Phase I trial of interleukin-2 after unmodified HLA-matched sibling bone marrow transplantation for children with acute leukemia

Allogeneic bone marrow transplantation (BMT) for advanced acute leukemia is associated with a high risk of relapse. It is postulated that interleukin-2 (IL-2) administered after BMT might induce or amplify a graft-versus-leukemia effect and thereby reduce the relapse rate. To identify an IL-2 regimen for testing this hypothesis, a phase I trial of IL-2 (Roche) was performed in children in complete remission (CR) without active graft-versus-host disease (GVHD) off immunosuppressive agents after unmodified allogeneic matched-sibling BMT for acute leukemia beyond first remission. Beginning a median of 68 days after BMT, 17 patients received escalating doses of induction IL-2 (0.9, 3.0, or 6.0 x 10(6) IU/m2/d representing levels I, II, and III) for 5 days by continuous intravenous infusion (CIV). After 6 days of rest, they received maintenance IL-2 (0.9 x 10(6) IU/m2/d) for 10 days by CIV infusion. Levels I and II were well-tolerated, but, of 6 patients at level III, 1 developed pulmonary infiltrates, 1 developed hypotension (both resolved), and 1 died of bacterial sepsis and acute respiratory distress syndrome. Grade II acute GVHD developed in 1 patient at level I and 1 at level III. The maximum tolerated dose of induction IL-2 was level II. IL-2 induced lymphocytosis, with an increase in CD56+ and CD8+ cells. Ten patients remain in CR at 5+ to 67+ months. Thus, a regimen of IL-2 has been identified that did not induce a high incidence of acute GVHD when administered to children after unmodified allogeneic BMT. Its clinical activity will be assessed in a phase II trial.     

The influence of the crutch setup on stability and weight-bearing parameters in post total hip replacement surgery patients during quiet standing

Purpose: The purpose of this study is to evaluate the influence of the crutch setup on standing, in post total hip replacement (THR) surgery patients.

Materials and methods: Thirty patients after THR were randomly assigned to walking with the elbow flexed (EF) or elbow straight (ES) crutch setup. Subjects were asked to stand on a force platform in a comfortable position with the crutch positioned on the unaffected side, facing forward for 10?seconds. Centre of pressure total path and maximal excursion were evaluated in both medio-lateral and anterior–posterior planes. Difference in the asymmetry of left/right acromial height, measured with and without the crutch, was calculated (ACdiff). Percentage of body weight borne by the crutch (Fcr), symmetry (SIload) between operated and healthy limbs loading during the trial, together with shoulder forces and moments were measured.

Results: No significant differences between the two groups (p?>?.05) were found for stability parameters. ACdiff, Fcr and shoulder load increased significantly (p?Conclusions: The present study showed that the ES setup reduced the force borne by the crutch, the load on the shoulder joint and it minimized postural and loading asymmetries when compared to EF setup. Conversely, postural stability was not influenced by the crutch setup.

• Implications for Rehabilitation

• Static posture and weight-bearing parameters are influenced by crutch setup during quiet standing.

• Crutch setup does not influence postural stability.

• Adjusting the crutch according to the elbow straight setup reduces the force borne by the crutch and the asymmetry in lower limbs loading.

• Forces and moments at the shoulder joint were reduced for the elbow straight setup group.

     

Practice-Based Research Priorities for Palliative Care: Results From a Research-to-Practice Consensus Workshop

We employed the research-to-practice consensus workshop (RTP; workshops held in New York City and Tompkins County, New York, in 2013) model to merge researcher and practitioner views of translational research priorities in palliative care. In the RTP approach, a diverse group of frontline providers generates a research agenda for palliative care in collaboration with researchers. We have presented the major workshop recommendations and contrasted the practice-based research priorities with those of previous consensus efforts. We uncovered notable differences and found that the RTP model can produce unique insights into research priorities. Integrating practitioner-identified needs into research priorities for palliative care can contribute to addressing palliative care more effectively as a public health issue.Over the past 2 decades, palliative care has become established as a promising approach for addressing the needs of individuals with life-threatening illnesses from a holistic, interdisciplinary perspective. For this project, we defined palliative care as an approach that improves the quality of life of patients and families facing the problems encountered in life-threatening illness by preventing and relieving suffering. Core components of palliative care include providing relief from pain and other distressing symptoms, affirming dying as a normal process, integrating psychological and spiritual aspects of care, enhancing the quality of life of patients, and offering support systems to patients and their families to help them live as fully as possible until death occurs.Research suggests that palliative care results in positive patient outcomes, greater patient and family satisfaction, and significant cost savings.1,2 The American Public Health Association, the World Health Organization, and the Institute of Medicine3–6 have identified the development of a robust palliative care delivery system as a key public health issue because of the documented ability of palliative care to deliver effective and efficient patient- and symptom-focused care to a growing population in need.In its 2013 report the American Public Health Association specifically detailed the public health implications of palliative care, acknowledged the growing burden of advanced chronic illness and disease in older adults, and recommended key steps to address the problem. This policy statement called for federal, state, and local efforts to promote effective symptom management in populations with serious illness or at the end of life. Other recommended initiatives included the development of a palliative care workforce, educational programs to improve uptake and use of palliative and hospice care, and research funding to support the expansion of palliative care initiatives. Achieving these goals will require moving beyond traditional medical practices to include both policies and initiatives at the public health level.Despite the potential of palliative care to address the mental and physical health needs of individuals with advanced illness, significant knowledge gaps impede its reach and effectiveness. Reports from scientific bodies and consensus workshops have highlighted weaknesses in the literature and called for more research on palliative care and improved research methods.7–10 Thus, although both interest in and demand for palliative care are increasing, reviews of the knowledge base continue to lament the lack of research on many key issues.11,12Especially urgent is a research agenda that fits most closely with the needs of providers who deliver palliative care. The systematic engagement of community practitioners in a consensus process can lead to particularly useful and actionable recommendations for research,13–15 which are greatly needed at this stage in the development of the field. Therefore, to shed new light on research priorities in palliative care, we used a structured, participatory method designed to solicit practitioner input on research priorities: the research-to-practice consensus workshop (RTP) model.16We employed the RTP approach to identify knowledge gaps and types of studies that should be conducted to improve providers’ ability to deliver palliative care most effectively. This model harnesses practice wisdom by engaging clinicians, agency staff, and other practitioners with researchers in a process of articulating and refining research questions and research priorities that honors scientific expertise and practice wisdom.     

