Therapeutic versus neuroinflammatory effects of passive immunization is dependent on Aβ/amyloid burden in a transgenic mouse model of Alzheimer's disease

Background

Passive immunization with antibodies directed to Aβ decreases brain Aβ/amyloid burden and preserves memory in transgenic mouse models of Alzheimer's disease (AD). This therapeutic strategy is under intense scrutiny in clinical studies, but its application is limited by neuroinflammatory side effects (autoimmune encephalitis and vasogenic edema).

Methods

We intravenously administered the monoclonal Aβ protofibril antibody PFA1 to aged (22 month) male and female 3 × tg AD mice with intermediate or advanced AD-like neuropathologies, respectively, and measured brain and serum Aβ and CNS cytokine levels. We also examined 17 month old 3 × tg AD female mice with intermediate pathology to determine the effect of amyloid burden on responses to passive immunization.

Results

The 22 month old male mice immunized with PFA1 had decreased brain Aβ, increased serum Aβ, and no change in CNS cytokine levels. In contrast, 22 month old immunized female mice revealed no change in brain Aβ, decreased serum Aβ, and increased CNS cytokine levels. Identical experiments in younger (17 month old) female 3 × tg AD mice with intermediate AD-like neuropathologies revealed a trend towards decreased brain Aβ and increased serum Aβ accompanied by a decrease in CNS MCP-1.

Conclusions

These data suggest that passive immunization with PFA1 in 3 × tg AD mice with intermediate disease burden, regardless of sex, is effective in mediating potentially therapeutic effects such as lowering brain Aβ. In contrast, passive immunization of mice with a more advanced amyloid burden may result in potentially adverse effects (encephalitis and vasogenic edema) mediated by certain proinflammatory cytokines.     

Phase II study of use of a single cycle of induction chemotherapy and concurrent chemoradiotherapy containing capecitabine/cisplatin followed by surgery for patients with resectable esophageal squamous cell carcinoma: long-term follow-up data

Purpose

This phase II study evaluated the feasibility and efficacy of one cycle of induction chemotherapy, followed by concurrent chemoradiotherapy (CRT) featuring capecitabine/cisplatin, followed in turn by surgery, in the treatment of patients with resectable esophageal squamous cell carcinoma.

Methods

Between March 2003 and April 2005, 54 patients with stage II or III esophageal cancer were treated with induction chemotherapy (cisplatin 60?mg/m² on day 1; capecitabine 1,000?mg/m² bid on days 1?C14) followed by concurrent radiotherapy (46?Gy in 23 fractions) and chemotherapy (cisplatin 30?mg/m² on days 1, 8, 15, and 22; capecitabine 800?mg/m² bid 5?days/week). Surgery was performed within 8?weeks of the end of radiotherapy.

Results

Median age of the patients was 64.5?years (range, 45?C74?years). After CRT, 52 patients (96%) showed a clinical response, including 26 (48%) who exhibited a complete response (CR). Surgery was performed on 41 patients (76%), with 20 (37%) achieving pathologic CR and 3 (6%) dying of postoperative pneumonia. At a median follow-up time of 74.2?months (range, 64.3?C84.8?months), 16 patients (30%) had experienced tumor recurrence and 36 (67%) had died. Of the 41 patients who underwent esophagectomy, 5 (12%) had exclusively locoregional disease and 7 (17%) had distant metastasis, whereas no one had both. The 5-year progression-free and overall survival rates were 30.2% (95% confidence interval [CI], 18.0?C42.4%) and 37.0% (95% CI, 24.1?C50.0%), respectively.

Conclusions

A trimodal approach, consisting of a single cycle of induction chemotherapy, CRT containing capecitabine and cisplatin, and surgery, was feasible and effective in patients with resectable esophageal squamous cell carcinoma.     

Simulation of liver lesions for pediatric CT

PURPOSE: To develop and validate a technique based on characteristics of real lesions for simulating realistic small liver lesions on pediatric computed tomographic (CT) images. MATERIALS AND METHODS: The institutional review board provided exempt status for this study, determined that it was not subject to HIPAA compliance, and did not require informed consent. Patient identification information was removed from clinical images from contrast material-enhanced multi-detector row CT examinations performed in 10 children. Patients were infants or children up to 18 years old. Information about sex was not available. Children had one or more liver lesions of 2-6 mm in maximum transverse diameter. Images with more than one lesion were rendered multiple times, and each time, all but one of the lesions were digitally removed in sequence. This process provided images (n = 19) with a single real lesion. For consistency, the same image backgrounds (images with all real lesions removed) were used to create an identical number of images (n = 19), each with a single simulated lesion. Subsequently, three radiologists independently assessed images of real and simulated lesions that were presented in random order with a score on a continuous scale of 0 (definitely simulated) to 100 (definitely real). Mixed-model analysis of variance was used to test the null hypothesis that the difference in population mean scores between the two lesion types was zero. RESULTS: The observer study did not reveal a significant difference in the ability of any radiologist to discriminate between real and simulated lesions (P > .31). The differences in mean scores for discrimination between real and simulated lesions for the three observers were -6, 9, and -7, respectively. The estimated overall difference was -1. CONCLUSION: Mathematic simulation of liver lesions is a feasible technique for creating realistic lesions for image quality or dose reduction studies in pediatric CT.     

