Immunogenicity and safety of a novel yeast Hansenula polymorpha-derived recombinant Hepatitis B candidate vaccine in healthy adolescents and adults aged 10–45 years

The aim was to determine whether the immunogenicity of an investigational hepatitis B vaccine (spHB) is at least as high as that of a licensed control vaccine, Engerix B^®, and to evaluate its safety before inclusion in new pediatric combination vaccines. Two randomized, controlled, blind-observer, Phase 3 trials were performed: one in Argentina (344 participants aged 10–15 years, 10 μg HBsAg/dose) and one in Uruguay (344 participants aged 16–45 years, 20 μg HBsAg/dose). Both vaccines were given in a 0, 1, 6 month schedule to all participants with a baseline anti-Hep B antibody titer <0.6 mIU/mL. Antibody titers were measured pre-dose 1, 1 month after dose 2, pre-dose 3, and 1 month after dose 3. Statistical non-inferiority analyses were performed on seroprotection rates (SP) post-dose 3 (% with anti-Hep B titers ≥10 mIU/mL; delta non-inferiority limit of −10%). In both studies, SP for the spHB vaccine was 100% and the spHB vaccine was non-inferior in terms of SP to the licensed control vaccine. GMTs post-dose 3 were approximately 1.8- and 4.1-fold higher for spHB in the 10–15 year and 16–45 year age groups, respectively. Reactogenicity was low for each vaccine, after each dose. This highly immunogenic hepatitis B candidate vaccine was selected for further investigation as a component of new pediatric combination vaccines.     

食品添加剂KAl（SO4）2中Al的吸收,排泄,蓄积实验研究

目的：探讨我国主要含铝食品添加剂——硫酸铝钾中铝的吸收、排泄和贮留的基本情况。方法：１．采用６月龄日本雄性大耳兔８只进行３天的代谢平衡实验。２．选用２～３月龄２１只雄性兔进行３２周的蓄积实验。结果：代谢实验表明铝的表观吸收率平均在１０％左右，约９０％的口服铝在粪中排出。尿铝随摄入铝的增加而增加，但肾排铝能力不足吸收的１０％。兔的蓄积实验证明在３２周实验后实验兔随铝摄入的增加其主要脏器均有不同程度的铝蓄积。其蓄积量的顺序为：骨＞肝＞肾＞脑＞心（３．８９～１０５．４６ｍｇ／ｋｇ干重）；蓄积增长倍数为：肝＞脑＞肾＞骨＞心（１．５１～４．５８倍）。结论：１．食品添加剂硫酸铝钾中铝的表观吸收率平均在１０％左右。尿铝随摄入铝的增加而增加，但肾排铝量不足吸收的１０％。２．长期大量摄入含铝食品添加剂可导致机体铝蓄积，其中脑、骨、肝、肾蓄积较明显。     

Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson's disease: a LAMMA study

The Laser Microprobe Mass Analyzer (LAMMA) is a sensitive instrument for identifying and localizing trace elements in tissue samples. Using LAMMA, we have examined melanin-containing neurons of the substantia nigra in patients with Parkinson's disease (PD) and controls. We found that iron significantly accumulates within neuromelanin granules of patients with PD compared to controls. Increased aluminum was found in the neuromelanin granules of 2 of 3 PD cases but in no controls. The accumulation of iron and aluminum, which are known to promote oxidant stress, may account for the selective degeneration of neuromelanin-containing neurons in PD.     

Alterations in short-term retention, conditioned avoidance response acquisition and motivation following aluminum induced neurofibrillary degeneration

Aluminum chloride induced neurofibrillary degeneration may provide a useful model for the study of a human dementia process. This possibility was assessed in cats trained to perform on a delayed-response task, a conditioned avoidance task, visual and temporal discrimination tasks and a motivational task involving rewarding intracranial electrical stimulation. After an initial asymptomatic period short term retention and acquisition of a conditioned avoidance response were selectively impaired. The associated ultrastructural abnormalities plausibly implicate the cytoplasmic streaming mechanism in the cellular substrate for some retention and acquisition phenomena.     

