Inhibition of calpain prevents NMDA-induced cell death and β-amyloid-induced synaptic dysfunction in hippocampal slice cultures

Background and purpose:

Alzheimer''s disease (AD) is a multifactorial, neurodegenerative disease, which is in part caused by an impairment of synaptic function, probably mediated by oligomeric forms of amyloid-β (Aβ). While the Aβ pathology mainly affects the physiology of neurotransmission, neuronal decline is caused by excitotoxic cell death, which is mediated by the NMDA receptor. A comprehensive therapeutic approach should address both Aβ-induced synaptic deficits, as well as NMDA receptor-mediated neurodegeneration, via one molecular target. This study was designed to test whether calpain could be involved in both pathological pathways, which would offer a promising avenue for new treatments.

Experimental approach:

Application of the specific, water-soluble calpain inhibitor A-705253 was used to inhibit calpain in hippocampal slice cultures. We examined whether inhibition of calpain would prevent Aβ-induced deficits in neurotransmission in CA1, as well as NMDA-induced neuronal cell death.

Key results:

A-705253 dose-dependently prevented excitotoxicity-induced neurodegeneration at low nanomolar concentrations, determined by propidium iodide histochemistry. Inhibition of the NMDA receptor similarly protected from neuronal damage. Caspase staining indicated that calpain inhibition was protective by reducing apoptosis. Electrophysiological analysis revealed that inhibition of calpain by A-705253 also fully prevented Aβ oligomer-induced deficits in neurotransmission. The protective effect of calpain was compared to the clinically available NMDA receptor antagonist memantine, which was also effective in this model.

Conclusions and implications:

We suggest that inhibition of calpain exhibits a promising strategy to address several aspects of the pathology of AD that may go beyond the available therapeutic intervention by memantine.     

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The development of cellular immunity to Epstein-Barr virus after allogeneic bone marrow transplantation

Epstein-Barr virus-induced lymphoproliferative disease (EBV-LPD) is a potentially lethal complication during the first 6 months after allogeneic bone marrow transplantation (BMT). To determine whether deficiencies of EBV-specific cellular immunity contribute to EBV-LPD susceptibility and distinguish patients at risk, we performed limiting dilution analysis to quantify anti-EBV cytotoxic T-lymphocyte precursor (CTLp) frequencies in 26 recipients of unmodified or T-cell-depleted (TCD) grafts from EBV-seropositive donors. At 3 months post-BMT (n = 26), only five patients had EBV CTLp frequencies in the range of seropositive normal controls, irrespective of the type of transplant administered. By 6 months post-BMT, 9 of 13 patients tested had EBV CTLp frequencies within the normal range. The time period in which these patients had deficient cellular immunity to EBV corresponds to the period in which we have observed EBV-LPD in most prior patients. One patient with a low EBV CTLp frequency at 4 months post-BMT developed an EBV-LPD. Within 2 weeks of receiving an infusion of donor peripheral blood mononuclear cells (PBMC) providing less than 1,200 EBV- specific cytotoxic T-cell precursors, populations of EBV-specific CTL in the circulation were restored to levels detected in normal seropositive adults. Concurrently, the patient achieved a regression of the EBV-LPD, which has been sustained without further therapy. These studies indicate that recipients of both unmodified and TCD marrow grafts have profound deficiencies of EBV-specific T cell-mediated immunity early posttransplant, and that the period of risk for EBV-LPD closely corresponds to this interval of severe deficiency. Treatment of one patient with EBV-LPD with marrow donor-derived PBMC induced a rapid expansion of EBV-specific cytotoxic T-cell populations that occurred contemporaneously with the clinical regression of disease.     

食管切除术后病人的护理

在美国,食管癌是死亡率最高的恶性肿瘤之一,男性多于女性,其发病率随年龄增长而增加。食管癌临床表现早期食管癌临床表现不明显,吞咽困难是最常见的初始症状,但由于食管壁的柔韧性,病人到晚期才感觉到,从不能吞咽固体开始,进展到最终不能吞咽液体。此外,病人还可有吞咽时疼痛、体重减轻、营养不良和虚弱等表现。晚期表现还包括胸骨后疼痛、呃逆、呼吸困难、胃烧灼感、口臭、声音嘶哑、咳嗽、流涎过多及夜间误吸等。食管切除术后病人的护理食管切除术后24~48 h病人在重症监护室度过,通常带有气管插管等多种导管,护士应加强心肺及各方面的监护…     

An Assessment of Radiologically Inserted Transoral and Transgastric Gastroduodenal Stents to Treat Malignant Gastric Outlet Obstruction

Introduction

Self-expanding metallic stents (SEMS) are used to palliate malignant gastric outlet obstruction (GOO) and are useful in patients with limited life expectancy or severe medical comorbidity, which would preclude surgery. Stenting can be performed transorally or by a percutaneous transgastric technique. Our goal was to review the outcome of patients who underwent radiological SEMS insertion performed by a single consultant interventional radiologist.

