Donor‐specific chimeric antigen receptor Tregs limit rejection in naive but not sensitized allograft recipients

Cell therapy with autologous donor‐specific regulatory T cells (Tregs) is a promising strategy to minimize immunosuppression in transplant recipients. Chimeric antigen receptor (CAR) technology has recently been used successfully to generate donor‐specific Tregs and overcome the limitations of enrichment protocols based on repetitive stimulations with alloantigens. However, the ability of CAR‐Treg therapy to control alloreactivity in immunocompetent recipients is unknown. We first analyzed the effect of donor‐specific CAR Tregs on alloreactivity in naive, immunocompetent mice receiving skin allografts. Tregs expressing an irrelevant or anti‐HLA‐A2‐specific CAR were administered to Bl/6 mice at the time of transplanting an HLA‐A2⁺ Bl/6 skin graft. Donor‐specific CAR‐Tregs, but not irrelevant‐CAR Tregs, significantly delayed skin rejection and diminished donor‐specific antibodies (DSAs) and frequencies of DSA‐secreting B cells. Donor‐specific CAR‐Treg–treated mice also had a weaker recall DSA response, but normal responses to an irrelevant antigen, demonstrating antigen‐specific suppression. When donor‐specific CAR Tregs were tested in HLA‐A2‐sensitized mice, they were unable to delay allograft rejection or diminish DSAs. The finding that donor‐specific CAR‐Tregs restrain de novo but not memory alloreactivity has important implications for their use as an adoptive cell therapy in transplantation.     

New tools for the evaluation of toxic ocular surface changes in the rat

PURPOSE: To assess the usefulness of noninvasive combined technologies used to observe ocular surface changes in toxicology studies. METHODS: Benzalkonium chloride (BAC) at 0.01%, 0.1%, 0.25%, and 0.5% was applied to rat corneas for 11 days. The eye was evaluated macroscopically from day (D)0 to D52. The cornea was examined with the slit lamp, a fluorescein test was performed, and a confocal microscope was used in vivo to calculate corneal thickness, score corneal epithelial and endothelial defects, and quantify corneal stromal inflammation and neovascularization. Conjunctival impression and brush cytology specimens were taken for labeling with MUC-5AC antibodies and sub-G1 peak analysis by flow cytometry, respectively. Histologic analyses were performed on D11. RESULTS: Although macroscopic and slit lamp examinations revealed signs of ocular irritation in the 0.25% and 0.5% BAC-treated eyes only, in vivo confocal microscopy revealed epithelial defects in the 0.01% and 0.1% BAC-treated corneas, and sub-G1 peak analyses showed increased apoptosis for all the BAC concentrations on D8 and D11. BAC at 0.25% and 0.5% induced increased corneal thickness, loss of goblet cells, reversible corneal inflammation, and persistent neovascularization. CONCLUSIONS: Sub-G1 peak analysis of conjunctival brushings, in conjunction with in vivo confocal microscopy of the cornea and immunolabeling of conjunctival imprints, constitutes a noninvasive, reliable, and sensitive tool to evaluate toxic drug-induced ocular surface damage in rats, in addition to standard clinical assessments and at a wide range of concentrations, including the lowest ones. This study is consistent with the international strategy aimed at reducing the use of animals and refining animal toxicologic models.     

Public health impact of neovascular age-related macular degeneration treatments extrapolated from visual acuity

PURPOSE: To estimate the potential public health impact of treatment with new medications intended to preserve vision in patients with neovascular age-related macular degeneration (AMD). METHODS: A Markov model was used to simulate the natural history of AMD over the lifetime of patients with diagnosed neovascular AMD from clinical trials and epidemiologic surveys. It applied to a cohort of patients aged 75 years, with newly diagnosed neovascular AMD in one eye, whose visual acuity was 0.7 logMAR. Probabilities were calculated for the risk of AMD in the remaining eye and for premature mortality. Results of the model were expressed as the duration of low vision (worse eye VA>1.0 and better eye VA>0.7 logMAR) and blindness (bilateral VA >1.0 logMAR). Health consequences of blindness and low vision were estimated for depression, hip fractures, institutionalization, and life expectancy. RESULTS: For AMD patients with a 50% probability of VA >1.0 logMAR at 1 year, in one eye, the probability of lifetime bilateral blindness was >47%. The patients would live approximately 7 years with monocular vision >1.0 logMAR and an additional 4 years with bilateral blindness and a >15% probability of depression due to AMD. Life expectancy was decreased by approximately 2 years, >90/1000 patients would sustain a new hip fracture, and 1.5% of the patients would require institutional care for visual impairment due to AMD. To achieve a defined public health outcome (visual impairment and consequent comorbidity), it was necessary for the VA effectiveness of new treatments to increase in parallel with disease severity. CONCLUSIONS: Comorbidity related to visual impairment contributes significantly to the public health impact of AMD. Aggressive lesions need highly effective treatments. Models may be used to compare the public health impact of placebo-controlled clinical trial results.     

