细菌性脑脓肿的抗感染治疗进展

细菌性脑脓肿指细菌引起的颅内脓腔性感染,虽然发病率不高,但可导致严重后果。导致细菌性脑脓肿的病原体中,以链球菌、葡萄球菌最多,在我国及亚洲地区,革兰阴性杆菌也是重要病原体。第3代头孢菌素联合甲硝唑是最常用的经验性用药方案,能覆盖细菌性脑脓肿的最常见病原体。细菌性脑脓肿抗感染治疗的疗程一般长于6周,且须密切监测患者临床表现和头颅影像学改变。目前多采用手术联合内科药物的治疗方案,可明显缩短疗程,预后也大大改善。单纯保守治疗在脓肿较小、病情轻等情况下可考虑,以避免手术等有创操作的风险。但总体来说,细菌性脑脓肿的药物治疗方案仍缺乏足够的循证医学证据。     

Therapeutic efficacy of differentiated versus undifferentiated mesenchymal stem cells in experimental type I diabetes in rat

Selective MSCs differentiation protocol into pancreatic beta cells was conducted in the present study using exendin-4 and TGF-beta. Differentiated and undifferentiated MSCs were assessed in experimental type I diabetes in rats. Ninety female white albino rats were included in the study and divided equally (n=15/group) into 6 groups: healthy control, healthy control rats received acellular tissue culture medium, diabetic rats, diabetic rats received acellular tissue culture medium, diabetic rats received undifferentiated MSCs and diabetic rats received differentiated MSCs. Therapeutic efficacy of undifferentiated versus differentiated MSCs was evaluated via assessment of quantitative gene expressions of insulin1, insulin 2, Smad-2, Smad-3, PDX-1, PAX-4, neuroD. Blood glucose and insulin hormone levels were also assessed. Results showed that quantitative gene expressions of all studied genes showed significant decrease in diabetic rat groups. Use of undifferentiated and differentiated MSCs led to a significant elevation of expression levels of all genes with more superior effect with differentiated MSCs except smad-2 gene. As regards insulin hormone levels, use of either undifferentiated or differentiated MSCs led to a significant elevation of its levels with more therapeutic effect with differentiated MSCs. Blood glucose levels were significantly decreased with both undifferentiated and differentiated MSCs in comparison to diabetic groups but its levels were normalized 2 months after injection of differentiated MSCs. In conclusion, use of undifferentiated or differentiated MSCs exhibited significant therapeutic potentials in experimental type I diabetes in rats with more significant therapeutic effect with the use of differentiated MSCs.     

Comparative efficacy of fluconazole and amphotericin B in the parenteral treatment of experimental paracoccidioidomycosis in the rat

Patients with severe and complicated paracoccidioidomycosis are treated with amphotericin B by the intravenous route. Fluconazole is active in vitro against Paracoccidioides brasiliensis and can also be administered intravenously, but few clinical or experimental data are available about its action against the infection caused by this fungus. In the present study, the efficacy of fluconazole andamphotericin B was assessed comparatively in rats inoculated parenterally with P. brasiliensis. The treatment was performed 3 times a week for 4 weeks starting one week after infection. Fluconazole administered intraperitoneally (14 mg/kg bodyweight/dose) was more effective (P > 0.001)than amphotericin B (2 mg/kg body weight/dose) in reducing the number of colony forming units in the lungs and spleen. When administered intravenously at the dose of 3 mg/kg body weight, fluconazole was as effective as amphotericin B (0.8 mg/kg body weight) in reducing the pulmonary fungal burden. Under these conditions, the rats treated with fluconazole had a smaller number of colony forming units than untreated animals (P > 0.001), but amphotericin B was more effective than fluconazole in reducing spleen infection (P > 0.005). Except for this result obtained with a low dose, fluconazole showed an antifungal action equal to or higher than that of amphotericin B. The activity of fluconazole at doses equivalent to those used for human treatment suggests that this antifungal agent may be an alternative to amphotericin B for the early intravenous treatment of patients with paracoccidioidomycosis. This revised version was published online in June 2006 with corrections to the Cover Date.     