Assessment and treatment of severe pancreatitis. Protease inhibitor

From the theoretical point of view, antiproteolytic therapy would seem to be the rationale for acute pancreatitis management. Unfortunately, clinical human trials studying the role of antiproteases in the treatment of acute pancreatitis differ in several respects in terms of their basic design. As a consequence, any form of homogeneous analysis of the reported data as a whole is impossible. Considering the data emerging from a meta-analysis of five trials a rational use of antiproteases may result in a reduction of complications requiring surgery and of patient management costs only in selected cases, meaning by that severe and necrotic forms. As regards presumptive applications, over 400 patients were prospectively tested versus placebo in a double-blind trial with the aim of preventing acute pancreatitis after ERCP. The complication incidence was significantly lower among the pretreated patients; anyway, also in this field of protease inhibitor clinical application it is necessary to identify the patients with the greatest risk to develop post-ERCP acute pancreatitis. In conclusion, antiproteases can still play a role when given prophylactically or when used in the very early phases of the disease; moreover a 'multiple drugs approach' (including, for example, suitable antibiotics) seems to represent nowadays the most modern and rational treatment of acute pancreatitis.     

Life Change Events,Ballistocardiography and Coronary Death

Abstract

Thirty-six men and women who experienced a documented myocardial infarction, half of whom ultimately died from their disease and half of whom survived over a six-year period, provided longitudinal recent life changes and ballistocardiographic data. The 18 patients who died from their coronary disease indicated a significant buildup in life changes which peaked approximately one year prior to death; their serial ballistocardiograms indicated a significant buildup in average force of contraction which was seen to peak approximately six months prior to death. The 18 post-infarction patients who survived the six-year follow-up showed neither a buildup in life change nor a buildup in the ballistocardiographic index of cardiac contraction force. These findings of a life change peak preceding ballistocardiographic evidence of an “overworked” heart are discussed in terms of their possible medical and psychophysiological significances.     

Effect of BH4 on blood phenylalanine and tyrosine variations in patients with phenylketonuria

BackgroundIn patients with phenylketonuria, stability of blood phenylalanine and tyrosine concentrations might influence brain chemistry and therefore patient outcome. This study prospectively investigated the effects of tetrahydrobiopterin (BH4), as a chaperone of phenylalanine hydroxylase on diurnal and day-to-day variations of blood phenylalanine and tyrosine concentrations.MethodsBlood phenylalanine and tyrosine were measured in dried blood spots (DBS) four times daily for 2 days (fasting, before lunch, before dinner, evening) and once daily (fasting) for 6 days in a randomized cross-over design with a period with BH4 and a period without BH4. The sequence was randomized. Eleven proven BH4 responsive PKU patients participated, 5 of them used protein substitutes during BH4 treatment. Natural protein intake and protein substitute dosing was adjusted during the period without BH4 in order to keep DBS phenylalanine levels within target range. Patients filled out a 3-day food diary during both study periods. Variations of DBS phenylalanine and Tyr were expressed in standard deviations (SD) and coefficient of variation (CV).ResultsBH4 treatment did not significantly influence day-to-day phenylalanine and tyrosine variations nor diurnal phenylalanine variations, but decreased diurnal tyrosine variations (median SD 17.6 μmol/l, median CV 21.3%, p = 0.01) compared to diet only (median SD 34.2 μmol/l, median CV 43.2%). Consequently, during BH4 treatment diurnal phenylalanine/tyrosine ratio variation was smaller, while fasting tyrosine levels tended to be higher.ConclusionBH4 did not impact phenylalanine variation but decreased diurnal tyrosine and phenylalanine/tyrosine ratio variations, possibly explained by less use of protein substitute and increased tyrosine synthesis.     

Plasma PCSK9 levels and sepsis severity: an early assessment in the emergency department

Clinical and Experimental Medicine - The aim of the study is to evaluate the prognostic value of early PCSK9 levels in non-intubated septic patients admitted to the emergency department. This...