New immunosuppressive agents in transplantation

Immunosuppressive agents have enabled the development of allogenic transplantation during the last 40 years, allowing considerable improvement in graft survival. However, several issues remain such as the nephrotoxicity of calcineurin inhibitors, the cornerstone of immunosuppressive regimens and/or the higher risk of opportunistic infections and cancers. Most immunosuppressive agents target T cell activation and may not be efficient enough to prevent allo-immunization in the long term. Finally, antibody mediated rejection due to donor specific antibodies strongly affects allograft survival.Many drugs have been tested in the last decades, but very few have come to clinical use. The most recent one is CTLA4-Ig (belatacept), a costimulation blockade molecule that targets the second signal of T cell activation and is associated with a better long term kidney function than calcineurin inhibitors, despite an increased risk of acute cellular rejection.The research of new maintenance long-term immunosuppressive agents focuses on costimulation blockade. Agents inhibiting CD40-CD40 ligand interaction may enable a good control of both T cells and B cells responses. Anti-CD28 antibodies may promote regulatory T cells. Agents targeting this costimulation pathways are currently evaluated in clinical trials.Immunosuppressive agents for ABMR treatment are scarce since anti-CD20 agent rituximab and proteasome inhibitor bortezomib have failed to demonstrate an interest in ABMR. New drugs focusing on antibodies removal (imlifidase), B cell and plasmablasts (anti-IL-6/IL-6R, anti-CD38…) and complement inhibition are in the pipeline, with the challenge of their evaluation in such a heterogeneous pathology.     

Ungewöhnlicher Verlauf einer α-Mannosidose mit Symptomen einer paranoid-halluzinatorischen Psychose

Zusammenfassung Wir berichten über eine 27-jährige Patientin, bei der nach 10-jährigem Krankheitsverlauf mit rezidivierenden paranoid-halluzinatorischen Episoden und Behandlung unter der Diagnose einer schizophrenen Psychose eine -Mannosidose als Ursache der psychiatrischen Symptome gesichert werden konnte. Die -Mannosidose ist eine seltene autosomal-rezessiv vererbte lysosomale Speichererkrankung mit verminderter Aktivität des Enzyms -Mannosidase. Im vorliegenden Fall wurde die Diagnose erst relativ spät nach therapierefraktärem Behandlungsverlauf und zusätzlichem Auftreten einer progredienten kognitiven Störung gestellt. Erst nach umfangreicher differenzialdiagnostischer Abklärung wurde über den Nachweis einer verminderten -Mannosidase-Aktivität in Serum und Leukozyten die Diagnose etabliert. Diese Kasuistik veranschaulicht, dass außergewöhnliche klinische Verläufe oder auffällige Symptomkonstellationen, insbesondere in Verbindung mit organischer Komorbidität, bei psychotischen Patienten zu differenzialdiagnostischen Überlegungen in Richtung hereditärer Stoffwechselerkrankungen Anlass geben sollten.     

High Bioavailability of α-Tocopherol Loaded into Poly (DL-Lactic-co-Glycolic Acid) Microspheres in Apolipoprotein B Knockout Mice

PURPOSE: To assess the potential clinical value of alpha-tocopherol-loaded poly (DL-lactic-co-glycolic acid) (PLGA) microspheres, we examined the disposition kinetics of alpha-tocopherol after administration of the microspheres to apolipoprotein B (apo B) knockout mice as a model of abetalipoproteinemia. METHODS: PLGA microspheres containing alpha-tocopherol were prepared by a solvent-evaporation method. The concentration of alpha-tocopherol was measured by gas chromatography-mass spectrometry. RESULTS: The mean value of particle size of alpha-tocopherol-loaded PLGA microspheres was 108 microm. The loading and the trapping efficiency of alpha-tocopherol in PLGA microspheres were 20.8% and 86.6%, respectively. When alpha-tocopherol solution (25 mg/kg) was subcutaneously administered to apob (+/+) and apob (+/-) mice, the plasma concentrations of alpha-tocopherol reached a peak at 6 h and decreased to the endogenous level within 4 days in both types of mice. However, the area under the plasma concentration-time curve (AUC) of apob (+/-) mice was significantly smaller than that in the case of apob (+/+) mice. When alpha-tocopherol-loaded PLGA microspheres (100 mg/kg) were subcutaneously administered, the plasma concentrations of alpha-tocopherol increased slowly and remained about 2-fold higher than the endogenous level at 5 to 10 days after administration in both types of mice, and there was no significant difference between the AUC values. CONCLUSIONS: The PLGA microsphere preparation of alpha-tocopherol is expected to be a very useful drug delivery system in vitamin E supplementation therapy for abetalipoproteinemia.     