喉垂直切除会厌下移喉重建术治疗早期声带癌的疗效观察

目的:评价喉垂直切除会厌下移喉重建术(Tucker技术)治疗早期声带癌(T1b,T2)的效果,明确Tucker技术的手术适应证。方法:回顾性分析139例接受Tucker技术治疗患者的临床资料,其中127例是首次接受治疗的患者(T1b48例,T279例),12例(Tr)是声带癌曾接受过放射治疗或声带切除后复发的患者。计算生存率和评估喉功能恢复情况。结果:T1期患者的5年生存率为91.0%,肿瘤局部控制率为100%;T2期患者的5年生存率为86%,肿瘤局部控制率为94.0%;Tr期患者的5年生存率为64.0%,肿瘤局部控制率为82%。喉功能保留方面:气管拔管率为100%,平均拔管时间10d。胃管拔除率为99.3%(138/139),6例因误咽施行了胃造漏术,1例因顽固性误咽导致吸入性肺炎施行了功能性全喉切除术;平均胃管拔管时间为15d。121例(87.1%)患者获得了好或较好的发声,18例患者的发声质量较差如同耳语声。结论:喉垂直切除会厌下移喉重建术(Tucker技术)是治疗T和T期声带癌的有效手术方法。     

Characterization and Management of Arrhythmic Events in Young Patients With Brugada Syndrome

Background

Information on young patients with Brugada syndrome (BrS) and arrhythmic events (AEs) is limited.

Atrial flutter termination by overdrive transesophageal pacing and the facilitating effect of oral propafenone

Transesophageal overdrive atrial pacing is effective and safe for atrial flutter termination. The influence of antiarrhythmic drug therapy on this procedure is controversial. In this study, we investigated whether oral propafenone may facilitate this procedure. Thirty patients with type I atrial flutter were randomized into 2 groups in which transesophageal pacing was attempted: group A, without treatment; and group B, after oral administration of propafenone 600 mg. Transesophageal pacing was effective in interrupting atrial flutter in 53% of patients (8 of 15) in group A and in 87% of patients (13 of 15) in group B. A significant lengthening of the flutter cycle was observed with respect to the baseline in patients given propafenone (261 ± 23 vs 217 ± 25, p < 0.01). Sinus rhythm resumed at a shorter paced cycle in group A patients (166 ± 13 vs 187 ± 14 ms, p < 0.01). The transesophageal threshold for stable atrial capture was significantly lower in group A (20.5 ± 0.2 vs 23.3 ± 1.2, p < 0.01). In no patient was the threshold for atrial capture higher than the pain threshold. We did not observe abrupt enhancement of atrioventricular conduction. We conclude that propafenone is effective and safe when used with transesophageal pacing in the termination of atrial flutter. The slowing effect of the drug on intraatrial conduction and the possible stabilizing effect on the reentry circuit appear to be outweighed by the positive effect of propafenone on the excitable gap of the circuit, facilitating its capture and accounting for the beneficial effect of the drug on arrhythmia termination.     

Ileal patch duodenoplasty after right colectomy extended to the duodenal wall

After radical resection of cancer of the right colonic flexure, a parietal defect can be created in case of duodenal invasion. In this paper the authors describe an "easy and safe" duodenoplasty surgical technique using an ileal patch.     

Successful heart transplantation following melphalan plus dexamethasone therapy in systemic AL amyloidosis

Recurrence in the allograft and progression in other organs increase mortality after cardiac transplantation in AL amyloidosis. Survival may be improved after suppression of monoclonal light chain (LC) production following high dose melphalan and autologous stem cell transplantation (HDM/ASCT). However, because of high treatment related mortality, this tandem approach is restricted to few patients without significant extra-cardiac involvement. A diagnosis of systemic AL amyloidosis was established in a 45-year old patient with congestive heart failure related to restrictive cardiomyopathy, nephrotic syndrome, peripheral neuropathy, postural hypotension, macroglossia, and lambda LC monoclonal gammopathy. After melphalan and dexamethasone (M-Dex) therapy, which resulted in 80% reduction of serum free lambda LC, he underwent orthotopic cardiac transplantation. Two years later, he remains in a sustained hematologic remission, with no evidence of allograft or extra-cardiac amyloid accumulation. M-Dex should be considered as an alternative therapy in AL amyloid heart transplant recipients ineligible for HDM/ASCT.     

A hybrid image fusion system for endovascular interventions of peripheral artery disease

Purpose

Interventional endovascular treatment has become the first line of management in the treatment of peripheral artery disease (PAD). However, contrast and radiation exposure continue to limit the feasibility of these procedures. This paper presents a novel hybrid image fusion system for endovascular intervention of PAD. We present two different roadmapping methods from intra- and pre-interventional imaging that can be used either simultaneously or independently, constituting the navigation system.

Methods

The navigation system is decomposed into several steps that can be entirely integrated within the procedure workflow without modifying it to benefit from the roadmapping. First, a 2D panorama of the entire peripheral artery system is automatically created based on a sequence of stepping fluoroscopic images acquired during the intra-interventional diagnosis phase. During the interventional phase, the live image can be synchronized on the panorama to form the basis of the image fusion system. Two types of augmented information are then integrated. First, an angiography panorama is proposed to avoid contrast media re-injection. Information exploiting the pre-interventional computed tomography angiography (CTA) is also brought to the surgeon by means of semiautomatic 3D/2D registration on the 2D panorama. Each step of the workflow was independently validated.

Results

Experiments for both the 2D panorama creation and the synchronization processes showed very accurate results (errors of 1.24 and \(2.6 \pm 1.4\) mm, respectively), similarly to the registration on the 3D CTA (errors of \(1.5 \pm 0.7\) mm), with minimal user interaction and very low computation time. First results of an on-going clinical study highlighted its major clinical added value on intraoperative parameters.

Conclusion

No image fusion system has been proposed yet for endovascular procedures of PAD in lower extremities. More globally, such a navigation system, combining image fusion from different 2D and 3D image sources, is novel in the field of endovascular procedures.