一起由磷化铝引起的家庭聚集性中毒事件的调查分析

目的 分析一起由磷化铝引起的家庭聚集性中毒事件的流行病学特征,为今后处置类似事件提供科学的依据。方法 对2021年济南市商河县一起急性中毒事件开展现场流行病学调查和实验室检测。调查主要针对病例及其家属进行面访,并入户考察和采集食品、环境标本和病例标本。结果 本事件共涉及7人,其中病例6例,罹患率85.7%,病例男女比例1∶1.33（3∶4）,1例死亡。指示病例发病时间为23日20时左右,末例发病时间为24日6时左右,推测潜伏期为8～12小时。临床表现以呕吐（100%）、阵发性腹痛（100%）、恶心（43%）和腹泻（43%）为主。未发现家庭成员有可疑共同暴露餐次和可疑暴露食品。实验室在所采集的环境空气样本和死亡病例的血中检出磷化氢（PH3）。结论 本次事件是一起磷化铝使用不当引起的家庭聚集性磷化铝中毒事件,储粮间的磷化铝吸潮挥发产生的磷化氢是主要致病因素。     

姜黄素对氯化铝染毒的NG108 - 15细胞凋亡及PKC - NMDAR通路表达的影响

目的 探讨姜黄素对氯化铝染毒所致NG108 - 15细胞凋亡的影响及其机制,为铝致学习记忆损伤的治疗提供参考。方法 取对数生长期NG108 - 15细胞,随机分为空白对照组、DMSO组（溶剂对照）、姜黄素组（16 μmol/L姜黄素）、铝组（160 mg/L氯化铝染毒 ）、铝+姜黄素组（160 mg/L氯化铝染毒24 h后,给予16 μmol/L姜黄素处理24 h）。收集各组细胞,采用吖啶橙/嗅化乙锭（AO/EB）双荧光染色观察细胞凋亡形态,计数凋亡细胞数并计算凋亡率;流式细胞术检测细胞凋亡率, qRT - PCR检测细胞中PKC、NMDAR1、NMDAR2B 的mRNA表达水平,western blot检测细胞中凋亡相关蛋白（caspase3、Bax）和PKC、NMDAR1、NMDAR2B的蛋白表达水平。多组间均数的比较采用单因素方差分析（one - way ANOVA）,组间两样本均数的比较采用LSD法。结果 与空白对照组相比,铝染毒组的caspase3、Bax蛋白表达水平升高（t = - 5.547、 - 4.948,P＜0.001）,PKC、NMDAR1、NMDAR2B的mRNA（t = 4.926,P = 0.003;t = 6.330,P＜0.001;t = 4.224,P = 0.019）和蛋白（t = 20.638,P＜0.001;t = 4.509,P＜0.001;t = 17.388,P = 0.002）表达水平降低, AO/EB染色和流式细胞术结果均表明细胞凋亡率升高（t = - 5.153、 - 7.390,P＜0.001）;加入姜黄素处理后,与铝染毒组相比,铝+姜黄素组的caspase3、Bax蛋白表达水平降低（t = 2.930,P = 0.006;t = 4.907,P＜0.001）,PKC、NMDAR1、NMDAR2B 的mRNA（t = - 10.337、 - 6.621、 - 6.847,P＜0.001）和蛋白（t = - 30.551、 - 7.451、 - 26.294,P＜0.001）表达水平升高,AO/EB染色和流式细胞术结果均表明细胞凋亡率降低（t = 2.707,P = 0.01;t = 4.632,P＜0.001）。结论 上调PKC - NMDAR信号通路表达,可能是姜黄素减轻氯化铝染毒所致NG108 - 15细胞凋亡的机制之一。     

Reversibility of neurofilamentous inclusion formation following repeated sublethal intracisternal inoculums of AlCl3 in New Zealand white rabbits