Organ culture of the postnatal mouse crista ampullaris part I

Summary The 2 day post partum mouse Crista ampullaris was cultured in vitro for 7 days. The differentiation into secretory and sensory areas was preserved. The ultrastructure of the dark cells of the secretory region was well maintained. The hair cell morphologically was considerably changed though the hair cells themselves survived 7 days in culture.Supported by grants from Karolinska Institutet, and Swedish Medical Research Council (Grant No. 12X-720)     

Different steric characteristics of β1- and β2-adrenoceptors

Summary -Adrenoceptors of lung (75% ₂) and heart (95% ₁) of calf were labelled with ³H-(–)-propranolol. The stereoisomers of 10 ligands were used to inhibit the binding of ³H-(–)-propranolol to membrane particles. The affinity ratio of sereoisomers is consistently greater for ₁-adrenoceptors than for ₂-adrenoceptors, regardless of whether the ligands are agonists, partial agonists or antagonists. The ₁-adrenoceptor appears to possess stricter steric requirements than the ₂-adrenoceptor. This property may prove helpful in differentiating the -adrenoceptor subtypes during receptor solubilization and purification.     

A phase 2b randomized,controlled trial of the efficacy of the GMZ2 malaria vaccine in African children

BackgroundGMZ2 is a recombinant protein malaria vaccine, comprising two blood-stage antigens of Plasmodium falciparum, glutamate-rich protein and merozoite surface protein 3. We assessed efficacy of GMZ2 in children in Burkina Faso, Gabon, Ghana and Uganda.MethodsChildren 12–60 months old were randomized to receive three injections of either 100 μg GMZ2 adjuvanted with aluminum hydroxide or a control vaccine (rabies) four weeks apart and were followed up for six months to measure the incidence of malaria defined as fever or history of fever and a parasite density ⩾5000/μL.ResultsA cohort of 1849 children were randomized, 1735 received three doses of vaccine (868 GMZ2, 867 control-vaccine). There were 641 malaria episodes in the GMZ2/Alum group and 720 in the control group. In the ATP analysis, vaccine efficacy (VE), adjusted for age and site was 14% (95% confidence interval [CI]: 3.6%, 23%, p-value = 0.009). In the ITT analysis, age-adjusted VE was 11.3% (95% CI 2.5%, 19%, p-value = 0.013). VE was higher in older children. In GMZ2-vaccinated children, the incidence of malaria decreased with increasing vaccine-induced anti-GMZ2 IgG concentration. There were 32 cases of severe malaria (18 in the rabies vaccine group and 14 in the GMZ2 group), VE 27% (95% CI −44%, 63%).ConclusionsGMZ2 is the first blood-stage malaria vaccine to be evaluated in a large multicenter trial. GMZ2 was well tolerated and immunogenic, and reduced the incidence of malaria, but efficacy would need to be substantially improved, using a more immunogenic formulation, for the vaccine to have a public health role.     

