A new immunodeficient retinal dystrophic rat model for transplantation studies using human-derived cells

Graefe's Archive for Clinical and Experimental Ophthalmology - To create new immunodeficient Royal College of Surgeons (RCS) rats by introducing the defective MerTK gene into athymic nude rats....     

Cavernosal nerve functionality evaluation after magnetic resonance imaging-guided transurethral ultrasound treatment of the prostate

AIM: To evaluate the feasibility of using therapeutic ultrasound as an alternative treatment option for organ-confined prostate cancer.METHODS: In this study, a trans-urethral therapeutic ultrasound applicator in combination with 3T magnetic resonance imaging (MRI) guidance was used for real-time multi-planar MRI-based temperature monitoring and temperature feedback control of prostatic tissue thermal ablation in vivo. We evaluated the feasibility and safety of MRI-guided trans-urethral ultrasound to effectively and accurately ablate prostate tissue while minimizing the damage to surrounding tissues in eight canine prostates. MRI was used to plan sonications, monitor temperature changes during therapy, and to evaluate treatment outcome. Real-time temperature and thermal dose maps were calculated using the proton resonance frequency shift technique and were displayed as two-dimensional color-coded overlays on top of the anatomical images. After ultrasound treatment, an evaluation of the integrity of cavernosal nerves was performed during prostatectomy with a nerve stimulator that measured tumescence response quantitatively and indicated intact cavernous nerve functionality. Planned sonication volumes were visually correlated to MRI ablation volumes and corresponding histo-pathological sections after prostatectomy.RESULTS: A total of 16 sonications were performed in 8 canines. MR images acquired before ultrasound treatment were used to localize the prostate and to prescribe sonication targets in all canines. Temperature elevations corresponded within 1 degree of the targeted sonication angle, as well as with the width and length of the active transducer elements. The ultrasound treatment procedures were automatically interrupted when the temperature in the target zone reached 56 °C. In all canines erectile responses were evaluated with a cavernous nerve stimulator post-treatment and showed a tumescence response after stimulation with an electric current. These results indicated intact cavernous nerve functionality. In all specimens, regions of thermal ablation were limited to areas within the prostate capsule and no damage was observed in periprostatic tissues. Additionally, a visual analysis of the ablation zones on contrast-enhanced MR images acquired post ultrasound treatment correlated excellent with the ablation zones on thermal dose maps. All of the ablation zones received a consensus score of 3 (excellent) for the location and size of the correlation between the histologic ablation zone and MRI based ablation zone. During the prostatectomy and histologic examination, no damage was noted in the bladder or rectum.CONCLUSION: Trans-urethral ultrasound treatment of the prostate with MRI guidance has potential to safely, reliably, and accurately ablate prostatic regions, while minimizing the morbidities associated with conventional whole-gland resection or therapy.     

Protective efficacy of mitochondrial targeted antioxidant MitoQ against dichlorvos induced oxidative stress and cell death in rat brain

Dichlorvos is a synthetic insecticide that belongs to the family of chemically related organophosphate (OP) pesticides. It can be released into the environment as a major degradation product of other OPs, such as trichlorfon, naled, and metrifonate. Dichlorvos exerts its toxic effects in humans and animals by inhibiting neural acetylcholinesterase. Chronic low-level exposure to dichlorvos has been shown to result in inhibition of the mitochondrial complex I and cytochrome oxidase in rat brain, resulting in generation of reactive oxygen species (ROS). Enhanced ROS production leads to disruption of cellular antioxidant defense systems and release of cytochrome c (cyt c) from mitochondria to cytosol resulting in apoptotic cell death. MitoQ is an antioxidant, selectively targeted to mitochondria and protects it from oxidative damage and has been shown to decrease mitochondrial damage in various animal models of oxidative stress. We hypothesized that if oxidative damage to mitochondria does play a significant role in dichlorvos induced neurodegeneration, then MitoQ should ameliorate neuronal apoptosis. Administration of MitoQ (100 μmol/kg body wt/day) reduced dichlorvos (6 mg/kg body wt/day) induced oxidative stress (decreased ROS production, increased MnSOD activity and glutathione levels) with decreased lipid peroxidation, protein and DNA oxidation. In addition, MitoQ also suppressed DNA fragmentation, cyt c release and caspase-3 activity in dichlorvos treated rats compared to the control group. Further electron microscopic studies revealed that MitoQ attenuates dichlorvos induced mitochondrial swelling, loss of cristae and chromatin condensation. These results indicate that MitoQ may be beneficial against OP (dichlorvos) induced neurodegeneration.     