MyD88-dependent signals are essential for the host immune response in experimental brain abscess

Brain abscesses form in response to a parenchymal infection by pyogenic bacteria, with Staphylococcus aureus representing a common etiologic agent of human disease. Numerous receptors that participate in immune responses to bacteria, including the majority of TLRs, the IL-1R, and the IL-18R, use a common adaptor molecule, MyD88, for transducing activation signals leading to proinflammatory mediator expression and immune effector functions. To delineate the importance of MyD88-dependent signals in brain abscesses, we compared disease pathogenesis using MyD88 knockout (KO) and wild-type (WT) mice. Mortality rates were significantly higher in MyD88 KO mice, which correlated with a significant reduction in the expression of several proinflammatory mediators, including but not limited to IL-1beta, TNF-alpha, and MIP-2/CXCL2. These changes were associated with a significant reduction in neutrophil and macrophage recruitment into brain abscesses of MyD88 KO animals. In addition, microglia, macrophages, and neutrophils isolated from the brain abscesses of MyD88 KO mice produced significantly less TNF-alpha, IL-6, MIP-1alpha/CCL3, and IFN-gamma-induced protein 10/CXCL10 compared with WT cells. The lack of MyD88-dependent signals had a dramatic effect on the extent of tissue injury, with significantly larger brain abscesses typified by exaggerated edema and necrosis in MyD88 KO animals. Interestingly, despite these striking changes in MyD88 KO mice, bacterial burdens did not significantly differ between the two strains at the early time points examined. Collectively, these findings indicate that MyD88 plays an essential role in establishing a protective CNS host response during the early stages of brain abscess development, whereas MyD88-independent pathway(s) are responsible for pathogen containment.     

The effect of prenatal procarbazine treatment on brain development in the rat

Groups of pregnant Sprague-Dawley rats were treated orally with procarbazine, an antineoplastic drug, at dose levels of 0, 1.0, 2.5, 5.0, 7.5, and 10.0 mg/kg/day from days 12 through 15 of gestation. Following normal delivery, offspring were raised until day 21 and sacrificed, and their brains removed and weighed. A dose-dependent micrencephaly, characterized by hypoplasia of the cerebral hemispheres, was seen starting at 2.5 mg/kg/day. In a second study, groups of pregnant female rats were given a single dose of 10 mg/kg procarbazine on gestation day 12, 13, 14, or 15. Micrencephaly occurred in 21-day-old offspring from all groups, with the greatest effect induced on days 13, 14 and 15. Analysis of brain region weights revealed a maximum reduction in neocortex weight in offspring from groups treated on days 13 and 14. The hippocampus, cerebellum, and diencephalon-midbrain were also reduced in size, depending on the day of treatment, while the corpus striatum and pons-medulla were spared. In a final study, embryos from females treated on gestation days 12 through 15 were removed, fixed, and sectioned at 24-hour intervals starting on gestation days 13. Necrosis and cellular degeneration were observed with decreasing severity in the telencephalon, diencephalon, mesencephalon, and medulla. The neocortex of 20-day treated fetuses was characterized by a thickening of the ventricular zone and reduced cellularity of the cortical plate.     

凝结芽胞杆菌(TBC169)片治疗便秘的实验研究和临床疗效

目的观察凝结芽胞杆菌片（BC1）对便秘的药理作用和I临床疗效。方法昆明种雄性小鼠随机分为6组（每组10只）。BC1片（3个剂量）和BCz片治疗组小鼠口服BC。片和BC2片,空白对照组小鼠和模型对照组小鼠口服自来水,每天1次,共7d。之后,两治疗组和模型对照组小鼠在禁食12h后．均口服复方地芬诺酯（CDX）片,引发便秘。成人慢性便秘38例患者随机分为治疗组（20例）和对照组（18例）,分别口服BC1片和金双歧片（BG）,每天3次,共14～21d。结果BC1片能明显地减少便秘小鼠的首次排便时间（P〈0．05）和显著地增加大便粒数及重量（P〈0．05）。在临床试验中,治疗成人慢性便秘,BC1片的治愈率为45％,总有效率为70％,而相对的BG片分别为44％和72％,两药均未见不良反应或副作用。结论BC1片对小鼠实验性便秘和成人慢性便秘均有明显的治疗作用,在临床试验中未见不良反应或副作用。     

Succinate oxidation by rat brain mitochondria in experimental convulsions

Corasole-induced convulsive fits are accompanied by the activation of succinate oxidation in the isolated mitochondria, paralleled by the mounting effect of factors limiting succinate dehydrogenase activity. Diverse seasonal sensitivity to corasole correlates with the inhibition of succinate-dependent energy supply for the functional neuronal activity.     

