Thrombosis is associated with inferior survival in multiple myeloma.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.Patients with multiple myeloma are at an increased risk of venous thromboembolism and arterial thrombosis. We assessed the impact of venous and arterial thrombosis on survival in a population-based study of 9,399 multiple myeloma patients diagnosed in Sweden from 1987 to 2005. We found multiple myeloma patients with venous thromboembolism to have a higher mortality at 1-, 5-, and 10-years of follow up compared with those without, with hazard ratios of 2.9 (95% confidence interval (CI) 2.4-3.5), 1.6 (95% CI: 1.5-1.8), and 1.6 (95% CI: 1.4-1.7), respectively. There was an increase in risk of death among multiple myeloma patients with arterial thrombosis, with hazard ratios of 3.4 (95% CI: 3.0-3.8), 2.2 (95% CI: 2.0-2.3), and 2.1 (95% CI: 1.9-2.1), respectively. In landmark analyses at six months, early arterial but not venous thromboembolism was associated with a higher risk of death. Thus, in contrast to prior smaller studies, we found the development of thrombosis to be associated with significantly poorer survival. The prevention of thrombosis in multiple myeloma is an important goal in the management of these patients.regional agreement on medical training and clinical research (ALF) between Stockholm County Council regional agreement on medical training and clinical research (ALF) between Karolinska Institutet Cancer Society in Stockholm Intramural Research Program of the NIH, NC

Circulating Biomarkers to Identify Responders in Cardiac Cell therapy.

Bone marrow mononuclear cell (BM-MNC) therapy in ST-elevation acute myocardial infarction (STEMI) has no biological inclusion criteria. Here, we analyzed 63 biomarkers and cytokines in baseline plasma samples from 77 STEMI patients treated with BM-MNCs in the TIME and Late-TIME trials as well as 61 STEMI patients treated with placebo. Response to cell therapy was defined by changes in left ventricular ejection fraction, systolic/diastolic volumes, and wall motion indexes. We investigated the clinical value of circulating proteins in outcome prediction using significance testing, partial least squares discriminant analysis, and receiver operating characteristic (ROC) analysis. Responders had higher biomarker levels (76-94% elevated) than non-responders. Several biomarkers had values that differed significantly (P < 0.05) between responders and non-responders including stem cell factor, platelet-derived growth factor, and interleukin-15. We then used these lead candidates for ROC analysis and found multiple biomarkers with values areas under the curve >0.70 including interleukin 15. These biomarkers were not involved in the placebo-treated subjects suggesting that they may have predictive power. We conclude that plasma profiling after STEMI may help identify patients with a greater likelihood of response to cell-based treatment. Prospective trials are needed to assess the predictive value of the circulating biomarkers

Author Correction: Circulating Biomarkers to Identify Responders in Cardiac Cell therapy.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper

A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial

Aims: CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. Methods and results: Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. Conclusions: This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Prevention of Elderly Pedestrian Injury - A Comprehensive Approach and Analysis

The mortality rate for elderly pedestrians struck by vehicles is the highest of any age group, approaching 30% in several large series. Currently, there is a lack of epidemiological studies of the risk factors associated with elderly pedestrian injury; in particular, few prospective studies of elderly pedestrian injuries have been performed. The primary purpose of this project was to identify risk factors that will lead to the development and implementation of effective prevention strategies to reduce the risk of pedestrian injury in this vulnerable population. The project had three phases. In phase 1, pilot studies were performed and identified potential risk factors for elderly pedestrians and confirmed their ability to recall accident details. Risk factors identified included certain walking and street crossing behaviors, as well as the lack of use of assistive devices. In Phase 2, the relatively new case-crossover design was utilized to investigate the association of transient (proximate) triggers or exposures with elderly pedestrian injuries. The relative risk of injury if not obeying the traffic signal is five-fold (odds ratio = 5.2; 95% confidence interval = 1.8 – 15.1). Risk factors such as use of sedating or mood altering medications, or the use of alcohol did not have sufficient discordance for analysis. The behavioral findings suggested that educational programs and behavioral modification might play an important role in designing future interventions. Therefore, in Phase 3, an elderly pedestrian safety program called Safe Crossings was created and evaluated. Over 700 subjects participated in the programs, with 99% reporting they felt it was an important topic and 93% acknowledging they learned something from the program. Focus groups were also utilized to help refine the content and delivery of the program. Posters and brochures were created and distributed in English, Spanish and Creole. The program is now set for wider dissemination and validation.</p