The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development

Splenic marginal zone lymphoma (SMZL) is a B cell malignancy of unknown pathogenesis, and thus an orphan of targeted therapies. By integrating whole-exome sequencing and copy-number analysis, we show that the SMZL exome carries at least 30 nonsilent gene alterations. Mutations in NOTCH2, a gene required for marginal-zone (MZ) B cell development, represent the most frequent lesion in SMZL, accounting for ～20% of cases. All NOTCH2 mutations are predicted to cause impaired degradation of the NOTCH2 protein by eliminating the C-terminal PEST domain, which is required for proteasomal recruitment. Among indolent B cell lymphoproliferative disorders, NOTCH2 mutations are restricted to SMZL, thus representing a potential diagnostic marker for this lymphoma type. In addition to NOTCH2, other modulators or members of the NOTCH pathway are recurrently targeted by genetic lesions in SMZL; these include NOTCH1, SPEN, and DTX1. We also noted mutations in other signaling pathways normally involved in MZ B cell development, suggesting that deregulation of MZ B cell development pathways plays a role in the pathogenesis of ～60% SMZL. These findings have direct implications for the treatment of SMZL patients, given the availability of drugs that can target NOTCH, NF-κB, and other pathways deregulated in this disease.     

Welfare properties of restrictions to health care based on cost effectiveness

In this note we explore the welfare properties of access restrictions to health care based on cost effectiveness. We show that such instrument can improve the average effectiveness of health care, but it is optimal only under specific assumptions relating to the shape of the welfare function and the utility of health care. Copyright © 2009 John Wiley & Sons, Ltd.     

Bail-out intracranial stenting with Solitaire AB device after unsuccessful thrombectomy in acute ischemic stroke of anterior circulation

Background

Recent trials established the efficacy of mechanical stent-retriever thrombectomy for treatment of stroke patients with large vessel occlusion (LVO) in the anterior circulation. However, stent-retriever thrombectomy may not accomplish successful recanalization in all patients. The aim of this study is to report the role of bail-out permanent stenting after failure of mechanical thrombectomy.

Bronchopulmonary dysplasia of the premature baby

Prematurely born infants who required assisted ventilation may develop chronic lung disease or bronchopulmonary dysplasia (BPD). The cells involved in the reparative process of the premature lung are not well defined. The repair of injured tissues is a highly standardized process and the most important cells are activated (modulated) fibroblasts (myofibroblasts). A key cytokine in controlling repair is transforming growth factor-β (TGF-β). To characterize the cells involved in the repair process of the premature lung, we employed immunocytochemical techniques and examined the lungs of 39 autopsied premature babies who had neonatal respiratory distress syndrome (RDS). All were treated in neonatal intensive care units and required mechanical ventilation and supplemental oxygen; all survived for at least 12 hours. Antibodies were employed against vimentin, α-smooth muscle (α-SM) actin, total muscle actin, desmin, MAC387, and TGF-β. Our study indicates that myofibroblasts are normally present along terminal airways in the developing lung. These cells increase in number some days after lung injury, form bundles of cells encircling terminal air spaces, and acquire desmin contractile filaments shortly thereafter. Myofibroblasts do not lose their contractile filaments with time, suggesting a conversion to smooth muscle metaplasia. The proliferation and migration of such myofibroblasts at sites of lung injury is associated with the presence of TGF-β. These findings suggest that myofibroblasts play an important role in premature lung repair. They may point the way to experimental and clinical trials that will identify drugs antagonistic to TGF-β (or other cytokines). Such antagonists may protect the neonates who are at high risk of developing BPD. Pediatr. Pulmonol. 1997;24:22–28. © 1997 Wiley-Liss, Inc.     

Effect of ionizing radiation on cell-cycle progression and cyclin B1 expression in human melanoma cells

In the present study we investigated the effect of γ-irradiation (2.5 and 10 Gy) on cell-cycle progression of a human melanoma cell line, M14, characterized by a moderate radiosensitivity (SF2 = 0.5). Flow cytometric analysis showed a dose-dependent S-phase accumulation, which was detectable 8 hr after treatment with 2 and 5 Gy and was still persistent at 12 hr after 10 Gy exposure. Such a delay in S-phase was paralleled or followed by an accumulation of cells in G₂M, which was transient at the lowest radiation doses and still persistent at 72 hr after 10 Gy. Such an accumulation was, at least in part, due to a block in G₂-M transition, as demonstrated by mitotic index analysis. Bivariate flow cytometric analysis of DNA content and cyclin B₁ expression showed that, following 2 and 5 Gy, the fraction of cyclin B₁-expressing cells was superimposable upon that of G₂M cells. Conversely, in cells treated with 10 Gy, the fraction of cyclin B₁-expressing cells was half the G₂M cell fraction. Northern-blot analysis indicated that the radiation-induced decrease in cyclin B₁ protein expression was accompanied by a reduced cyclin B mRNA level. On the whole, our results indicate a direct inhibitory effect of 10 Gy irradiation on cyclin B₁ expression as a possible cause for the persistent G₂ block in irradiated M14 cells. © 1996 Wiley-Liss, Inc.     

1H-MR Spectroscopy in Traumatic Brain Injury

Traumatic brain injury (TBI) is a common cause of neurological damage and disability. Conventional imaging (CT scan or MRI) is highly sensitive in detecting lesions and provides important clinical information regarding the need for acute intervention. However, abnormalities detected by CT scan or conventional MRI have limited importance in the classification of the degree of clinical severity and in predicting patients’ outcome. This can be explained by the widespread microscopic tissue damage occurring after trauma, which is not observable with the conventional structural imaging methods. Advances in neuroimaging over the past two decades have greatly helped in the clinical care and management of patients with TBI. The advent of newer and more sensitive imaging techniques is now being used to better characterize the nature and evolution of injury and the underlying mechanisms that lead to progressive neurodegeneration, recovery or subsequent plasticity. This review will describe the role of proton magnetic resonance spectroscopic (MRS), an advanced MRI technique as related to its use in TBI. Proton MRS is a noninvasive approach that acquires metabolite information reflecting neuronal integrity and function from multiple brain regions and allows to assess clinical severity and to predict disease outcome.     

Emotions in physician agency

Two ingredients seem essential in understanding the patient-physician relationship: (i) the physician's informational advantage and (ii) the relevance of the patient's emotions. Health economics has placed great emphasis on the first phenomenon, whereas the second has been considered only recently, that is with the growth of fields of analysis such as Economics and Psychology and Behavioral Medicine, and few investigations have been undertaken. In this article, we survey and discuss the important changes of perspective which the theory that studies the patient-physician relationship has undergone over time. We focus, in particular, on the attitude of patients towards health information and on the role of patient information in physician agency.