In this report, we describe the clinical, topographical and immunohistochemical characteristics of neurofilament (NF) inclusion formation induced by the intracisternal inoculation of young adult New Zealand white rabbits at 28-day intervals with 100 g AlCl₃ over the course of 267 days. The ability to recover following cessation of aluminum exposure has also been assessed. The extent of neurofilamentous inclusion formation was proportionate to the cumulative amount of AlCl₃ inoculated and initially consisted of fusiform axonal distention in the ventral spinal cord at day 51 following the initial inoculum. Spinal motor neuron perikaryal inclusions and discrete axonal spheroids were observed at day 107 and supraspinal neurofilamentous pathology by day 156. Perikaryal inclusions were immunoreactive to antibodies recognizing both poorly phosphorylated (SMI 32) and more highly phosphorylated high molecular weight NF (NFH). In contrast, axonal spheroids were intensely immunoreactive at all stages with antibodies recognizing highly phosphorylated NFH and an age-dependent NFH phosphorylation state (SMI 34) with only faint SMI 32 immunoreactivity. Immunoreactivity to an antibody recognizing ubiquitin-protein conjugates did not appear until day 156, whereas inclusions were not immunoreactive to antibodies recognizing either phosphatase-dependent or-independent microtubule-associated protein tau at any stage. Upon withdrawal from further AlCl₃ exposure after intervals of 51, 107 or 156 days following the initial inoculum, clinical recovery ensued in all rabbits. In all but the most severely affected rabbits, perikaryal neurofilamentous inclusions resolved. However, axonal spheroids continued to be prominent. However, axonal spheroids continued to be prominent. These studies demonstrate that the repetitive intracisternal inoculation of AlCl₃ in New Zealand white rabbits induces a reversible process of neurofilamentous inclusion formation that preferentially affects motor neurons, and in which recovery will occur in those inclusions containing an admixture of both poorly and highly phosphorylated NFH.     

Failure to find a relationship between mnestic skills of octogenarians and aluminum in drinking water

Summary High concentrations of aluminum (>80 g/l) in drinking water have been related to an elevated incidence of Alzheimer's disease. Mnestic and naming skills of residents living for >15 years in districts with high (98 g/l) or low (4 g/l) aluminum concentrations [Al] in the drinking water were evaluated in a population survey by examining 800 residents aged 81 to 85 using the mnestic subtest of the Mini Mental Status test (Zurich variant). The mnestic and naming performance of the octogenarians did not differ between the high- and low-content-areas. Since 73% of dementias are at least partly caused by Alzheimer's disease in the area examined and because the short test used discriminates demented from healthy octagenarians as well as tests involving extensive examinations, the findings of this study suggest with a high probability that the [Al] of drinking water is not an essential factor in the pathogenesis of senile dementia. The serum [Al] the urinary [Al] and the urinary [Al]/creatinine ratio were measured twice in ten clinically diagnosed Alzheimer patients and ten controls in both areas. No significant difference was found, which confirms the negative epidemiological findings.Parts of this study were presented at the joint meeting of the Swedish and Swiss Neurological Association in Interlaken, Switzerland, on May 22, 1990     

Phospholipase D in heart: basal activity and stimulation by phorbol esters and aluminum fluoride

