The Relationship Between Protein Aggregation and Molecular Mobility Below the Glass Transition Temperature of Lyophilized Formulations Containing a Monoclonal Antibody

Purpose. To find out if the physical instability of a lyophilized dosage form is related to molecular mobility below the glass transition temperature. Further, to explore if the stability data generated at temperatures below the glass transition temperature can be used to predict the stability of a lyophilized solid under recommended storage conditions. Methods. The temperature dependence of relaxation time constant, , was obtained for sucrose and trehalose formulations of the monoclonal antibody (5 mg protein/vial) from enthalpy relaxation studies using differential scanning calorimetry. The non-exponentiality parameter, , in the relaxation behavior was also obtained using dielectric relaxation spectroscopy. Results. For both sucrose and trehalose formulations, the variation in with temperature could be fitted Vogel-Tammann-Fulcher (VTF) equation. The two formulations exhibited difference sensitivities to temperature. Sucrose formulation was more fragile and exhibited a stronger non-Arrhenius behavior compared to trehalose formulation below glass transition. Both formulations exhibited <2% aggregation at t values <10, where t is the time of storage. Conclusions. Since the relaxation times for sucrose and trehalose formulations at 5°C are on the order of 10⁸ and 10⁶ hrs, it is likely that both formulations would undergo very little (<2%) aggregation in a practical time scale under refrigerated conditions.     

异丙酚复合芬太尼维持麻醉对脑代谢的影响

观察异丙酚复合芬太尼维持麻醉对脑代谢的影响。方法： 择期手术病人８ 例, 芬太尼、硫贲妥钠、维库溴铵诱导插管, 静脉联接Ｇｒａｓｅｂｙ 微泵异丙酚８ ｍｇ／ （ｋｇ·ｈ） , 芬太尼１ μｇ／ （ｋｇ·ｈ）维持麻醉。连续监测ＭＡＰ、心电图、脉搏氧饱和度和呼气末二氧化碳分压, 同步采集动脉血和颈内静脉血作血气分析, 计算动－ 静脉氧含量差（Ｄａ － ｖＯ２） 和脑氧摄取率（ＥＲＯ２） 。结果： 异丙酚麻醉维持平稳, Ｄａ － ｖＯ２ 和ＥＲＯ２ 在给药３０ ｍｉｎ 、６０ ｍｉｎ 较气管插管后５ ｍｉｎ 无明显改变, 有平均动脉压下降和心动过缓。结论： 异丙酚复合芬太尼维持麻醉可保持脑氧供需平衡稳定。     

Neurological prognosis correlated with variations over time in the number of subependymal nodules in tuberous sclerosis

In tuberous sclerosis (TS), brain CT reveals subependymal nodules, cortical tubers and white matter lesions. This study is a retrospective analysis of the relationship between the variations over time in the number of subependymal nodules and the clinical course in cases of tuberous sclerosis. Twenty-four children with tuberous sclerosis, who attended the National Children's Hospital as outpatients, were followed by means of brain CT examinations for 7 years and 1 month on average. Cranial MRI was also performed in 22 cases. Brain CT disclosed subependymal nodules already in early infancy. In almost all cases, the number of subependymal nodules gradually increased with age, especially around the frontal horn of the lateral ventricle. The increase stopped at around age 10. The cases with five or more subependymal nodules at the initial or subsequent CT examination (17 patients; Group A) exhibited a significantly greater number of cortical tubers than those with less than five (five patients; Group B) and had white matter lesions unlike Group B. In addition, the number of cases with either infantile spasms or mental retardation was significantly higher in Group A than Group B (P<0.005). In conclusion, the number of ventricular subependymal nodules may allow prediction of the severity of the cerebral dysfunction in TS. Our results suggest that its variation may reflect the degree of the embryologic disorder when neuronal cells grow in the early gestational period.     

Efficiency of Superfine Glass Fiber Membrane\= Filters for Depleting Leukocytes

ＩｎｔｒｏｄｕｃｔｉｏｎＩｎｔｈｅｄｏｎｏｒｂｌｏｏｄｃｏｌｅｃｔｅｄｂｙｂｌｏｏｄｃｅｎ－ｔｅｒｓ,ｌｅｕｋｏｃｙｔｅｓｈａｖｅｎｏｔｈｅｒａｐｅｕｔｉｃｆｕｎｃｔｉｏｎｔｏｐａｔｉｅｎｔｓｂｕｔｍａｙｉｎｄｕｃｅｍａｎｙｓｉｄｅｅｆｅｃｔｓ．Ｃｏ...     

Cancer of the stomach and the colon-rectum among workers in a coke gas plant.

Four thousand nine hundred and eight male workers of the Hamburg gas plant, employed for 10 or more years during the period from January 1, 1900 to December 31, 1989, have been traced for cancer mortality. Based on their jobs, they were grouped into three subcohorts: gas furnace workers, workers in other parts of the plant, and white-collar workers. Despite the general "healthy worker effect," gas furnace workers showed a significant incidence of cancer of all sites (standardized mortality ratio [SMR] = 186), particularly cancers of the lung (SMR = 288), stomach (SMR = 177), and the colon-rectum (SMR = 184). In comparison to the death rates of white-collar workers, the manual workers in other parts of the plant also showed an excess of cancer mortality for cancer of these sites. The reason for this excess in cancer mortality seems to be due to the working conditions. The results contribute to the current evidence that exposure to coal carbonization fumes causes not only lung cancer, but also cancers of the stomach and colon-rectum.     

