Neuronal activity in the globus pallidus of multiple system atrophy patients.

The pathophysiological changes in neural activity that characterize multiple system atrophy (MSA) are largely unknown. We recorded the activity of pallidal neurons in 3 patients with clinical and radiological features of MSA who underwent unilateral microelectrode-guided pallidotomy for disabling parkinsonism. Findings in these patients were compared with 4 control patients with a clinical diagnosis of Parkinson's disease (PD). The position, firing rates, and firing patterns of single neurons in the pallidal complex were analyzed in both MSA and PD patients. The mean spontaneous firing rate of neurons in the internal segment of the globus pallidus internus (GPii) was significantly lower in MSA than in PD patients. There were no significant differences between MSA and PD patients, however, in firing rates of neurons in the external globus pallidus (GPe) or in the external segment of GPi (GPie). In addition, no significant differences in firing pattern were found between MSA and PD patients. In conclusion, this study has shown that firing rates of neurons in GPii but not in GPie and GPe are different in MSA patients compared with that in PD patients, a finding that may reflect the poor clinical results of pallidotomy reported in patients with MSA.     

Vaccine-Induced Protection from Homologous Tier 2 SHIV Challenge in Nonhuman Primates Depends on Serum-Neutralizing Antibody Titers

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消渴灵冲剂治疗糖尿病的实验研究

目的 :观察消渴灵冲剂对Alloxan糖尿病大鼠的治疗作用。方法 :设立高、低剂量组与西药二甲双胍组作对照 ,动态地观察大鼠FBG、IRI及血流变等指标。结果 :消渴灵可降低Alloxan糖尿病大鼠异常升高的FBG、GHb水平 ,升高空腹IRI水平 ,与治疗前相比差异显著 (P <0 .0 1)。其降糖作用与二甲双胍组相比无差异。消渴灵可降低Alloxan糖尿病大鼠异常升高的Hr、Lr、Br等血流变指标 ,对抗血液的高凝高粘状态 ,其疗效优于二甲双胍 (P <0 .0 1) ,消渴灵有助于糖尿病大鼠恢复体重。结论 :其机理可能在于促进胰岛 β细胞的分泌功能 ,升高血中IRI水平 ,增进细胞对葡萄糖的利用 ,增强免疫功能 ,改善营养状态 ,改善血流变等。     

Telemedicine and type 1 diabetes: Is technology per se sufficient to improve glycaemic control?

AimIn the TELEDIAB-1 study, the Diabeo system (a smartphone coupled to a website) improved HbA_1c by 0.9% vs controls in patients with chronic, poorly controlled type 1 diabetes. The system provided two main functions: automated advice on the insulin doses required; and remote monitoring by teleconsultation. The question is: how much did each function contribute to the improvement in HbA_1c?MethodsEach patient received a smartphone with an insulin dose advisor (IDA) and with (G3 group) or without (G2 group) the telemonitoring/teleconsultation function. Patients were classified as “high users” if the proportion of “informed” meals using the IDA exceeded 67% (median) and as “low users” if not. Also analyzed was the respective impact of the IDA function and teleconsultations on the final HbA_1c levels.ResultsAmong the high users, the proportion of informed meals remained stable from baseline to the end of the study 6 months later (from 78.1 ± 21.5% to 73.8 ± 25.1%; P = 0.107), but decreased in the low users (from 36.6 ± 29.4% to 26.7 ± 28.4%; P = 0.005). As expected, HbA_1c improved in high users from 8.7% [range: 8.3–9.2%] to 8.2% [range: 7.8–8.7%] in patients with (n = 26) vs without (n = 30) the benefit of telemonitoring/teleconsultation (−0.49 ± 0.60% vs −0.52 ± 0.73%, respectively; P = 0.879). However, although HbA_1c also improved in low users from 9.0% [8.5–10.1] to 8.5% [7.9–9.6], those receiving support via teleconsultation tended to show greater improvement than the others (−0.93 ± 0.97 vs −0.46 ± 1.05, respectively; P = 0.084).ConclusionThe Diabeo system improved glycaemic control in both high and low users who avidly used the IDA function, while the greatest improvement was seen in the low users who had the motivational support of teleconsultations.     

