Propafenone Hepatotoxicity: Report of a New Case and Review of the Literature

Propafenone is a class Ic antiarrhythmic drug. It is a beta-adrenergic blocker that causes bradycardia and bronchospasm. It is metabolized primarily in the liver. Its bioavailability and plasma concentration differ among patients under long-term therapy. They are genetically determined by the hepatic cytochrome P-450 2D6. Hepatic toxicity is highly uncommon. To date, only eight patients were reported in the reviewed world literature. In this article, one new case will be reported emphasizing the importance of medication history taking in patients presenting with new-onset liver enzymes abnormalities.     

频域OCT在病理性近视眼黄斑区神经上皮层厚度检测中的分析研究

目的应用频域OCT（光学相干断层扫描成像,Optical coherence tomography）技术分析研究病理性近视眼黄斑区视网膜神经上皮层厚度的变化特点。方法选取2012年2—12月在该院眼科行黄斑区频域OCT检查的病理性近视眼患者63例（63眼）作为观察组和正常眼患者54例（54眼）作为对照组,对其黄斑区视网膜进行测量,记录黄斑区9个分区的视网膜神经上皮层的平均厚度。结果 A1、A5区察组（病理性近视眼组）和对照组（正常眼组）之间的差异均无统计学意义（均为P〉0.05）;A2、A3区观察组（病理性近视眼组）均低于对照组（正常眼组）,P〈0.05,两组间的差异均有统计学意义;A4、A6、A7、A8、A9区,观察组（病理性近视眼组）均低于对照组（正常眼组）,P〈0.01,两组间的差异均有显著的统计学意义。结论病理性近视对视网膜特别是黄斑部的影响是确实存在的,频域OCT能够精确量化该厚度的变化。     

Poly-k-trend tests for survival adjusted analysis of tumor rates formulated as approximate multiple contrast test

In long-term rodent carcinogenicity studies without cause of death information, poly-k-adjusted tumor rates are commonly used to assess the carcinogenic potential of a compound. Testing trend on proportions, global tests such as the Cochran-Armitage test and Williams-type test have been proposed. Here are introduced simultaneous confidence intervals and adjusted p-values for multiple contrasts on poly-k-adjusted tumor rates, based on approximation with the multivariate normal distribution. Williams-type contrasts and Dunnett-type comparisons to control are special cases of this approach. In simulation studies, the acceptable performance for finite sample sizes is demonstrated. The methods are applied to a real data example and are implemented in a package for R.     

Structure and domain dynamics of human lactoferrin in solution and the influence of Fe(III)-ion ligand binding

Background

Human lactoferrin is an iron-binding protein of the innate immune system consisting of two connected lobes, each with a binding site located in a cleft. The clefts in each lobe undergo a hinge movement from open to close when Fe³⁺ is present in the solution and can be bound. The binding mechanism was assumed to relate on thermal domain fluctuations of the cleft domains prior to binding. We used Small Angle Neutron Scattering and Neutron Spin Echo Spectroscopy to determine the lactoferrin structure and domain dynamics in solution.

Results

When Fe³⁺ is present in solution interparticle interactions change from repulsive to attractive in conjunction with emerging metas aggregates, which are not observed without Fe³⁺. The protein form factor shows the expected change due to lobe closing if Fe³⁺ is present. The dominating motions of internal domain dynamics with relaxation times in the 30–50 ns range show strong bending and stretching modes with a steric suppressed torsion, but are almost independent of the cleft conformation. Thermally driven cleft closing motions of relevant amplitude are not observed if the cleft is open.

Conclusion

The Fe³⁺ binding mechanism is not related to thermal equilibrium fluctuations closing the cleft. A likely explanation may be that upon entering the cleft the iron ion first binds weakly which destabilizes and softens the hinge region and enables large fluctuations that then close the cleft resulting in the final formation of the stable iron binding site and, at the same time, stable closed conformation.

     

Bispecific-armed, interferon gamma-primed macrophage-mediated phagocytosis of malignant non-Hodgkin's lymphoma

To show that macrophages can be effectively targeted against malignant B cells, bispecific antibodies (BsAb) were constructed from two antibodies having specificity for the high-affinity Fc receptor for IgG (Fc gamma RI/CD64) and the B-cell differentiation antigens CD19 and CD37. Using a flow cytometry-based assay and confocal imaging, we show that these constructs mediated significant phagocytosis of B lymphocytes by macrophages that could be enhanced with interferon gamma (IFN gamma) and IFN gamma in combination with macrophage colony- stimulating factor. BsAb-dependent phagocytosis was triggered through Fc gamma RI and could be blocked only by using F(ab')2 fragments from the parent molecule or by cross-linking Fc gamma RI. BsAb-dependent phagocytosis was not blocked by antibodies to the other Fc receptors, Fc gamma RII and Fc gamma RIII. Because these antibody constructs bind to an epitope outside the Fc gamma RI ligand binding site, we show that autologous serum, polyclonal IgG, and monomeric IgG1 did not block BsAb- dependent phagocytosis, whereas autologous serum and the IgG fractions blocked parent molecule monoclonal antibody-dependent phagocytosis due to the avid binding of monomeric IgG to Fc gamma RI. Finally, BsAb- mediated phagocytosis was effective against the malignant B cells of patients with mantle cell lymphoma, prolymphocytic leukemia, and chronic lymphocytic leukemia. Based on these studies, we propose that BsAbs may provide an effective means of immunomodulation for patients with B-cell malignancies.     

Frequency, onset and clinical impact of somatic DNMT3A mutations in therapy-related and secondary acute myeloid leukemia

The recent identification of DNMT3A mutations in de novo acute myeloid leukemia prompted us to determine their frequency, patterns and clinical impact in a cohort of 98 patients with either therapy-related or secondary acute myeloid leukemia developing from an antecedent hematologic disorder. We identified 24 somatic mutations in 23 patients with a significantly higher frequency in secondary acute myeloid leukemia (35.1%) as compared to therapy-related acute myeloid leukemia (16.4%, P=0.0486). DNMT3A mutations were associated with a normal karyotype and IDH1/2 mutations, but did not affect survival. In contrast to de novo acute myeloid leukemia, most mutations did not affect arginine on position 882, but were predominantly found in the methyltransferase domain. All DNMT3A mutations identified in secondary acute myeloid leukemia were already present in the antecedent disorders indicating an early event. Reduction to homozygosity by uniparental disomy was observed in 2 patients with secondary acute myeloid leukemia during disease progression.