Forces and moments on the human leg in the frontal plane during static bipedal stance.

An experimental apparatus was assembled that permitted measurement of the vertical and lateral ground reaction forces as the hip is abducted, resulting in foot separations ranging from 0.25 to 71 cm, with the knee in 0 degree flexion. Twelve healthy volunteers (8 men and 4 women) were tested. The hip joint was located by means of center of rotation measurements on each subject's legs, and the location of the knee joint was determined using anatomical measurements. It was observed that the mediolateral force was nonzero and directed toward the body midline, even when the subject's feet were placed together. With the feet placed at shoulder width, the population mean mediolateral force was 3% of body weight. It was determined that simplifying assumptions based upon either "zero lateral force," or "zero hip moment," produced errors, when compared with our measured values, over various ranges of foot separation, with the zero hip moment assumption providing accuracy over a broader range. The inclination of the tibial plateau, with respect to the long axis of the tibia, that would produce minimal mediolateral shear at the knee is presented. Research and clinical applications of our results and techniques are discussed.     

In vivo efficacy of a novel double liposome as an oral dosage form of salmon calcitonin

A simple method for the preparation of the inner liposomes for double liposomes (DL) was developed. The encapsulation efficiency of erythrosine in liposomes prepared by this new method is superior to that of the previous method because of the concentration of the drug in the lipid membrane. To evaluate the usefulness of DL prepared by the glass‐filter method modified in this study as an oral dosage form of salmon calcitonin (SCT), a suspension of liposomes containing SCT was administered to rats at a dose of 10 μg SCT/kg. Each type of DL showed better efficacy than its inner liposomes alone. The decrease in plasma calcium level was dependent on the electrical charge and particle size of the inner liposomes. The hypocalcemic efficacy of DL encapsulating SCT‐loading cationic liposomes relative to that after subcutaneous administration of SCT at a dose of 1 μg/kg was 6.47%, which was the largest value obtained. These results indicated that not only the particle size but also the electrical charge of inner liposomes affect intestinal absorption. This study verified that the efficacy was increased because of the decrease in diameter of the inner liposomes and the use of lipid with a positive charge. These findings concluded that DL might be useful as an oral dosage form of SCT. Drug Dev. Res. 58:253–257, 2003. © 2003 Wiley‐Liss, Inc.     

人肝细胞癌及癌周组织内P53蛋白表达的研究

 应用LSAB免疫组化方法检测73例原发性肝细胞癌(HCC))及其癌旁组织中P53蛋白的异常表达。 结果显示:P53蛋白在HCC中阳性表达率显著高于癌旁组织, 且与HCC分化程度呈显著正相关，低分化组P53蛋白阳性表达率显著高于高分化组(P<0.05); 癌旁组织中, p53蛋白表达仅见于增生结节中, 肝硬化组织内未见p53蛋白阳性表达。 提示P53基因突变是HCC的频发事件, 在HCC的发生发展中发挥重要作用; 增生结节是HCC的癌前病变。     

Two cases of intrapulmonary lymph node presenting as a peripheral nodular shadow: Diagnostic differentiation from lung cancer

We present two cases of intrapulmonary lymph node. The patients were a 44-year-old woman and a 71-year-old man each with a small peripheral nodule in the lung. On computed tomography (CT) scans, both nodules were spiculated. Since histological diagnosis could not be obtained by bronchoscopic examination or CT-guided needle biopsy, they underwent video-assisted thoracoscopic surgery. Histological examination of the resected material revealed that both nodules were composed of lymph node. Intrapulmonary lymph node has until recently been assigned no clinical significance; however, differential diagnosis of this lesion from lung cancers and other metastatic tumors is now clinically important.     

区域注射磷—32玻璃微球对裸鼠移植性人肝细胞癌的形态学影响

目的：研究－３２玻璃微球（３２Ｐ－ＧＭＳ）区域注射对裸鼠移植性人肝细胞癌的形态学影响及其意义。方法：应用光镜、免疫组织化学及电镜观察对照组及治疗组的肿瘤组织学和超微结构特征。结果：对照组中，瘤体长径约３ｃｍ，瘤细胞排列紧密，呈小梁状，富于血窦，约５％瘤细胞坏死。治疗组中，瘤体长径为０．４～２ｃｍ，其中少部分瘤体边缘细胞排列紧密，大部分瘤细胞排列松散，呈网状或假腺样且被纤维血管束分割成巢。４０％～８０％的瘤细胞呈凝固性坏死。７５％以上排列紧密的瘤细胞ＰＣＮＡ阳性，而排列松散的ＰＣＮＡ阳性瘤细胞不足２５％。松散排列的瘤细胞较紧密排列的瘤细胞，桥粒显著减少、细胞变性坏死增多。结论：本研究提示局部内放射３２Ｐ－ＧＭＳ明显具有杀伤癌细胞和抑制肿瘤生长的作用。这为３２Ｐ－ＧＭＳ对肝癌治疗的实验研究和临床应用提供形态学依据。