Recombinant HIV envelope trimer selects for quaternary-dependent antibodies targeting the trimer apex

Broadly neutralizing antibodies (bnAbs) targeting the trimer apex of HIV envelope are favored candidates for vaccine design and immunotherapy because of their great neutralization breadth and potency. However, methods of isolating bnAbs against this site have been limited by the quaternary nature of the epitope region. Here we report the use of a recombinant HIV envelope trimer, BG505 SOSIP.664 gp140, as an affinity reagent to isolate quaternary-dependent bnAbs from the peripheral blood mononuclear cells of a chronically infected donor. The newly isolated bnAbs, named “PGDM1400–1412,” show a wide range of neutralization breadth and potency. One of these variants, PGDM1400, is exceptionally broad and potent with cross-clade neutralization coverage of 83% at a median IC₅₀ of 0.003 µg/mL. Overall, our results highlight the utility of BG505 SOSIP.664 gp140 as a tool for the isolation of quaternary-dependent antibodies and reveal a mosaic of antibody responses against the trimer apex within a clonal family.Multiple methods have been developed to isolate HIV broadly neutralizing antibodies (bnAbs) (1–12). Hybridoma and phage display techniques were used to isolate the first generation of bnAbs including b12, 2F5, 2G12, 4E10, and Z13 (13–20). These antibodies exhibit a range of neutralization breadth against primary isolates from 30 to 90% but have moderate neutralization potency (median IC₅₀ of ∼2–4 µg/mL). Access to infected donors who have high serum titers of bnAbs (21, 22) and the availability of newer approaches for isolating human mAbs have recently enabled the discovery of a new generation of more potent bnAbs (1–4, 6–8).One of the newer approaches involves the sorting and activation of large numbers of memory B cells using cytokine-secreting feeder cells and the subsequent high-throughput screening of supernatants for neutralization. This method led to the identification and characterization of the first of the new generation of bnAbs, PG9 and PG16 (1), and since then has revealed several sites of vulnerability to bnAb recognition on HIV envelope (Env) (1–4, 6, 7). An alternative method of bnAb isolation involves the use of soluble Env molecules or scaffold proteins as baits to select single IgG⁺ memory B cells of interest by cell sorting (6, 8, 9, 23, 24). However, soluble baits have not been successful in isolating antibody responses targeting quaternary epitopes, including the trimer-apex site surrounding the N160 glycan, because the protein constructs used to date have not properly mimicked native Env trimers. To address this problem, GFP-labeled 293T cells that express cell-surface Env, called “GFP-293T^BaL cells,” were used recently to isolate antibodies 3BC176 and 3BC315 (10, 25). These antibodies do not bind soluble monomeric gp120 but do bind Env trimer, demonstrating the utility of the approach, but the method was reported to be less efficient than the use of soluble protein baits (10, 25).The favorable antigenic profile of the soluble BG505 SOSIP.664 gp140 trimer opens the possibility of its use for isolating quaternary-specific antibodies by single-cell sorting (26). To this end, we used BG505 SOSIP.664 gp140 to select for memory B cells from a donor from whom we previously had isolated the trimer-specific bnAbs PGT141–145 (3, 21). (For naming of PGT and PGDM bnAbs, please see SI Materials and Methods, Antibody Nomenclature.) We describe the isolation of previously unidentified somatic variants that are highly divergent from PGT145 and display a range of neutralization breadth and potency, with some being broader and more potent than the previously described PGT145 family members. Overall, the results reveal a mosaic of antibody responses against the trimer-apex site of vulnerability that have important implications for immunogen design in general and for the future optimization of BG505 SOSIP.664 and related native-like trimers as vaccine candidates.     

nHA/BG涂层与Bio-Oss骨粉修复种植体骨缺损的实验研究

目的:评价生物玻璃/纳米羟基磷灰石(nHA/BG)涂层与Bio-Oss骨粉在种植体骨缺损中引导骨再生的效果。方法:选取6只Beagle犬,拔除两侧下颌前磨牙。3个月后预备种植窝,同时颊侧制造裂隙状骨缺损(2.25 mm×3 mm×4 mm)。按照分组植入种植体和骨粉,A组为nHA/BG+Bio-Oss,B组为nHA/BG+血凝块愈合,C组为微米级HA+Bio-Oss。术后2周、处死前2周和3 d分别进行四环素、钙黄绿素和茜素红荧光标记。术后8周和16周处死动物,行大体观察和组织学测量。采用SPSS13.0软件包对数据进行统计学分析。结果:3组骨-种植体结合率(BIC)在8周时分别为30%、18%、21%,16周时分别为61%、53%、46%;缺损区新骨面积(RA)在8周时分别为(2.1±0.6)mm3、(1.4±1.0)mm3、(0.6±0.1)mm3,16周时分别为(4.2±0.7)mm3、(2.2±1.2)mm3、(1.2±0.6)mm3。各组8周与16周的BIC和RA相比均有显著差异(P<0.05);8周时,A、C 2组的BIC和RA相比有显著差异(P<0.05),16周时,A、B 2组的RA相比有显著差异(P<0.05)。结论:在种植体周围2.25 mm骨缺损区,nHA/BG涂层能促进种植体-Bio-Oss替代骨-骨的骨结合。