Changing management of suspected appendicitis in the laparoscopic era

INTRODUCTION

The aims of this study were to examine the trends in performance of open and laparoscopic appendicectomy at a district general hospital, and to compare the diagnostic outcomes in the two patient groups.

PATIENTS AND METHODS

Data were collected prospectively from patients undergoing an open or laparoscopic procedure for cted appendicitis in an 8-year period between January 2000 and December 2007.

RESULTS

A total of 1700 patients (873 women, 827 men) with a median age of 24 years underwent surgery for suspected appendicitis in the study period. There were 1357 patients (group A) who underwent an open procedure for presumed appendicitis (610 women and 747 men [F:M ratio, 1:1.2]). There were 343 patients (group B) who underwent laparoscopy with or without laparoscopic appendicectomy (82 men and 261 women [F:M ratio, 1:0.31]). Over the study period, there was an increasing trend towards the performance of laparoscopic procedures for suspected appendicitis, increasing from 4% to 39% of the total per year. In group A, 1172 (86%) patients had appendicular pathology, while the appendix was normal histologi-cally in 178 (13%). Other pathologies were diagnosed intra-operatively in 1%. In group B, 193 patients (56%) had appendicular pathology while in 150 (44%) the appendix was normal. In the subgroup with a normal appendix, 56 patients (37%) had another cause for their symptoms identified.

CONCLUSIONS

Laparoscopic appendicectomy is increasingly being performed. Laparoscopy is often used as a diagnostic tool in general surgical patients, particularly women, with lower abdominal pain. In effect, these patients are undergoing diagnostic laparoscopy, with or without appendicectomy. This has resulted in a lower positive appendicectomy rate, but a higher yield of diagnoses other than appendicitis, in the laparoscopic group. Overall appendicectomy rates, however, have remained unchanged.     

A phase I study of bevacizumab, everolimus and panitumumab in advanced solid tumors

Purpose

Preclinical data suggest concurrent inhibition of VEGF, mTOR and EGFR pathways may augment antitumor and antiangiogenic effects compared to inhibition of each pathway alone. This study evaluated the maximum tolerated dose/recommended phase II dose and safety and tolerability of bevacizumab, everolimus and panitumumab drug combination.

Methods

Subjects with advanced solid tumors received escalating doses of everolimus and flat dosing of panitumumab at 4.8?mg/kg and bevacizumab at 10?mg/kg every 2?weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity.

Results

Thirty-two subjects were evaluable for toxicity; 31 subjects were evaluable for tumor response. DLTs were observed in cohorts with everolimus at 10 and 5?mg daily and included grade 3 mucositis, skin rash and thrombocytopenia. Therefore, everolimus was dose-reduced to 5?mg three times weekly, which improved the tolerability of the treatment regimen. Common adverse events were skin rash/pruritus (91?%), mucositis/stomatitis (75?%), hypomagnesemia (72?%), hypocalcemia (56?%) and hypokalemia (50?%). There were 3 partial responses; an additional 10 subjects had stable disease ??6?months. Three subjects with ovarian cancer and one with endometrial cancer achieved prolonged disease control ranging from 11 to >40?months.

Conclusions

The recommended phase II dose is everolimus at 5?mg three times weekly plus panitumumab at 4.8?mg/kg and bevacizumab at 10?mg/kg every 2?weeks. This dosing regimen has an acceptable safety and tolerability profile and appears to have moderate the clinical activity in refractory tumors.