Outcome of children requiring intensive care following haematopoietic SCT for primary immunodeficiency and other non-malignant disorders

Haematopoietic SCT (HSCT) is curative for many children with primary immunodeficiencies or other non-malignant conditions. Outcome for those admitted to intensive care following HSCT for oncology diagnoses has historically been very poor. There is no literature available specifically regarding the outcome for children with primary immunodeficiency requiring intensive care following HSCT. We reviewed our post-HSCT admission to intensive care over a 5-year period. A total of 111 children underwent HSCT. Median age at transplant was 1 year 4 months. The most common diagnosis was SCID. In all, 35% had at least one intensive care admission and 44% survived to be discharged from intensive care. Also, 73% of admission episodes requiring invasive ventilation but no inotropes or renal replacement therapy resulted in survival to discharge. Children undergoing HSCT for immunological diagnoses had a high rate of admission to intensive care. No factors were identified that could predict the need for admission. Invasive ventilation alone has a much better outcome than that in historical series. However, the need for multi-organ system support was still associated with a poor outcome. This information is useful when counselling families of children that have deteriorated and been admitted to intensive care during the HSCT procedure.     

Pan-canadian cardiovascular data definitions and quality indicators: a status update

After the 2009 publication of Building a Heart Healthy Canada, the Canadian Cardiovascular Society was commissioned to address a long-standing information gap related to the compatibility and comparability of data on the quality of cardiovascular care in Canada. Through collaboration between the Canadian Institute for Health Information, the Institute for Clinical Evaluative Sciences, the Public Health Agency of Canada, and 5 regional cardiovascular registries, 2 committees were tasked with developing standardized cardiovascular data definitions and quality indicators. The work culminated in national consensus on the definitions of 55 patient, disease, and therapeutic variables (core and optional) to facilitate cardiovascular care comparisons within and across Canada. Supplemental data definition chapters were then developed on acute coronary syndrome and coronary angiography/revascularization, with chapters on heart failure and atrial fibrillation electrophysiology to follow. This foundational work led to a critical appraisal of cardiac quality indicator development initiatives via the Appraisal of Guidelines for Research and Evaluation II (AGREE II) Quality Indicator tool, followed by the development of quality indicator catalogues on heart failure and atrial fibrillation. These indicators will be embedded within the clinical practice guidelines of the Canadian Cardiovascular Society, facilitating national comparisons across Canada on cardiovascular disease incidence, prevalence, patterns and quality of care, and clinical outcomes. This methodology-achieving national stakeholder consensus on a standardized process for the development and selection of cardiovascular quality indicators-illustrates the capacity to reach agreement by drawing on expertise and research across diverse organizational mandates and agendas, potentially contributing to improved cardiovascular care and outcomes for patients.     

Expression of pannexin isoforms in the systemic murine arterial network

Aims: Pannexins (Panx) form ATP release channels and it has been proposed that they play an important role in the regulation of vascular tone. However, distribution of Panx across the arterial vasculature is not documented. Methods: We tested antibodies against Panx1, Panx2 and Panx3 on human embryonic kidney cells (which do not endogenously express Panx proteins) transfected with plasmids encoding each Panx isoform and Panx1(-/-) mice. Each of the Panx antibodies was found to be specific and was tested on isolated arteries using immunocytochemistry. Results: We demonstrated that Panx1 is the primary isoform detected in the arterial network. In large arteries, Panx1 is primarily in endothelial cells, whereas in small arteries and arterioles it localizes primarily to the smooth muscle cells. Panx1 was the predominant isoform expressed in coronary arteries, except in arteries less than 100 μm where Panx3 became detectable. Only Panx3 was expressed in the juxtaglomerular apparatus and cortical arterioles. The pulmonary artery and alveoli had expression of all 3 Panx isoforms. No Panx isoforms were detected at the myoendothelial junctions. Conclusion: We conclude that the specific localized expression of Panx channels throughout the vasculature points towards an important role for these channels in regulating the release of ATP throughout the arterial network.     

