MR imaging of rheumatoid hand lesions: comparison with conventional radiology in 31 patients.

The purpose of this study was to evaluate the diagnostic accuracy of magnetic resonance imaging (MRI) in rheumatoid arthritis (RA) by comparing MRI with conventional radiology (CR) findings and by correlating these findings with the clinical and serological profile of the disease. The hands of 31 patients (24 females, 7 males) affected by classical RA were studied using a Magnetom 1.0 T tomograph. Coronal, axial, and/or sagittal SE T1 and GE (FLASH 2D FL: 70 degrees-15 degrees) images were obtained in all patients. Moreover, in 7 patients the MRI study was performed after i.v. injection of Gd DTPA contrast medium (0.2 mM/kg). Ten healthy volunteers were also studied as controls. In all patients a conventional radiological study was performed as well as a clinical and serological investigation. Two blinded observers evaluated the MRI and CR findings and checked 15 elementary pathological lesions, assigning an MRI and a CR score to each patient. MRI provided higher accuracy than CR in detecting rheumatoid soft tissue changes and minimal skeletal lesions, while the opposite was true for severe skeletal lesions. No correlations emerged between the MRI/CR findings and clinical and serological data. This study suggests that MRI and CR are complementary techniques in the evaluation of the anatomical changes in RA.     

Safety,pharmacokinetics and target engagement of novel RIPK1 inhibitor SAR443060 (DNL747) for neurodegenerative disorders: Randomized,placebo‐controlled,double‐blind phase I/Ib studies in healthy subjects and patients

RIPK1 is a master regulator of inflammatory signaling and cell death and increased RIPK1 activity is observed in human diseases, including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). RIPK1 inhibition has been shown to protect against cell death in a range of preclinical cellular and animal models of diseases. SAR443060 (previously DNL747) is a selective, orally bioavailable, central nervous system (CNS)–penetrant, small‐molecule, reversible inhibitor of RIPK1. In three early‐stage clinical trials in healthy subjects and patients with AD or ALS ({"type":"clinical-trial","attrs":{"text":"NCT03757325","term_id":"NCT03757325"}}NCT03757325 and {"type":"clinical-trial","attrs":{"text":"NCT03757351","term_id":"NCT03757351"}}NCT03757351), SAR443060 distributed into the cerebrospinal fluid (CSF) after oral administration and demonstrated robust peripheral target engagement as measured by a reduction in phosphorylation of RIPK1 at serine 166 (pRIPK1) in human peripheral blood mononuclear cells compared to baseline. RIPK1 inhibition was generally safe and well‐tolerated in healthy volunteers and patients with AD or ALS. Taken together, the distribution into the CSF after oral administration, the peripheral proof‐of‐mechanism, and the safety profile of RIPK1 inhibition to date, suggest that therapeutic modulation of RIPK1 in the CNS is possible, conferring potential therapeutic promise for AD and ALS, as well as other neurodegenerative conditions. However, SAR443060 development was discontinued due to long‐term nonclinical toxicology findings, although these nonclinical toxicology signals were not observed in the short duration dosing in any of the three early‐stage clinical trials. The dose‐limiting toxicities observed for SAR443060 preclinically have not been reported for other RIPK1‐inhibitors, suggesting that these toxicities are compound‐specific (related to SAR443060) rather than RIPK1 pathway‐specific.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

RIPK1 inhibition has been shown to protect against cell death in a range of preclinical cellular and animal models of diseases, including for Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS).

• WHAT QUESTION DID THIS STUDY ADDRESS?

Three early‐stage clinical trials evaluating a central nervous system (CNS) penetrant small molecule RIPK1 inhibitor in healthy subjects and patients with AD or ALS suggest central RIPK1 inhibition is safe and pharmacokinetic and peripheral target engagement can be reliably measured.WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?RIPK1 inhibition by SAR443060 was safe and well‐tolerated for up to 28 days in patients with AD and ALS. SAR443060 distributed into the cerebrospinal fluid CSF after oral administration and demonstrated median peripheral target engagement (pRIPK1‐inhibition in peripheral blood mononuclear cells) at steady‐state trough of 81.83% and 65.92% at a 50 mg b.i.d. dose level in patients with AD and ALS.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The combination of CSF‐distribution and robust peripheral target engagement offers an encouraging proof‐of‐mechanism that therapeutic modulation of RIPK1 in the CNS may be possible and further studies should be pursued.     