The protein of glial intermediate filaments in different areas of the rat brain at experimental neurosis

The content and polypeptide composition of glial fibrillary acidic protein (GFAP) in the rat cerebral cortex, cerebellum, hippocampus, and mesencephalon were studied under conditions of experimental neurosis. Significant changes of the total GFAP content were observed in the hippocampus, mesencephalon, and cerebellum. Both the content and polypeptide composition of soluble GFAP form were markedly modified. These changes of glial filament protein apparently reflect the peculiarities of the reorganization of the astrocyte intermediate filaments at the animal’s long-term neurotization.     

Establishing efficacy of a new experimental treatment in the 'gold standard' design

Provided that there are no ethical concerns, the comparison of an active drug with placebo in a randomized two-arm clinical trial provides the most convincing way to demonstrate the efficacy of a new experimental treatment. However, in a placebo-controlled clinical trial it is not sufficient to demonstrate merely a statistically significant treatment difference. Regulatory authorities strongly recommend to assess additionally whether the observed treatment difference is also of clinical relevance. The inherent issue is the necessity of the a priori definition of what constitutes a clinically relevant difference in efficacy. This problem can be solved in a three-arm study by including an active control group. We address the necessary conditions in the gold standard design which allow the claim of efficacy for the new treatment with particular focus on assay sensitivity.     

头孢曲松钠联合阿奇霉素治疗儿童重症社区获得性肺炎临床观察

目的观察头孢曲松钠联合阿奇霉素治疗儿童重症社区获得性肺炎的疗效。方法92例重症社区获得性肺炎患儿随机分为治疗组和对照组,各46例。对照组给予头孢曲松钠50～80mg／（kg·d）静脉滴注治疗;治疗组在对照组基础上加用阿奇霉素10mg/（kg·d）静脉滴注治疗,连用5～7d。结果治疗组在退热、肺部哕音及咳嗽消失时间、平均住院时间均较对照组短,差异有非常显著性（P〈0．01）。结论头孢曲松钠联合阿奇霉素治疗儿童重症社区获得性肺炎效果明显,不良反应少,值得临床推广。     

Liposomally-entrapped ATP: improved efficiency against experimental brain ischemia in the rat

ATP was entrapped inside negatively charged liposomes composed of sulfatide, in order to improve its penetration into the brain and to reduce its degradation into other tissues. These liposomes were prepared according to an original method allowing a satisfying stability of the formulation. Liposomally entrapped ATP was administered intracerebroventricularly to rats submitted to brain ischemic episodes by both carotid artery clamping and systemic blood pressure lowering (during 3 minutes every 15 minutes). Such treatment importantly increases the number of ischemic episodes before brain silence appeared. So, this paper allows new perspectives in the administration of drugs into the brain.     

The renin-angiotensin system in the rat brain

Summary The distribution of angiotensinogen containing cells was determined in the brain of rats using immunocytochemistry. Specific angiotensinogen immunoreactivity is demonstrated both in glial cells and neurons throughout the brain, except the neocortical and cerebellar territories. Positive neurons are easily and invariably detected in female brains, and haphazardly in male brain (sex hormone dependent). Angiotensinogen immunoreactivity in male brain neurons can be induced by water deprivation or binephrectomy in some areas and particularly in paraventricular nuclei. Finally, the highest concentrations of positive neurons are found in the anterior and lateral hypothalamus, preoptic area, amygdala and some well known nuclei of the mesencephalon and the brainstem.Our results confirm the wide distribution of angiotensinogen mRNA in the brain reported recently by Lynch et al. (1987). Thus the demonstration of angiotensinogen in neurons and glial cells allows a greater understanding of the biochemical and physiological data in accordance with multiple brain renin angiotensin systems.     