The effects of difficulty and gain versus loss on vocal physiology and acoustics

To examine the basis of emotional changes to the voice, physiological and electroglottal measures were combined with acoustic speech analysis of 30 men performing a computer task in which they lost or gained points under two levels of difficulty. Predictions of the main effects of difficulty and reward on the voice were not borne out by the data. Instead, vocal changes depended largely on interactions between gain versus loss and difficulty. The rate at which the vocal folds open and close (fundamental frequency; fo) was higher for loss than for gain when difficulty was high, but not when difficulty was low. Electroglottal measures revealed that fo changes corresponded to shorter glottal open times for the loss conditions. Longer closed and shorter open phases were consistent with raised laryngeal tension in difficult loss conditions. Similarly, skin conductance indicated higher sympathetic arousal in loss than gain conditions, particularly when difficulty was high. The results provide evidence of the physiological basis of affective vocal responses, confirming the utility of measuring physiology and voice in the study of emotion.     

Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist

Histone deacetylase inhibitors (HDACi) and agents such as recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic anti-TRAIL receptor (TRAIL-R) antibodies are anticancer agents that have shown promise in preclinical settings and in early phase clinical trials as monotherapies. Although HDACi and activators of the TRAIL pathway have different molecular targets and mechanisms of action, they share the ability to induce tumor cell-selective apoptosis. The ability of HDACi to induce expression of TRAIL-R death receptors 4 and 5 (DR4/DR5), and induce tumor cell death via the intrinsic apoptotic pathway provides a molecular rationale to combine these agents with activators of the TRAIL pathway that activate the alternative (death receptor) apoptotic pathway. Herein, we demonstrate that the HDACi vorinostat synergizes with the mouse DR5-specific monoclonal antibody MD5-1 to induce rapid and robust tumor cell apoptosis in vitro and in vivo. Importantly, using a preclinical mouse breast cancer model, we show that the combination of vorinostat and MD5-1 is safe and induces regression of established tumors, whereas single agent treatment had little or no effect. Functional analyses revealed that rather than mediating enhanced tumor cell apoptosis via the simultaneous activation of the intrinsic and extrinsic apoptotic pathways, vorinostat augmented MD5-1-induced apoptosis concomitant with down-regulation of the intracellular apoptosis inhibitor cellular-FLIP (c-FLIP). These data demonstrate that combination therapies involving HDACi and activators of the TRAIL pathway can be efficacious for the treatment of cancer in experimental mouse models.     

Intestinal obstruction promotes gut translocation of bacteria

PURPOSE: Translocation of enteric organisms has been implicated as a possible source of sepsis in susceptible patients. Animal studies have suggested that intestinal obstruction promotes bacterial translocation from the gut lumen. The aim of this study was to study the prevalence of bacterial translocation in patients with and without intestinal obstruction. METHODS: Serosal scrapings, mesenteric lymph nodes, and peripheral blood cultures were obtained from 254 patients. Scrapings and nodes were homogenized and incubated aerobically and anaerobically. Full-thickness biopsies underwent villous height analysis. The clinical course was followed for at least six weeks. RESULTS: Bacterial translocation to mesenteric nodes occurred more frequently in patients with large bowel obstruction than in patients without obstruction (14 of 36 patients vs.16 of 218 patients;P<0.001). Both aerobic and anaerobic bacteria were found to translocate. The more distal the obstruction, the more likely anaerobic bacteria were to be identified. Translocation of bacteria predisposed to postoperative septic complications (P<0.05). Villous height was not related to bacterial translocation. CONCLUSIONS: Gut translocation of bacteria is more common in patients with intestinal obstruction, and its association with septic complications appears to be of clinical significance.Supported by the Yorkshire Regional Health Authority Research Trust, Harrogate, United Kingdom.Read at the meeting of The American Society of Colon and Rectal Surgeons, Orlando, Florida, May 8 to 13, 1994.