Patterns of place‐based self‐regulation and associated mental health of urban adolescents

Efforts to simultaneously address adolescent self‐regulation, activity space (routine locations), and mental health represent a promising social ecological approach aimed at understanding the lives and development of urban youth. This type of examination of contextual influences on self‐regulation is considered an important area of developmental research, yet one that is understudied (McCabe, Cunnington, & Brooks‐Gunn, 2004 ). Little is known about the self‐regulatory experiences that might link specific types of locations with mental health problems, particularly with urban youth who live in areas characterized by chronic and severe stressors such as personal violence, criminal activity, and poverty. Recent research has demonstrated the “power of context” (Tolan, Gorman‐Smith, Henry, Chung, & Hunt, 2002 ) to influence coping styles and has demonstrated that without detailed and specified knowledge of the social ecology of urban youth, measurement of critical variables and interpretation of results are likely to be misinformed (Tolan & Grant, 2009 ). Given the importance of understanding youth through an interactive and contextual framework (Bronfenbrenner, 1979 ; Szapocznik & Coatsworth, 1999 ), the present study examined self‐regulatory experiences, specified favorite locations, and mental health with urban adolescents residing in low‐resource and high‐risk environments. © 2010 Wiley Periodicals, Inc.     

Consolidation therapy for adult acute myeloid leukemia: a systematic analysis according to evidence based medicine

Post-remission therapy in acute myeloid leukemia (AML) remains problematic. It has been demonstrated that younger patients can maintain longer complete remissions (CR) with aggressive post-remission therapies after induction treatment: allogeneic (allo), autologous (auto) stem cell transplantation (SCT), or intensive chemotherapy (ICC). The purpose of our study was to identify the most important randomized and controlled studies comparing these three therapeutic options, in order to draw conclusions and possible suggestions for post-remission therapy of AML, according to the evidence based medicine (EBM) rules. We performed an exhaustive analysis of the literature, searching either in electronic databases or among the references of the identified articles (hand searching). We searched the MEDLINE computer database for reports from 1985 through January 2005 and selected for analysis the clinical trials conducted over adults affected by newly diagnosed AML aged less than 65 years. The study design had to satisfy strict methodological criteria and must consider global mortality and/or disease free survival as primary outcomes. Overall we found 7750 papers; by using the limits "clinical trial" as publication type, "all adults 19+ years", we were able to select 344 papers. Among these, a further selection was made, based on two main clinical queries: 1) is auto-SCT superior to ICC/no other therapy in improving DFS and/or OS in adult AML patients in first CR? 2) is allo-SCT superior to auto-SCT/other therapeutic options in improving DFS and/or OS in adult AML patients in first CR? Concerning the first query, a possible advantage of auto-SCT over ICC was not clearly supported by data from clinical trials; there is no evidence that auto-SCT is superior in terms of OS to chemotherapy. Nevertheless, the reported TRM has been significantly reduced within the past years. Thus, the percentage of patients suitable for auto-SCT in CR has increased. Moreover, the scarce data concerning the comparison between auto-SCT and chemotherapy in different subsets of patients are unable to suggest a differentiated approach in patients with high-risk, standard-risk or low-risk AML. Data from the literature show that patients with unfavorable risk disease are more often addressed to allo-SCT and patients with low-risk disease receive more often intensive consolidation chemotherapy. Concerning the second query, interpretation of data from the main prospective studies about the role of allo-SCT in previously untreated AML is not easy. The first problem is the lack of real randomized clinical trials; in fact, according to the reported studies, AML patients generally receive allo-SCT on the basis of donor availability (the so called "genetic randomization"). The second problem is the frequent absence of intention to treat analysis. Despite methodological limitations, it was possible to compare allo-SCT with auto-SCT on a donor versus no-donor analysis and within risk groups. No overall benefit of allo-grafting on survival was demonstrated by any trial. In conclusion, the EBM approach highlighted the limitations observed in the published studies concerning consolidation therapy in AML; some suggestions, emerging from non-randomized, as well as randomized studies, are adequate, but not conclusive. This point, coupled with the intrinsic complexity to study AML biological heterogeneity, is probably a major obstacle to draw conclusive evidences for consolidation therapy in AML. These observations should plan to address new randomized studies on AML therapy; however, due to the emergence of genetic subgroups and new drugs targeting specific abnormalities, these trials should probably be designed directly focusing on the single entities. In this way, the cure of AML could eventually become the cure of each specific AML subset with its peculiar biological, molecular and prognostic features.     

Management of spontaneous soft-tissue hemorrhage secondary to anticoagulant therapy: A cohort study

Study objective

The optimal management of patients receiving heparin, warfarin or direct anti-coagulant therapy who experience spontaneous, severe, life-threatening soft-tissue hemorrhage (SSTH) is unclear. The purpose of this study is to investigate efficacy and safety of the interventional protocol implemented in our department.