The carbon footprint of an Australian satellite haemodialysis unit.

OBJECTIVES: This study aimed to better understand the carbon emission impact of haemodialysis (HD) throughout Australia by determining its carbon footprint, the relative contributions of various sectors to this footprint, and how contributions from electricity and water consumption are affected by local factors. METHODS: Activity data associated with HD provision at a 6-chair suburban satellite HD unit in Victoria in 2011 was collected and converted to a common measurement unit of tonnes of CO2 equivalents (t CO2-eq) via established emissions factors. For electricity and water consumption, emissions factors for other Australian locations were applied to assess the impact of local factors on these footprint contributors. RESULTS: In Victoria, the annual per-patient carbon footprint of satellite HD was calculated to be 10.2t CO2-eq. The largest contributors were pharmaceuticals (35.7%) and medical equipment (23.4%). Throughout Australia, the emissions percentage attributable to electricity consumption ranged from 5.2% to 18.6%, while the emissions percentage attributable to water use ranged from 4.0% to 11.6%. CONCLUSIONS: State-by-state contributions of energy and water use to the carbon footprint of satellite HD appear to vary significantly. Performing emissions planning and target setting at the state level may be more appropriate in the Australian context. What is known about the topic? Healthcare provision carries a significant environmental footprint. In particular, conventional HD uses substantial amounts of electricity and water. In the UK, provision of HD and peritoneal dialysis was found to have an annual per-patient carbon footprint of 7.1t CO2-eq. What does this paper add? This is the first carbon-footprinting study of HD in Australia. In Victoria, the annual per-patient carbon footprint of satellite conventional HD is 10.2t CO2-eq. Notably, the contributions of electricity and water consumption to the carbon footprint varies significantly throughout Australia when local factors are taken into account. What are the implications for practitioners? We recommend that healthcare providers consider local factors when planning emissions reduction strategies, and target setting should be performed at the state, as opposed to national, level. There is a need for more comprehensive and current emissions data to enable healthcare providers to do so.

Omacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cells.

Chronic myeloid leukaemia (CML) is maintained by a rare population of tyrosine kinase inhibitor (TKI)-insensitive malignant stem cells. Our long-term aim is to find a BcrAbl-independent drug that can be combined with a TKI to improve overall disease response in chronic-phase CML. Omacetaxine mepesuccinate, a first in class cetaxine, has been evaluated by clinical trials in TKI-insensitive/resistant CML. Omacetaxine inhibits synthesis of anti-apoptotic proteins of the Bcl-2 family, including (myeloid cell leukaemia) Mcl-1, leading to cell death. Omacetaxine effectively induced apoptosis in primary CML stem cells (CD34(+)38(lo)) by downregulation of Mcl-1 protein. In contrast to our previous findings with TKIs, omacetaxine did not accumulate undivided cells in vitro. Furthermore, the functionality of surviving stem cells following omacetaxine exposure was significantly reduced in a dose-dependant manner, as determined by colony forming cell and the more stringent long-term culture initiating cell colony assays. This stem cell-directed activity was not limited to CML stem cells as both normal and non-CML CD34(+) cells were sensitive to inhibition. Thus, although omacetaxine is not leukaemia stem cell specific, its ability to induce apoptosis of leukaemic stem cells distinguishes it from TKIs and creates the potential for a curative strategy for persistent disease.

Lonafarnib reduces the resistance of primitive quiescent CML cells to imatinib mesylate in vitro.

Recent studies indicate that a rare population of primitive quiescent BCR-ABL(+) cells are innately insensitive to imatinib mesylate (IM) and persist after IM therapy of patients with chronic myeloid leukemia (CML). New approaches to the eradication of these cells are therefore likely to be crucial to the development of curative therapies for CML. We have now found that Ara-C, LY294002 (a PI-3 (phosphatidylinositol-3' kinase) kinase inhibitor), 17AAG (a heat-shock protein (HSP)-90 antagonist) and lonafarnib (a farnesyltransfease inhibitor) all enhance the toxicity of IM on K562 cells and on the total CD34(+) leukemic cell population from chronic phase CML patients. However, for quiescent CD34(+) leukemic cells, this was achieved only by concomitant exposure of the cells to lonafarnib. Ara-C or LY294002 alone blocked the proliferation of these cells but did not kill them, and Ara-C, LY294002 or 17AAG in combination with IM enhanced the cytostatic effect of IM but did not prevent the subsequent regrowth of the surviving leukemic cells. These studies demonstrate the importance of in vitro testing of novel agents on the subset of primary leukemic cells most likely to determine long-term treatment outcomes in vivo.

