Management of parenteral nutrition associated hyperglycaemia: a comparison of subcutaneous and intravenous insulin regimen.

PN is associated with significant hyperglycaemia, which may be detrimental to clinical outcome. There are few data on the management of this phenomenon outside of intensive care units. In our unit, we studied the efficacy of protocol-based intravenous insulin delivery as compared to subcutaneous insulin prescribed individually outside of the critical care setting. In a retrospective review over a two-year period, we compared patients with PN-associated hyperglycaemia who had received both modes of insulin therapy. A total of 122 who developed PN-associated hyperglycaemia were identified. Those on the intravenous insulin regimen were within glycaemic target for more time than those on the subcutaneous regimen (62% Vs 43%, p = 0.008). We therefore conclude that outside of the critical care setting, intravenous insulin delivers better glycaemic control and should therefore be considered optimum therapy for patients with PN-associated hyperglycaemia.

Changes in leg ulcer management practice following training in an Irish community setting.

OBJECTIVE: To identify regional changes in leg ulcer management following leg ulcer training for community-based nurses which incorporated Doppler ankle brachial pressure index (ABPI) assessment. METHODS: This was a two-part study conducted in the Irish Health Service Executive, Mid-Western Area. An initial audit in 2005 gathered details on all leg ulcer patients treated in the community in one week, including patient demographics, ulcer aetiology, assessment and treatment. The first audit was carried out before the introduction of a training course for community-based nurses in leg ulcer assessment and management. The training programme was delivered in 2005 and again in 2006. In total 30 public health nurses and community registered nurses from this region completed the course. The second part of the study involved repeating the audit in 2007. By comparing the results from 2005 with 2007 we were able to identify changes in leg ulcer assessment and management. RESULTS: A total of 426 and 449 leg ulcers were identified, with a prevalence of 0.12% and 0.1% in 2005 and 2007 respectively. Prevalence increased to 1.2% (2005) and 1.1% (2007) in those aged over 70 years. Most ulcers were venous in origin (63.3% in 2005 versus 68.8% in 2007). From 2005 to 2007 the number of venous leg ulcers treated with high compression increased significantly, by almost 16% (p < 0.0001). Once-weekly dressing changes increased by a significant 10%, reducing the number of dressings requiring more frequent changes (p = 0.002). CONCLUSION: Significant improvements in leg-ulcer practices were noted in the 18-month study period. The results show very significant increases in number of patients treated with high compression and a significant reduction in more than once-weekly dressing changes. These positive changes may be partly attributed to the enhanced knowledge and skills nurses gained by participating in training.

E-selectin ligands recognised by HECA452 induce drug resistance in myeloma, which is overcome by the E-selectin antagonist, GMI-1271.

Multiple myeloma (MM) is characterized by the clonal expansion and metastatic spread of malignant plasma cells to multiple sites in the bone marrow (BM). Recently, we implicated the sialyltransferase ST3Gal-6, an enzyme critical to the generation of E-selectin ligands, in MM BM homing and resistance to therapy. Since E-selectin is constitutively expressed in the BM microvasculature, we wished to establish the contribution of E-selectin ligands to MM biology. We report that functional E-selectin ligands are restricted to a minor subpopulation of MM cell lines which, upon expansion, demonstrate specific and robust interaction with recombinant E-selectin in vitro. Moreover, an increase in the mRNA levels of genes involved in the generation of E-selectin ligands was associated with inferior progression-free survival in the CoMMpass study. In vivo, E-selectin ligand-enriched cells induced a more aggressive disease and were completely insensitive to Bortezomib. Importantly, this resistance could be reverted by co-administration of GMI-1271, a specific glycomimetic antagonist of E-selectin. Finally, we report that E-selectin ligand-bearing cells are present in primary MM samples from BM and peripheral blood with a higher proportion seen in relapsed patients. This study provides a rationale for targeting E-selectin receptor/ligand interactions to overcome MM metastasis and chemoresistance.

An exploration of current leg ulcer management practices in an Irish community setting.

