Clinical efficacy of carbapenems on hospital-acquired pneumonia in accordance with the Japanese Respiratory Society Guidelines for management of HAP

Hospital-acquired pneumonia (HAP) is the second most common cause of hospital-acquired infection and is the leading cause of death. In 2002, the Japanese Respiratory Society (JRS) published guidelines for the diagnosis and treatment of HAP (JRS GL 2002). In these guidelines, treatment with carbapenems is recommended for all disease types of HAP, excluding cases of mild or moderate pneumonia with no risk factors, and cases with early-onset ventilation-acquired pneumonia. To evaluate the efficacy of carbapenems on HAP in accordance with JRS GL 2002, we conducted a prospective study of HAP patients treated with carbapenems based on JRS GL 2002. The results of this study were also analyzed based on the revised guidelines published in June 2008 (JRS GL 2008), and the validity of the new guidelines was examined. Of the 33 subjects, 19 were judged as responders to the treatment, corresponding to a response rate of 57.6%. There were 3 deaths, corresponding to a mortality rate of 9.1%. The efficacy of carbapenems for the treatment of HAP based on JRS GL 2002 was confirmed. The severity rating system in JRS GL 2002 has a tendency to overestimate the severity of the cases and may lead to overtreatment in some cases. On the other hand, the severity rating system by JRS GL 2008 seemed to be more accurate and closely correlated with the efficacy of the treatment. It is suggested that JRS GL 2008 is more useful in clinical practice for accurately judging the severity of the disease and initiating appropriate subsequent antibiotic therapy.     

Inhibition of the formation of oral calcium phosphate precipitates: beneficial effects of Chinese traditional (Kampo) medicines

Screening tests on the formation of calcium phosphate precipitates using 23 different kinds of Kampo medicines (Chinese traditional medicines) were carried out, at concentrations where the effects of chelation are not significant. Four of them, Hochu-ekki-to (TJ-41), Kyuki-kyogai-to (TJ-77), Oren-to (TJ-120) and Inchin-ko-to (TJ-135) showed an inhibitory effect on the formation of amorphous calcium phosphate (ACP). The inhibitory effect on the induction time and the rate of transformation to hydroxyapatite (HAP) varied greatly among the 23 Kampo medicines. We classified them according to their effects on increasing the induction time and/or decreasing the rate of HAP transformation. Ethane-1-hydroxy-1, 1-diphosphonate (EHDP) was used as the standard. This compound is a common toothpaste additive which decreases dental calculus formation. Two of the 23 Kampo medicines showed little or no inhibition either on the induction time or on the rate of HAP transformation. Twelve of them reduced the rate of HAP transformation by 20-40% and with 1.9- to 4.0-fold increases in the induction time. The remaining nine showed even greater activity. Keishi-ninjin-to (TJ-82), Dai-kenchu-to (TJ-100), Toki-to (TJ-102), Rikko-san (TJ-110) and San'o-shashin-to (TJ-113) showed the same inhibitory effect as EHDP. Shigyaku-san (TJ-35;5.2-fold), Dai-kanzo-to (TJ-84;4.9-fold), Oren-gedoku-to (TJ-15:12.7-fold) and Inchin-ko-to (TJ-135;9.5-fold) had a greater effect on the increase of induction time than EHDP and reduced the rate of HAP transformation by 50-60%. These results suggest that these nine kinds of Kampo medicines may have potential as anticalculus agents in toothpastes and mouthwashes.     

The main hepatitis B virus (HBV) mutants resistant to nucleoside analogs are susceptible in vitro to non-nucleoside inhibitors of HBV replication

Long-term treatment of chronic hepatitis B with nucleos(t)ide analogs can lead to the emergence of HBV resistant mutants of the polymerase gene. The development of drugs with a different mode of action is warranted to prevent antiviral drug resistance. Only a few non-nucleosidic molecules belonging to the family of phenylpropenamides (AT-61 & AT-130) and heteroaryldihydropyrimidines (BAY41-4109) can prevent RNA encapsidation or destabilize nucleocapsids, respectively. The sensitivity of the main nucleos(t)ide analog- resistant mutants to these inhibitors was evaluated in vitro. HepG2 stable cell lines permanently expressing wild type (WT) HBV or the main HBV mutants resistant to lamivudine and/or adefovir (rtL180M + rtM204V, rtV173L + rtL180M + rtM204V, rtM204I, rtL180M + rtM204I, rtN236T, rtA181V, rtA181V + rtN236T, rtA181T, rtA181T + rtN236T) were treated with AT-61, AT-130 or BAY-41 4109. Analysis of intracellular encapsidated viral DNA showed that all mutants were almost as sensitive to these molecules as WT HBV; indeed, the fold-resistance ranged between 0.7 and 2.3. Furthermore, the effect of a combination of either AT-61 or AT-130 with BAY41-4109, and the combination of these compounds with tenofovir was studied on wild type HBV as well as on a lamivudine and an adefovir-resistant mutant (rtL180M + M204V and rtN236T, respectively). These combinations of compounds resulted in inhibition of viral replication but showed slight antagonistic effects on the three HBV species. Based on this in vitro study, BAY-41 4109, AT-61 and AT-130 molecules that interfere with capsid morphogenesis are active against the main lamivudine- and adefovir-resistant mutants. These results suggest that targeting nucleocapsid functions may represent an interesting approach to the development of novel HBV inhibitors to prevent and combat drug resistance.     

