Small-molecule XIAP antagonist restores caspase-9 mediated apoptosis in XIAP-positive diffuse large B-cell lymphoma cells

Clinical outcome in patients with primary nodal diffuse large B-cell lymphomas (DLBCLs) is correlated with expression of inhibitors of the intrinsic apoptosis pathway, including X-linked inhibitor of apoptosis protein (XIAP). XIAP suppresses apoptosis through inhibiting active caspase-3, caspase-7, and caspase-9. In this study, we investigated to see if the small-molecule XIAP antagonist 1396-12 induces cell death in cultured lymphoma cells of patients with DLBCL. Treatment with this XIAP antagonist resulted in relief of caspase-3 inhibition and in induction of apoptosis in 16 of 20 tested DLBCL samples. Sensitivity to the XIAP antagonist was observed in both chemotherapy-refractory and -responsive DLBCL, but did not affect peripheral blood mononuclear cells and tonsil germinal-center B cells from healthy donors. XIAP antagonist-sensitive samples were characterized by high expression levels of XIAP, relatively low expression levels of Bcl-2, and by constitutive caspase-9 activation. These data indicate that the small-molecule XIAP antagonist can induce apoptosis in cultured DLBCL cells and therefore should be considered for possible development as a therapy for these patients. In vitro sensitivity to the XIAP antagonist can be predicted based on biological markers, suggesting the possibility of predefining patients most likely to benefit from XIAP antagonist therapy.     

Development of a peptide‐functionalized imaging nanoprobe for the targeting of (FXYD2)γa as a highly specific biomarker of pancreatic beta cells

Diabetes is characterized by a progressive decline of the pancreatic beta cell mass (BCM), which is responsible for insufficient insulin secretion and hyperglycaemia. There are currently no reliable methods to measure non‐invasively the BCM in diabetic patients. Our work describes a phage display‐derived peptide (P88) that is highly specific to (FXYD2)γa expressed by human beta cells and is proposed as a molecular vector for the development of functionalized imaging probes. P88 does not bind to the exocrine pancreas and is able to detect down to ~156 human pancreatic islets/mm³ in vitro after conjugation to ultra‐small particles of iron oxide (USPIO), as proven by the R₂ measured on MR images. For in vivo evaluation, MRI studies were carried out on nude mice bearing Capan‐2 tumours that also express (FXYD2)γa. A strong negative contrast was obtained subsequent to the injection of USPIO–P88, but not in negative controls. On human histological sections, USPIO–P88 seems to be specific to pancreatic beta cells, but not to duodenum, stomach or kidney tissues. USPIO–P88 thus represents a novel and promising tool for monitoring pancreatic BCM in diabetic patients. The quantitative correlation between BCM and R₂ remains to be demonstrated in vivo, but the T₂ mapping and the black pixel estimation after USPIO–P88 injection could provide important information for the future pancreatic BCM evaluation by MRI. Copyright © 2015 John Wiley & Sons, Ltd.     

Diagnostic accuracy of three screening questions (3Q/TMD) in relation to the DC/TMD in a specialized orofacial pain clinic

Objective: To determine the diagnostic accuracy of three screening questions (3Q/TMD) in relation to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD), in a specialized clinic.

Material and methods: Consecutive patients,?>18 years, referred with a possible TMD complaint to the Orofacial Pain and Dysfunction clinic, Academic Centre for Dentistry Amsterdam, the Netherlands, were included in the study. All patients (n?=?449; mean age 44 years; 72% females), answered the 3Q/TMD and the DC/TMD questionnaire before a DC/TMD examination. The 3Q/TMD constitutes of two questions on weekly pain from the jaw, face and temple region (Q1), and on function (Q2), and one function-related question on weekly catching and/or locking of the jaw (Q3). Q1 and Q2 were evaluated in relation to a DC/TMD pain diagnosis and Q3 in relation to a subgroup of DC/TMD intra-articular diagnosis, referred to as the reference standard.

Results: In total, 44% of patients received a pain-related DC/TMD diagnosis and 33% an intra-articular reference DC/TMD diagnosis. Sensitivity for the two pain screening questions was high (0.83–0.94), whereas specificity was low (0.41–0.55). For the function-related question, sensitivity was low (0.48), whereas specificity was high (0.96).

Conclusions: In a specialized pain clinic, the two pain questions (Q1, Q2) are positive in most patients with pain-related TMD. Therefore, in case of a positive response, further diagnostic procedures for TMD pain are warranted. For the functional screening question (Q3), a positive response is indicative for an intra-articular DC/TMD diagnosis, while in case of a negative outcome, an intra-articular TMD might still be present.     

Acute Hemodynamic Effects of Amlodipine 15 Days After a Myocardial Infarction in Normotensive Patients Treated with Atenolol

The acute hemodynamic effects of 20 mg iv amlodipine were evaluated in a placebo-controlled study in 16 normotensive patients 15 ± 1 days after an acute myocardial infarction by covariance analysis. Atenolol was given orally for at least 1 week before the study to maintain the heart rate between 50 and 60 beats/min. All patients were given two doses of 10 mg of amlodipine, or 10 ml of a placebo twice, in iv infusion lasting 2 minutes each. Hemodynamic data were collected during the control period and 15 minutes after each of the two amlodipine or placebo infusions. At the time of the last measurements, 15 minutes after the second amlodipine or placebo infusion, the plasma amlodipine level was 31 ± 16 g/l and the plasma atenolol level was 773 ± 564 /l in the amlodipine group versus 795 ± 916 g/l in the placebo group. There were no chronotropic, dromotropic, or inotropic effects. The main hemodynamic effect was a fall in systemic vascular resistance (1548 ± 591 dynes.sec.cm^-5to 1176 ± 526 dynes.sec.cm^-5, p = 0.045) with decreases in aortic pressure and in the left ventricular stroke work index. The left ventricular ejection fraction was 51 ± 12% in the placebo group and 56 ± 15% in the amlodipine group (ns) during the control period, and did not change after infusion of placebo or amlodipine. Left ventricular compliance seemed to be enhanced by amlodipine, because the end-diastolic left ventricular volume index rose from 82 ± 11 ml/m² to 87 ± 11 ml/m² (p = 0.026) 15 minutes after the beginning of the second infusion of 10 mg of amlodipine, without any change in end-diastolic left ventricular pressure. Intravenous infusion of 20 mg of amlodipine is well tolerated 15 days after acute myocardial infarction in normotensive patients without deeply depressed left ventricular systolic function and chronically treated with atenolol. The main hemodynamic effects observed are potentially useful for such patients.     

Carpometacarpal dislocations of the fingers

Injuries to the carpometacarpal joints (II–V) in the hand are uncommon. They comprise less than 1% of all handand wrist mjuries.^1,2 Patients with these injuries may see a physician several times before the proper diagnosis is determined.³ This article reviews the anatomy, diagnosis, and treatment of carpometacarpal dislocations of the fingers.