OBJECTIVE: To establish the prevalence of leg ulceration in the Irish Health Service Executive (HSE) mid-western region and to determine the level of assessment and treatment patients have been receiving in the local community. METHOD: Before the introduction of a Doppler training programme, all public health and community health nurses working in the Irish HSE mid-western area were requested to complete an audit form on each patient being treated for leg ulceration during a predefined one-week period. This form recorded details on patient demographics, ulcer aetiology, assessment and treatment. Out of 97 nurses, 96 responded to this audit, giving a response rate of 98.9%. RESULTS: A total of 429 patients with 449 leg ulcers were identified. Mean age was 75.5 years (standard deviation 10.7). Overall prevalence was 0.12%, which increased to 1.2% in those aged 70 years and over. Women were almost twice as likely as men to be affected (ratio of 1.8:1). The main causes of ulceration were reported as venous incompetence accounting for 63.3% (284/449) and arterial insufficiency accounting for 8% (36/449) of all ulcers. Only 59.9% (269/449) of all ulcerated limbs had ABPI measurements performed. Of those reported as venous in origin, 71.8% (204/284) had ABPI measurements recorded. Evidence-based care was generally apparent in this group, with 47.5% (97/204) receiving high compression and 18.1% (37/204) receiving reduced compression. However, in venous leg ulcers where ABPIs were not recorded (n=80) care appeared haphazard and inappropriate. CONCLUSION: Our study has identified the benefit of ABPI Doppler assessment.This assessment could be done in local health centres by trained nurses who could provide more appropriate and timely care to patients, thereby improving outcomes and relieving pressure on acute hospital clinics.

Comparison of various methods for rapid glucose estimation.

We studied the accuracy of three techniques for the rapid estimation of the blood glucose concentration with reagent strips in samples of blood from inpatients with diabetes mellitus. We observed that the visual inspection of Dextrostix gave results that were too inaccurate for this technique to be of practical clinical benefit. In contrast, when performed by registered nurses, both the Dextrostix-Eyetone method and the visual inspection of Chemstrips yielded results that were closely correlated with the measured serum glucose concentrations. With both of the latter techniques, less than 11% of the determinations varied from the actual serum glucose concentration by more than 20%. We conclude that both these techniques are sufficiently accurate to be of potential use in the home monitoring of blood glucose concentrations.

Targeting the Pim kinases in multiple myeloma.

Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. Novel treatment strategies to improve survival are urgently required. The Pims are a small family of serine/threonine kinases with increased expression across the hematological malignancies. Pim-2 shows highest expression in MM and constitutes a promising therapeutic target. It is upregulated by the bone marrow microenvironment to mediate proliferation and promote MM survival. Pim-2 also has a key role in the bone destruction typically seen in MM. Additional putative roles of the Pim kinases in MM include trafficking of malignant cells, promoting oncogenic signaling in the hypoxic bone marrow microenvironment and mediating resistance to therapy. A number of Pim inhibitors are now under development with lead compounds entering the clinic. The ATP-competitive Pim inhibitor LGH447 has recently been reported to have single agent activity in MM. It is anticipated that Pim inhibition will be of clinical benefit in combination with standard treatments and/or with novel drugs targeting other survival pathways in MM.

MHC haplotypes affect the expression of opportunistic infections in HIV patients.

This study explores whether MHC genes affect manifestations of opportunistic infections in HIV patients not treated with highly active antiretroviral therapy (HAART) and immunopathologic responses to pre-existing infections in patients who achieved immune reconstitution following HAART (i.e., "immune restoration diseases" or IRD). HLA-B27 and B17 were relatively rare in all HIV patients, but no HLA-B alleles significantly affected cytomegalovirus (CMV) or Mycobacterium avium complex (MAC) disease in patients who had not received HAART. However coexpression of alleles previously defined as the 44.1 ancestral haplotype (HLA-A2, -B44, and -DR4) was more common in the MAC and CMV patients. After HAART, HLA-B44 and (HLA-A2, -B44, -DR4) were found in 66% and 33%, respectively, of patients who experienced an IRD manifested as CMV retinitis and/or encephalomyelitis. This was confirmed by examination of microsatellite alleles, where the C1_2_5 locus in the class I region was most concordant with the 44.1 haplotype in the patients. HLA-B44 was not associated with IRD initiated by Mycobacterium sp, cutaneous VZV or HSV, or HCV infections, suggesting distinct pathologic mechanisms are responsible. CMV retinitis/encephalomyelitis IRD patients had marginally lower pretreatment CD4 T-cell counts, but indices of immune reconstitution were similar in all groups and independent of HLA-B44.