Radiofrequency Ablation Combined with Transcatheter Arterial Chemoembolization for the Treatment of Single Hepatocellular Carcinoma of 2 to 5 cm in Diameter: Comparison with Surgical Resection

Objective

To compare the effectiveness of radiofrequency ablation (RFA) combined with transcatheter arterial chemoembolization (TACE) with surgical resection in patients with a single hepatocellular carcinoma (HCC) ranging from 2 to 5 cm.

Materials and Methods

The study participants were enrolled over a period of 29 months and were comprised of 37 patients in a combined therapy group and 47 patients in a surgical resection group. RFA was performed the day after TACE, and surgical resection was performed by open laparotomy. The two groups were compared with respect to the length of hospital stay, rates of major complication, and rates of recurrence-free and overall survival.

Results

Major complications occurred more frequently in the surgical resection group (14.9%) than in the combined therapy group (2.7%). However, there was no statistical significance (p = 0.059). The rates of recurrence-free survival at 1, 2, 3 and 4 years were similar between the combined therapy group (89.2%, 75.2%, 69.4% and 69.4%, respectively) and the surgical resection group (81.8%, 68.5%, 68.5% and 65%, respectively) (p = 0.7962, log-rank test). The overall survival rates at 1, 2, 3 and 4 years were also similar between groups (97.3%, 86.5%, 78.4% and 78.4%, respectively, in the combined therapy group, and 95.7%, 89.4%, 84.3% and 80.3%, respectively, in the surgical resection group) (p = 0.6321, log-rank test).

Conclusion

When compared with surgical resection for the treatment of a single HCC ranging from 2 to 5 cm, RFA combined with TACE shows similar results in terms of recurrence-free and overall survival rates.     

3D body segment oscillation and gait analysis for vestibular disorders

Objective

To investigate the patterns of gait and locomotion in three dimension space in patients with vestibular disorders.

Methods

A 3D motion analysis system was employed to evaluate locomotor pattern and body's oscillation during gait under different conditions (normal, slow, fast speeds walking with eye open and normal speed walking with eyes closed) of nine patients with vestibular disorders. Twenty-one markers placed on the subject to record kinematics and locomotions of the head, spine and pelvis segments while walking. For each locomotor trial, the walking speed, locomotor patterns as well as the absolute angular dispersions of six segments around the roll, pitch and yaw axes were calculated to assess the equilibrium strategies of head, trunk and pelvis. Data was also recorded in 10 healthy subjects as control.

Results

Patients’ cadence is faster, and the stride time at normal walking speed is shorter than that of the controls (p < 0.05). The body sway has also been documented some impairment in patients. With respect to the control, patients’ oscillation of trunk around yaw axis at fast speed is less (p < 0.05), which means the patient seems need less shoulder torsional movement. Moreover, the most prominent changes in patients are the sway of hip in roll, which is significant less than controls at fast (p < 0.01), slow speed (p < 0.01) and in eye-closed condition (p < 0.05).

Conclusion

Our investigation corroborates those reports that higher velocities would be helpful for the increased gait stability in patients with vestibular disorders. And the body always try to keep the stability of head during gait, even under vestibular deficit conditions.     

Echinocandins in invasive candidiasis

We summarise a recent meeting, sponsored by Pfizer Inc., where experts in Asia shared their clinical experience in managing IC. The echinocandins have demonstrated good activity against non‐albicans infections and also azole‐resistant strains, both preclinically and in recent clinical trials. As well as proving efficacious, echinocandins have a favourable safety profile and are well tolerated, including among inpatient subpopulations, such as transplant recipients and those with renal or hepatic dysfunction. In addition the echinocandins generally have minimal drug–drug interactions, unlike the oral azoles, which have multiple effects on cytochrome P450‐mediated drug metabolism. Echinocandins are characterised by a good safety profile, few drug–drug interactions and good susceptibilities. With the increase in potentially azole‐resistant non‐albicans infections, echinocandins may become the first‐line treatment of choice for many patients.