医院获得性肺炎继发脓毒症患者的预后分析

目的 分析医院获得性肺炎继发脓毒症患者临床特征及90d生存情况,探讨影响预后因素。方法 回顾性分析89例医院获得性肺炎继发脓毒症患者资料,Cox比例风险模型分别对预后行单因素与多因素分析,Kaplan-Meier法进行生存曲线比较。结果 随访率100%。90d生存(OS)率为60.7%,平均生存时间64.0d(95%CI:56.5d~71.5d)。单因素分析显示影响90dOS的因素为APACHE-Ⅱ评分(P<0.001)、血Cre(P=0.003)、△PCT(P<0.001)、心搏骤停(P=0.037)、MODS(P=0.014)。多因素分析显示APACHE-Ⅱ评分(P=0.002)与△PCT(P<0.001)是影响90dOS的独立预后因素。结论 医院获得性肺炎继发脓毒症患者生存率低,APACHE-Ⅱ评分与PCT变化程度是影响生存的独立因素。     

Molecular regulation of dendritic spine dynamics and their potential impact on synaptic plasticity and neurological diseases

The structure and dynamics of dendritic spines reflect the strength of synapses, which are severely affected in different brain diseases. Therefore, understanding the ultra-structure, molecular signaling mechanism(s) regulating dendritic spine dynamics is crucial. Although, since last century, dynamics of spine have been explored by several investigators in different neurological diseases, but despite countless efforts, a comprehensive understanding of the fundamental etiology and molecular signaling pathways involved in spine pathology is lacking. The purpose of this review is to provide a contextual framework of our current understanding of the molecular mechanisms of dendritic spine signaling, as well as their potential impact on different neurodegenerative and psychiatric diseases, as a format for highlighting some commonalities in function, as well as providing a format for new insights and perspectives into this critical area of research. Additionally, the potential strategies to restore spine structure–function in different diseases are also pointed out. Overall, these informations should help researchers to design new drugs to restore the structure–function of dendritic spine, a “hot site” of synaptic plasticity.     

Circulation of Fluorescently Labelled Phage in a Murine Model

Interactions between bacteriophages and mammals strongly affect possible applications of bacteriophages. This has created a need for tools that facilitate studies of phage circulation and deposition in tissues. Here, we propose red fluorescent protein (RFP)-labelled E. coli lytic phages as a new tool for the investigation of phage interactions with cells and tissues. The interaction of RFP-labelled phages with living eukaryotic cells (macrophages) was visualized after 20 min of co-incubation. RFP-labeled phages were applied in a murine model of phage circulation in vivo. Phages administered by three different routes (intravenously, orally, rectally) were detected through the course of time. The intravenous route of administration was the most efficient for phage delivery to multiple body compartments: 20 min after administration, virions were detected in lymph nodes, lungs, and liver; 30 min after administration, they were detectable in muscles; and 1 h after administration, phages were detected in spleen and lymph nodes. Oral and rectal administration of RFP-labelled phages allowed for their detection in the gastrointestinal (GI) tract only.     

纳米羟基磷灰石的制备及其抗肿瘤活性的研究

采用溶胶凝胶法合成了含CO32 - 的纳米羟基磷灰石 ,研究了热处理温度对羟基磷灰石结晶性能、粒子大小和形貌的影响。并采用体外细胞培养的方法对含CO32 - 纳米羟基磷灰石的抗肿瘤活性进行了初步的探索。结果表明 :以Ca(NO3) 2 ·4H2 O和PO(CH3O) 3为原料 ,采用溶胶凝胶法 ,6 0 0℃处理可得到结晶性能良好、分散均匀、5 0nm左右大小的含CO32 - 的羟基磷灰石粉体。MTT比色法研究结果表明纳米HAP粒子对正常肝细胞L 0 2的抑制率较小 ,而对BEL 74 0 2肝癌细胞有明显的抑制作用 ,且呈现明显的浓度和时间依赖性。荧光显微照片显示纳米HAP粒子能够诱导BEL 74 0 2肝癌细胞的凋亡。