Summary Evidence for a general role of phospholipase D in signal transduction is accumulating. In the present study, the activity of the enzyme was investigated in heart tissue under basal conditions and after addition of phorbol esters or aluminum fluoride (AlF _inf4 ^sup– ; 10 mM NaF plus 10 M AlCl₃). Atria of rats and chickens were incubated with [³H]-myristic acid in order to label preferentially phosphatidylcholine. Under basal conditions, the tissues generated choline and phosphatidic acid (PtdOH), the primary catalytic products of phospholipase D. When 0.5 or 2.0% ethanol was present, [³H]-phosphatidyl-ethanol (PETH) was rapidly formed at the expense of [³H]-PtdOH. This transphosphatidylation reaction is specific for phospholipase D activity. The basal formation of PETH was not inhibited by a Ca²⁺-free, EGTA-containing medium. - The phorbol ester 4-phorbol-12,13-dibutyrate (PDB), which is known to activate protein kinase C, enhanced the net formation of choline, whereas the inactive 4-phorbol-13-acetate (PAc) was ineffective. PDB (0.2 M), in contrast to PAc, also increased the formation of [³H]-PtdOH and, in the presence of ethanol, of [³H]-PETH. The PDB-evoked formation of PETH occurred again at the expense of PtdOH. Treshold and maximum effective concentrations of PDB were 10 nM and 0.2–0.6 M, respectively. The effects of PDB on either choline efflux and generation of PETH showed the same Ca^t+-dependency, i.e., both effects were blocked by a Ca²⁺-free, EGTA-containing medium, but not by a Ca²⁺-free medium without EGTA. In protein kinase C-deficient tissue which was prepared by pretreatment with 0.61 M PDB for 27 h, PDB failed to enhance the formation of PtdOH and PETH. - A1F4–, a known activator of G-proteins, increased not only the tissue content of inositol phosphates, but also markedly enhanced choline efflux and formation of [³H]-PtdOH and PETH. In conclusion, in mammalian and avian atria a high phospholipase D activity was found even under basal conditions. The enzyme was stimulated by protein kinase C and presumably by a G protein.Abbreviations IP inositol phosphate - DAG diacylglycerol - PL phospholipase - PtdOH phosphatidic acid - PETH phosphatidylethanol - PDB 4-phorbol-12,13-dibutyrate - PAc 4-phorbol-13-acetate - AlF _inf4 ^sup– aluminum fluoride - DMSO dimethylsulfoxide Correspondence to K. Löffelholz at the above address     

Single-dose toxicokinetics of aluminum in the rat

The toxicokinetics of aluminum (Al) in male Wistar rats was studied after single intragastric (IG) doses of 1000 and 12000 g Al/kg and intravenous (IV) doses of 10, 100, 1000, and 12000 g Al/kg. Serial blood samples, daily samples of urine and feces as well as brain, liver, kidney, spleen, quadriceps muscle, and femur samples were collected. Al was measured by atomic absorption spectrometry. Al blood profiles after IV doses were adequately described by a two-compartment open model. Al toxicokinetics was dose dependent and appeared to plateau at 12000 g/kg. At IV doses between 10 and 1000 g/kg the terminal half-life of elimination from whole blood (t_1/2) increased from 29.9±7.8 to 209.3±32.6 min, and the total body clearance (CL) decreased from 2.45±0.64 to 0.28±0.03 ml min^–1 kg^–1. Following an IV bolus of 10 and 100 g/kg the administered Al was recovered completely from urine (94.4%±9.9% and 98.5%±3.2%). Twenty-nine days after the IV dose of 1000 g/kg daily renal excretion decreased to baseline values while only 55.1%±8.0% of the dose was excreted. Nineteen days after the single IV dose of 1000 g/kg Al accumulated in liver (28.1±7.7 versus 1.7±0.5 g/g of control rats) and spleen (72.5±21.1 versus <0.4 g/g). After the single 1000 g/kg IG dose no absorption of Al was detectable. The IG dose of 12000 g/kg resulted in a maximum blood Al level of 47.9±12.4 g/l after 50 min. The blood concentration time curve fitted a one-compartment open model with a half-life of absorption of 28.2±3.6 min and a t_1/2 of 81.2±20.2 min. Cumulative renal Al excretion was 0.18%±0.10% of the dose and oral bioavailability was 0.02%. Seventeen days after the 12000 g/kg IG dose the Al content in femur samples was increased (2.7±1.3 versus 0.6±0.4 g/g). In no case was fecal elimination of incorporated Al observed.