慢性淋巴细胞性白血病患者miR-9-3甲基化异常及其意义

目的本研究旨在探讨microRNA-9-3(miR-9-3)在慢性淋巴细胞性白血病骨髓细胞中的甲基化异常及其意义。方法采用甲基化特异性聚合酶链反应(MSP)技术检测8例正常骨髓组织、78例新确诊的慢性淋巴细胞性白血病患者和7种白血病细胞株甲基化水平。结果正常对照组miR-9-3呈未甲基化状态;7种白血病细胞株中有5种呈未甲基化状态(71.4%);78例慢性淋巴细胞性白血病患者中65例呈miR-9-3甲基化,MSP阳性率为83%。5-氮杂-2'-脱氧胞苷(5-Aza Dc)处理白血病细胞株后I83-E95和WAC3CD5+细胞株miR-9-3呈未甲基化状态。结论慢性淋巴细胞性白血病患者存在miR-9-3表达受抑,可能与其基因甲基化异常有关。而miR-9-3甲基化在激活慢性淋巴细胞性白血病患者NF-κB1信号通路的作用值得进一步研究。     

基于MSP430动态心电存储系统的设计

目的：解决动态心电图存储容量有限、波形不能实时显示的不便。方法：设计一种基于TI公司超低功耗混合信号处理器MSP430F149的动态心电数据实时存储、传输系统。结果：此系统由MSP430F149单片机、心电数据采集、LCD显示、SD卡存储、USB数据传输等部分组成,它能完成心电数据的实时采集、显示、大容量存储,以及心电数据的USB传输。结论：经临床初步实验,该仪器具有较强的抗干扰能力、性能稳定、功耗低、携带方便,应用前景广阔。     

Biomonitoring of mercury and persistent organic pollutants in Michigan urban anglers and association with fish consumption

The 32-mile Detroit River and surrounding tributaries have been designated as a Great Lakes Area of Concern due to pollution from decades of municipal and industrial discharges, sewer overflows and urban development. Key pollutants in fish samples from the Detroit River include mercury, polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene (DDE), dioxins and furans. A biomonitoring study was conducted to assess exposures to these persistent toxic substances in Detroit urban shoreline anglers who may be at high exposure risk due to consumption of locally caught fish. Using a modified venue-based sampling approach, 287 adult shoreline anglers along the Detroit River were recruited and participated in the program. Study participants provided blood and urine specimens and completed a questionnaire following informed consent. We examined percentile estimates for total blood mercury, PCBs, DDE, and dioxin-like total toxic equivalency (TEQ) concentrations among study participants. Multiple linear regression was used to identify important predictors of contaminant concentrations. Participants consumed a median of 64 Detroit River caught fish meals in the past year. The Detroit urban anglers’ median total blood mercury concentrations was 3.2 times higher than that for the general adult U.S. population. PCB concentrations among the Detroit anglers aged 18–39 years were higher than the U.S. population of the same race/ethnicity. Elevated levels of DDE and total TEQ concentrations were not observed in the cohort. Eating more locally caught fish was associated with higher total blood mercury and serum PCB concentrations. The biomonitoring data served to inform public health officials and help guide environmental public health actions to reduce harmful exposures.     

Design and synthesis of novel organometallic complexes using boronated phenylalanine derivatives as potential anticancer agents

Drug design and discovery studies are important because of the prevalence of diseases without available medical cures. New anticancer agents are particularly urgent because of the high mortality rate associated with cancer. A series of mononuclear gold (III) and platinum (II) complexes based on boronated phenylalanine (BPA) were designed and synthesized using 4,4’-dimethyl-2,2’-dipyridyl (L1) or 1,10-phenanthroline-5,6-dion (L2) ligands to obtain promising anticancer drug candidates. Proton nuclear magnetic resonance, infrared, mass spectrometry, and elemental analyses were utilized for chemical characterizations. Cell viability, cancer cell colony formation, endothelial tube formation, and cytoskeleton staining assays were performed using A549 lung adenocarcinoma and human umbilical vein endothelial cells (HUVECs) to investigate preliminary pharmacological activities. L1-based platinum (II) complex (BPA-L1-Pt) was the most promising complex, and has similar activity with the approved chemotherapy drug cis-platinum. Half maximal inhibitory concentration values for BPA-L1-Pt were 9.15 µM on A549s and 16.61 µM on HUVECs; the values for cis-platinum were 5.24 µM on A549s and 23.14 µM on HUVECs. Consequently, further synthesis studies should be performed to boost the cancer cell selectivity feature of BPA by varying metal and ligand types.