Gast (P < 0.05). There were no differences in ET [116.0 ± 11.2 (Sol), 119.1 ± 18.5 (Gast), and 91.4 ± 19.2 mmol/kg dry wt (TA)]. It is proposed that the differences in metabolite levels may be due to the differences in fiber-type composition and deposition of metabolites due to the adaptation of different muscles during locomotion.