The effect of steroid treatment on lipocortin immunoreactivity of rat brain

Lipocortin-1, lipocortin-2 and lipocortin-5 were immunohistochemically assessed in rats. Apart from animals receiving no treatment, other animals received pretreatment with methylprednisolone, or the 21-aminosteroid U-74389F. Whereas Hpocortin immunoreactivity was absent in the greater part of the brain in animals not pretreated with steroid (except in sporadic microglial cells and choroid plexus), there was obvious immunostaining of parenchymatous elements in steroid pretreated animals. In the steroid pretreated animals lipocortin immunoreactivity of the brain tissue may indicate local formation of lipocortin under the influence of steroids that had entered the tissue. The cellular elements which showed immunostaining included meningeal cells, neurones, ependyma, oligodendroglia and capillary endotheHum.     

脑组织核因子-κB激活对实验性变态反应性脑脊髓炎的作用

为探讨脑组织核因子－κB（NF－κB）对实验性变态反应性脑脊髓炎（EAE）的作用,分别用凝胶电泳迁移分析和NF－κB p65免疫组化方法测定了CFA－GPSCH诱导大鼠EAE1、7、14和21d时脑组织NF－κB活性和蛋白表达的动态变化,并观察了这些变化与EAE症状之间的关系。结果表明;对照组大鼠脑组织仅有少量NF－κB蛋白表达,其活性也很低;诱导EAE后,伴随着大鼠EAE症状及脑组织病理损伤的出现和进行性加重,其NF－κB活性和蛋白表达量逐渐增高;在免疫后14d达到高峰,NF－κB阳性细胞主要位于脉络丛、穹隆下器、血管“套袖样”病灶的周围,与EAE病变部位一致,此时大鼠EAE发病率最高、病情最重、体重减轻最显著、脑组织病理改变也最明显;21h脑组织NF－κB活性和蛋白表达量逐渐下降,大鼠EAE症状也逐渐恢复。应用NF－κB特异性抑制剂PDTC以抑制脑内组织NF－κB活性和蛋白表达量逐渐下降,大鼠EAE症状也逐渐恢复。应用NF－κB特异性抑制剂PDTC以抑制脑内NF－κB蛋白表达后,大鼠EAE症状和脑组织损伤明显减轻,说明脑组织NF－κB的动态变化与EAE症状及脑组织损伤程度密切相关。结论：脑组织NF－κB的激活对EAE的发病起着关键的作用,应用NF－κB抑制剂可能是防治该病的有效方法之一。     

Catecholamine content of the rat brain at different stages of experimental alcoholism

Changes in the noradrenaline (NA) content in the hypothalamus, dopamine (DA) and homovanillic acid (HVA) in the striatum were determined in rats after chronic alcohol administration. A single injection of alcohol (2.5 g/kg i.p.) provoked a 30% decrease in NA only in rats predisposed to ethanol intake. Voluntary intake of 15% ethanol for 10 days made the NA content return to normal, the 4-month use of ethanol did not change whereas the 8-month use reduced the NA content by 17%, DA by 31% and raised the content of HVA by 25%. Twenty-four hours after alcohol abstinence the HVA content dropped by 13%. It is concluded that the noradrenergic system is involved in the formation and development of alcohol motivation and that the dopaminergic system participates in the development of the physical dependence and abstinence.     

Clinical efficacy of chloroquine versus artemether-lumefantrine for Plasmodium vivax treatment in Thailand

Chloroquine remains the drug of choice for the treatment of vivax malaria in Thailand. Mixed infections of falciparum and vivax malaria are also common in South-East Asia. Laboratory confirmation of malaria species is not generally available. This study aimed to find alternative regimens for treating both malaria species by using falciparum antimalarial drugs. From June 2004 to May 2005, 98 patients with Plasmodium vivax were randomly treated with either artemether-lumefantrine (n = 47) or chloroquine (n = 51). Both treatments were followed by 15 mg of primaquine over 14 days. Adverse events and clinical and parasitological outcomes were recorded and revealed similar in both groups. The cure rate was 97.4% for the artemether-lumefantrine treated group and 100% for the chloroquine treated group. We concluded that the combination of artemether-lumefantrine and primaquine was well tolerated, as effective as chloroquine and primaquine, and can be an alternative regimen for treatment of vivax malaria especially in the event that a mixed infection of falciparum and vivax malaria could not be ruled out.