Methods

Patients were identified from a prospectively collected database held by one consultant radiologist. Data were retrieved from radiological reports, multidisciplinary team meetings, and the patients’ case notes. Univariate survival analysis was performed.

Results

Between December 2000 and January 2011, 100 patients (63 males, 37 females) had 110 gastroduodenal stenting procedures. Median age was 73 (range 39–89) years. SEMS were inserted transorally (n = 66) or transgastrically (n = 44). Site of obstruction was the stomach (n = 37), duodenum (n = 50), gastric pull-up (n = 10), or gastroenterostomy (n = 13). Seven patients required biliary stents. Technical success was 86.4 %: 83.3 % for transoral insertion, 90.9 % for transgastric insertion. Eleven patients developed complications. Median GOO severity score: 1 pre-stenting, 2 post-stenting (p = 0.0001). Median survival was 54 (range 1–624) days. Post-stenting GOO severity score was predictive of survival (p = 0.0001).

Conclusions

The technical success rate for insertion of palliative SEMS is high. Insertional technique can be tailored to the individual depending on the location of the tumor and whether it is possible to access the stomach percutaneously. Patients who have successful stenting and return to eating a soft/normal diet have a statistically significant increase in survival.     

Feasibility of a radiation dose conserving CT protocol for myocardial function assessment

Objective:

Assessment of myocardial function can be performed at higher noise levels than necessary for coronary arterial evaluation. We evaluated image quality and radiation exposure of a dose-conserving function-only acquisition vs retrospectively electrocardiogram(ECG)-gated coronary CTA with automatic tube current modulation.

Methods:

Of 26 patients who underwent clinically indicated coronary CTA for coronary and function evaluation, 13 (Group I) underwent prospectively ECG-triggered coronary CTA, followed by low-dose retrospectively ECG-gated scan for function (128-slice dual-source, 80 kVp; reference tube current, 100 mA; 8-mm-thick multiplanar reformatted reconstructions) performed either immediately (n = 6) or after 5- to 10-min delay for infarct assessment (n = 7). 13 corresponding controls (Group II) underwent retrospectively ECG-gated protocols (automatic tube potential selection with CARE kV/CARE Dose 4D; Siemens Healthcare, Forchheim, Germany) with aggressive dose modulation. Image quality assessment was performed on the six Group I subjects who underwent early post-contrast dedicated function scan and corresponding controls. Radiation exposure was based on dose–length product.

Results:

Contrast-to-noise ratio (CNR) was preserved throughout the cardiac cycle in Group I and varied according to dose modulation in Group II. Visual image quality indices were similar during end systole but were better in Group II at end diastole. Although the total radiation exposure was equivalent in Group I and Group II (284 vs 280 mGy cm), the median radiation exposure associated with only the dedicated function scan was 138 mGy cm (interquartile range, 116–203 mGy cm).

Conclusion:

A low-dose retrospective ECG-gated protocol permits assessment of myocardial function at a median radiation exposure of 138 mGy cm and offers more consistent multiphase CNR vs traditional ECG-modulation protocols. This is useful for pure functional evaluation or as an adjunct to single-phase scan modes.

Advances in knowledge:

Radiation exposure can be limited with a tailored myocardial function CT protocol while maintaining preserved images.Technological advances in coronary CT angiography (CTA) have resulted in a dramatic reduction in effective radiation exposure for patients. Various methods can and have been employed to decrease effective dose for evaluation of coronary arteries, including tube current modulation, reduction of tube voltage, use of prospectively triggered acquisitions and, more recently, high-pitch helical prospectively electrocardiogram (ECG)-triggered scanning.^1–6 Use of such methods has reduced the routine radiation dose for coronary CTA to levels similar to that of yearly natural background radiation levels.⁷The use of prospectively ECG-triggered or high-pitch helical acquisitions typically do not allow for complete evaluation of myocardial function because images are acquired during only a portion of the cardiac cycle, generally within mid-diastole to ensure minimal coronary motion. However, cardiac CT has the capability of providing reliable and reproducible quantification of left and right ventricular systolic functions and chamber volumes, when compared with other non-invasive cardiac imaging modalities.^8–15 Evaluation of left and right ventricular function has been shown to have important prognostic value in patients with coronary artery disease, acute coronary syndromes and pulmonary emboli.^16–18 It is conceivable that if information on myocardial function could be provided using cardiac CT without significant additional radiation expense, independently or at the time of coronary CTA, this might provide a useful and robust alternative means of determining accurate quantitative volumetric and functional data.We evaluated the image quality and excess “radiation expense” associated with performing a dedicated cardiac CT acquisition with parameters tailored for the evaluation of myocardial thickening and left ventricular volumetric and functional assessment. This technique involves performing a dedicated low-dose scan for myocardial function. Appreciating that relatively large structures such as cardiac chambers and myocardial contours (as opposed to coronary arteries) allow for increased noise and lower spatial resolution demands, we allowed a lower uniform tube current setting and relied on thicker slice reconstructions akin to those used in cardiac MRI. Furthermore, since contrast attenuation is enhanced at lower tube voltages, which are closer to the k-edge of iodine, we utilized a low tube voltage of 80 kVp. This method was compared with the conventional approach of utilizing retrospective ECG gating with aggressive dose modulation down to 4% of the peak prescribed tube current (MinDose®; Siemens Healthcare, Forchheim, Germany) during systole for the simultaneous assessment of coronary arteries and myocardial function.     

A randomised comparison of microwave endometrial ablation with transcervical resection of the endometrium: follow up at a minimum of 10 years

Objective  To compare outcomes and further operations at a minimum of 10 years following microwave endometrial ablation (MEA^TM) or transcervical resection of the endometrium (TCRE).
Design  Follow up of a randomised controlled trial using postal questionnaires and operative databank review.
Setting  Gynaecology department of a large UK teaching hospital.
Main outcome measures  Women's satisfaction with treatment, menstrual symptoms, changes in health-related quality of life, and additional treatments received.
Results  One-hundred and eighty-nine of the original 263 women returned questionnaires (72%) after a minimum of 10 years post-treatment. Those totally or generally satisfied with treatment numbered 77/129 (60%) in the microwave arm and 70/134 (52%) in the resection arm, the difference is not statistically significant. Bleeding and pain scores were highly significantly reduced and similar following both MEA^TM and TCRE, achieving amenorrhoea rates of 83 and 88% respectively. The hysterectomy rate after 10 years was significantly different with 22 (17%) in the MEA^TM and 38 (28%) in the TCRE arm (95% CI: −0.21, −0.13).
Conclusions  Both techniques achieve significant and comparable improvements in menstrual symptoms, health-related quality of life and high rates of satisfaction. With the known operative advantages, lower costs and fewer hysterectomies, it is clear that MEA™ is a more effective and efficient treatment for heavy menstrual loss than TCRE.     

Penetrating keratoplasty for silicone oil keratopathy

Purpose : Penetrating keratoplasty for silicone oil keratopathy is associated with high risks and limited visual prognosis. This study examined the outcomes and factors influencing graft failure. Methods : A retrospective, non‐comparative, interventional case series of patients attending Moorfields Eye Hospital, London. Results : A total of 24 penetrating keratoplasties were performed in 17 patients (13 men and four women) from 1991 to 2000. The mean age of patients undergoing surgery was 43.6 years (range 17–84 years, SD ± 21.0). Silicone oil was removed before or during the time of initial penetrating keratoplasty in nine patients (52.9%) and left in situ in eight patients (47.1%). Ten out of 24 grafts survived (41.7%). The median duration of graft survival was 21 months (range 2 weeks–98 months) with median duration of follow up 33 months (range 2–100 months). At final follow up, the number of patients with a clear graft who had oil removed before or during the time of penetrating keratoplasty was seven out of 10 (70.0%). Risk factors for graft failure included hypotony, multiple keratoplasty, corneal neovascularization, rejection episode, silicone oil left in situ and postoperative glaucoma. Conclusions : Management of these complex patients requires a combined approach from anterior segment and vitreoretinal subspecialties. The long‐term success of the graft can be improved if silicone oil is removed prior or during the time of penetrating keratoplasty.