A prospective study of real-time panfungal PCR for the early diagnosis of invasive fungal infection in haemato-oncology patients.

A blinded prospective study was performed to determine whether screening of whole blood using a real-time, panfungal polymerase chain reaction (PCR) technique could predict the development of invasive fungal infection (IFI) in immunocompromised haemato-oncology patients. In all, 78 patients (125 treatment episodes) were screened twice weekly by real-time panfungal PCR using LightCyclertrade mark technology. IFI was documented in 19 treatment episodes (five proven, three probable and 11 possible), and in 12, PCR was sequentially positive. PCR positivity occurred in: 4/5 proven; 2/3 probable; 6/11 possible; and 29/106 with no IFI. In 8/12 with IFI and sequentially positive PCR results, PCR positivity occurred before (median 19.5 days) and in 4/12 (median 10.5 days) after the initiation of empirical antifungal therapy. Based on sequential positive results for proven/probable IFI sensitivity, specificity, positive predictive value and negative predictive value were 75, 70, 15 and 98%, respectively. Real-time panfungal PCR is a sensitive tool for the early diagnosis of IFI in immunocompromised haemato-oncology patients. It may be most useful as a screening method in high-risk patients, either to direct early pre-emptive antifungal therapy or to determine when empirical antifungal therapy can be withheld in patients with antibiotic--resistant neutropenic fever. However, these strategies require further assessment in comparative clinical trials.

Successful haemopoietic stem cell transplantation does not correct mannan-binding lectin deficiency.

It has been reported that in allogeneic stem cell transplantation, the mannan-binding lectin (MBL) status of the donor has prognostic value for the recipient. Two MBL-deficient patients, with coexisting haematological malignancy, were identified who were treated with bone marrow from donors with normal MBL concentrations. Although both patients engrafted successfully and remain in complete remission, neither seroconverted to the MBL sufficiency status of his donor over a follow-up period exceeding 2 years. This does not support the concept of MBL replacement by stem cell therapy, and does not provide an explanation for high MBL concentrations in stem cell donors protecting recipients from post transplant infections.

No strong relationship between mannan binding lectin or plasma ficolins and chemotherapy-related infections.

Chemotherapy causes neutropenia and an increased susceptibility to infection. Recent reports indicate that mannan-binding lectin (MBL) insufficiency is associated with an increased duration of febrile neutropenia and incidence of serious infections following chemotherapy for haematological malignancies. We aimed to confirm or refute this finding and to extend the investigation to the plasma ficolins, P35 (L-ficolin) and the Hakata antigen (H-ficolin). MBL, L-ficolin and H-ficolin were measured in 128 patients with haematological malignancies treated by chemotherapy alone or combined with bone marrow transplantation. Protein concentrations were related to clinical data retrieved from medical records. MBL concentrations were elevated compared with healthy controls in patients who received chemotherapy, while L-ficolin concentrations were decreased and H-ficolin levels were unchanged. There was no correlation between MBL, L-ficolin or H-ficolin concentration and febrile neutropenia expressed as the proportion of neutropenic periods in which patients experienced fever, and there was no relation between abnormally low (deficiency) levels of MBL, L-ficolin or H-ficolin and febrile neutropenia so expressed. Patients with MBL < or =0.1 microg/ml had significantly more major infections than no infections within the follow-up period (P<0.05), but overall most patients had signs or symptoms of minor infections irrespective of MBL concentration. Neither L-ficolin nor H-ficolin deficiencies were associated with infections individually, in combination or in combination with MBL deficiency. MBL, L-ficolin and H-ficolin, independently or in combination, did not have a major influence on susceptibility to infection in these patients rendered neutropenic by chemotherapy. These results cast doubt on the potential value of MBL replacement therapy in this clinical context.

Evaluation of a panel of human monoclonal antibodies to D and exploration of the synergistic effects of blending IgG1 and IgG3 antibodies on their in vitro biologic function.