Assessment of immune function by lymphoproliferation underestimates lymphocyte functional capacity in HIV patients treated with highly active antiretroviral therapy.

The objective of this study was to evaluate T cell responses in HIV-infected patients after highly active antiretroviral therapy (HAART), using four assays of immune function, and to determine which best reflects the presence of CD4(+) T cells able to respond to CMV antigen. Peripheral blood mononuclear cells from 41 HIVinfected patients and 31 healthy HIV-seronegative controls were cultured with mitogen (PMA/Ca(2+) ionophore) or antigen (CMV). Production of interferon gamma (IFN-gamma) determined by ELISpot assay was compared with lymphoproliferation, IFN-gamma production assessed by ELISA, and CD69 expression and intracellular IFN-gamma assessed by flow cytometry. Cells from patients whose CD4(+) T cells counts increased 4-fold or to >200 cells/microl after HAART responded as well as control cells when assessed by IFN-gamma production and CD69 expression after mitogenic stimulation, but lymphoproliferation responses were depressed by about 52%. Patients who did not meet these criteria for immune reconstitution had lymphoproliferative responses up to 30-fold lower than control subjects, while intracellular IFN-gamma and CD69 expression and ELISpot counts were less than 3-fold lower. Responses to CMV antigen could not be detected by flow cytometry, but were readily detected by ELISpot in CMV-seropositive patients whose CD4(+) T cell counts had increased after HAART. This included patients with low responses assessed by lymphoproliferation. Moreover, ELISpot responses measured with fresh and frozen cells were comparable, while lymphoproliferation assays required fresh cells. In conclusion, the ELISpot assay is a sensitive and efficient technique for detecting CMV-specific IFN-gamma responses in samples that display poor responses when assessed by lymphoproliferation assays.

Immune dysfunction and immune restoration disease in HIV patients given highly active antiretroviral therapy.

BACKGROUND: Some immune defects caused by HIV infection resolve following treatment with highly active antiretroviral therapy (HAART), but residual immune dysfunction may cause disease. Problems with the regulation of the restored immune system in the first six months of treatment can lead to atypical presentations of mycobacterial, cytomegalovirus (CMV), hepatitis B virus or hepatitis C virus (HCV) disease. We defined these conditions as immune restoration diseases (IRD) and showed that they occur in 30-40% of individuals who begin HAART from low CD4 T cell counts. OBJECTIVES: Analysis of immune dysregulation in patients who have responded to HAART. STUDY DESIGN: Patients with successful immune reconstitution following HAART were selected from a database containing details of all patients managed at Royal Perth Hospital (Western Australia) on the basis a CD4 T cell count <100/microl before HAART and an increase of >4-fold or to >200 CD4 T cells/microl. RESULTS: Patients who had experienced an IRD demonstrated increased levels of bioavailable IL-6 and increased expression of CCR5 and CCR3 on monocytes and granulocytes, but numbers of gammadeltaT-cells were similar to patients with similar CD4 T cell counts without an IRD. Carriage of HLA-A2, -B44 was associated with a history of CMV retinitis and/or encephalomyelitis as an IRD, but not with IRD initiated by Mycobacterium sp., cutaneous varicella zoster or herpes simplex infections or HCV. We also identified a patient with Graves' thyrotoxicosis and pronounced lymphadenopathy after HAART, and demonstrated that thyroid stimulating hormone receptor antibody production was associated with an increase in serum soluble CD30, suggesting acquired immune dysregulation. CONCLUSIONS: IRD are associated with persistent immune activation, where differences in genetic profiles suggest that distinct pathological mechanisms are responsible for retinitis/encephalomyelitis IRD. Further studies are important as dysregulated T-cell responses may cause disease later in the course of immune reconstitution.