BACKGROUND: The D immunoprophylaxis program has successfully reduced the incidence of Rh hemolytic disease of the newborn (HDN), but it has also reduced the availability of plasma-derived polyclonal anti-D, which constitutes the current therapeutic product. Human monoclonal anti-D from hybridoma cell lines may be an acceptable alternative, and clinical efficacy of each anti-D is being evaluated in several centers. STUDY DESIGN AND METHODS: This study represents the largest assessment (outside of the International Workshops) of human D monoclonal antibodies for potential therapeutic use. The in vitro biologic activity and immunologic and serologic reactivity of a coded panel of 20 D antibodies (THERAD) was investigated. The bioassays used were lymphocyte (K-cell) antibody-dependent cell-mediated cytotoxicity (ADCC), monocyte ADCC, and monocyte chemiluminescence, which together reflect the processes involved in antibody-coated red cell destruction in vivo. From this panel, six antibodies (THERADs 14, 19, 22, 23, 27, and 28, comprising 3 IgG1 and 3 IgG3 D monoclonal antibodies) were further selected to investigate the effects of blending in the three bioassays. RESULTS: Several THERAD blends displayed greater activity than their component parts, in the range of 6 to 124 percent. There was no evidence to suggest functional blocking effects with this restricted panel of antibodies. CONCLUSION: The THERAD blends containing both IgG1 and IgG3 anti-D appeared to be the most functionally active, as did blends containing antibodies to two distinct D epitopes. This in vitro evidence has important implications for the future formulation of an effective monoclonal preparation for the prevention of Rh HDN.

Murine monoclonal antibody with anti-e-like specificity: suitability for screening for e-negative cells.

A directly agglutinating murine monoclonal antibody of the IgG3 isotype has been produced after mice were immunized with papain-treated Bombay phenotype, e-positive red cells (RBCs). The antibody strongly agglutinated all e-positive RBCs and gave negative reactions with RBCs from Rhnull persons and those homozygous for Rh deletion genes. Variable reactivity was found with e-negative RBCs, ranging from weak to negative with R2R2, slightly stronger with r"r", and stronger still with RzRz. These reactions, together with results from tests with a large panel of Rh-variant RBCs, suggested a specificity for an epitope that is part of the e mosaic but is also expressed at least partially on e-negative RBCs and is influenced by the presence of C. This antibody has been standardized for use as a screening reagent for R2R2 cells by a microplate technique, and over 6000 donations have been screened in this way. No discrepancies have been found in confirmatory tests for e-negative status using human anti-e.

Serological characterisation of a mouse monoclonal anti-P-like antibody.

An IgM mouse monoclonal antibody, LM 147/328, raised against an Escherichia coli immunogen, was found to possess anti-P-like specificity. It is proposed that this antibody recognises an epitope on a Gal beta 1-3GalNAc disaccharide structure (GalNAc = N-acetyl-D-galactosamine). The haemagglutinating activity of this antibody was consistently strong with adult erythrocytes, but gave significantly weak reactions with about 7% of cord erythrocyte samples.

The potentiation of "incomplete" mouse monoclonal anti-Lea agglutination with colloids.

Mouse monoclonal anti-Lea produced in this center was found to agglutinate only Le(a+) red cells which had been modified with proteases. In order to provide a stable medium in which the monoclonal anti-Lea would directly agglutinate unmodified red cells, the potentiating effect of a variety of colloids was assessed. Satisfactory results were obtained when 10 percent (wt/vol) dextran and 2 percent (wt/vol) bovine serum albumin were added to the culture supernatant containing anti-Lea. It is suggested that direct hemagglutination mediated by these colloids resulted from a combination of increased antibody uptake by Le(a+) red cells and change in the shape of these red cells induced by dextran.

Mouse monoclonal antibodies reacting with M blood group-related antigens.

Four mouse monoclonal antibodies were produced with specificities related to human blood group M antigen. The antibodies react in direct hemagglutination systems, and their specificities were investigated by their reactions with variant and enzyme-modified red cells. The effects of temperature and pH on their hemagglutination reactions also were investigated, and all four were murine IgG antibodies. Physicochemical and serologic investigations showed them to be four distinct antibodies, and each one could be used for M blood grouping under appropriate conditions.

Production and immunochemical characterization of mouse monoclonal antibodies to human Lewis blood group structures.

Two mouse monoclonal antibodies with specificity for the Lea blood group determinant of human red cells have been produced by immunising mice with soluble Lewis substance. Both antibodies were of the IgM class and agglutinated only trypsinised or papainised Lea-positive red cells. The precise antigenic conformations recognised by these antibodies have been defined by inhibition studies with monosaccharides, disaccharides and synthetic blood group oligosaccharides. These studies have suggested that the alpha-side of a 1-substituted D-galactosyl residue is a central part of the determinants recognised by the antibodies. Preliminary studies have shown these antibodies to be superior to many of the presently available human and animal polyclonal reagents for routine Lea typing of red cells.