In Situ Pre-Treatment of Vascularized Composite Allografts With a Targeted Complement Inhibitor Protects Against Brain Death and Ischemia Reperfusion Induced Injuries.

Introduction: Donor brain death (BD) is an unavoidable component of vascularized composite allograft (VCA) transplantation and a key contributor to ischemia-reperfusion injury (IRI). Complement is activated and deposited within solid organ grafts as a consequence of BD and has been shown to exacerbate IRI, although the role of BD and complement in VCA and the role it plays in IRI and VCA rejection has not been studied. Methods: BD was induced in Balb/c donors, and the VCA perfused prior to graft procurement with UW solution supplemented with or without CR2-Crry, a C3 convertase complement inhibitor that binds at sites of complement activation, such as that induced on the endothelium by induction of BD. Following perfusion, donor VCAs were cold stored for 6 hours before transplantation into C57BL/6 recipients. Donor VCAs from living donors (LD) were also procured and stored. Analyses included CR2-Crry graft binding, complement activation, toxicity, injury/inflammation, graft gene expression and survival. Results: Compared to LD VCAs, BD donor VCAs had exacerbated IRI and rejected earlier. Following pretransplant in-situ perfusion of the donor graft, CR2-Crry bound within the graft and was retained post-transplantation. CR2-Crry treatment significantly reduced complement deposition, inflammation and IRI as compared to vehicle-treated BD donors. Treatment of BD donor VCAs with CR2-Crry led to an injury profile not dissimilar to that seen in recipients of LD VCAs. Conclusion: Pre-coating a VCA with CR2-Crry in a clinically relevant treatment paradigm provides localized, and therefore minimally immunosuppressive, protection from the complement-mediated effects of BD induced exacerbated IRI.

Targeting the Complement Alternative Pathway Permits Graft Versus Leukemia Activity while Preventing Graft Versus Host Disease.

PURPOSE: Application of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with hematologic disorders is limited by the development of GVHD. Separation of GVHD and graft-versus-leukemia (GVL) remains a great challenge in the field. We investigated the contribution of individual pathways involved in the complement cascade in GVH and GVL responses to identify specific targets by which to separate these two processes. EXPERIMENTAL DESIGN: We used multiple preclinical murine and human-to-mouse xenograft models involving allo-HCT recipients lacking components of the alternative pathway (AP) or classical pathway (CP)/lectin pathway (LP) to dissect the role of each individual pathway in GVHD pathogenesis and the GVL effect. For translational purposes, we used the AP-specific complement inhibitor, CR2-fH, which localizes in injured target organs to allow specific blockade of complement activation at sites of inflammation. RESULTS: Complement deposition was evident in intestines of mice and patients with GVHD. In a preclinical setting, ablation of the AP, but not the CP/LP, significantly improved GVHD outcomes. Complement activation through the AP in host hematopoietic cells, and specifically dendritic cells (DC), was required for GVHD progression. AP deficiency in recipients decreased donor T-cell migration and Th1/Th2 differentiation, while increasing the generation of regulatory T cells. This was because of decreased activation and stimulatory activity of recipient DCs in GVHD target organs. Treatment with CR2-fH effectively prevented GVHD while preserving GVL activity. CONCLUSIONS: This study highlights the AP as a new therapeutic target to prevent GVHD and tumor relapse after allo-HCT. Targeting the AP by CR2-fH represents a promising therapeutic approach for GVHD treatment.

Heterogeneous Photochemistry of Agrochemicals at the Leaf Surface: A Case Study of Plant Activator Acibenzolar-S-methyl.

The photoreactivity of plant activator benzo(1,2,3)thiadiazole-7-carbothioic acid S-methyl ester (BTH), commonly named acibenzolar-S-methyl, was studied on the surfaces of glass, paraffinic wax films, and apple leaves. Experiments were carried out in a solar simulator using pure and formulated BTH (BION). Surface photoproducts were identified using liquid chromatography coupled with electrospray ionization and high-resolution Orbitrap mass spectrometry, while volatile photoproducts were characterized using an online thermal desorption system coupled to a gas chromatography-mass spectrometry (GC-MS) system. Pure BTH degraded quickly on wax surfaces with a half-life of 5.0 ± 0.5 h, whereas photolysis of formulated BTH was 7 times slower (t1/2 = 36 ± 14 h). On the other hand, formulated BTH was found to photolyze quickly on detached apple leaves with a half-life of 2.8 h ± 0.4 h. This drastic difference in photoreactivity was attributed to the nature and spreading of the BTH deposit, as influenced by the surfactant and surface characteristics. Abiotic stress of irradiated apple leaf was also shown to produce OH radicals which might contribute to the enhanced photodegradability. Eight surface photoproducts were identified, whereas GC-MS analyses revealed the formation of gaseous dimethyl disulfide and methanethiol. The yield of dimethyl disulfide ranged between 1.5% and 12%, and a significant fraction of dimethyl disulfide produced was found to be absorbed by the leaf. This is the first study to report on the formation of volatile chemicals and OH radicals during agrochemical photolysis on plant surfaces. The developed experimental approach can provide valuable insights into the heterogeneous photoreactivity of sprayed agrochemicals and could help improve dissipation models.

Photomineralization of aqueous salicylic acids. Photoproducts characterization and formation of light induced secondary OH precursors (LIS-OH).

The photolysis of aqueous 5-chlorosalicylic acid (ClSA) and dihydroxybenzoic acid (DHBA), its main photoproduct, was studied to determine the extent of degradation caused by simulated solar light. Photoproducts identification was achieved using high resolution LC-MS and GC-MS. About 40 photoproducts from C19 to C1 were characterized, including a dihydroxycyclopentadienic acid, a ring contraction photoproduct, and numerous carbonyls and carboxylic acid derivatives that were detected thanks to derivatization. UV-visible spectral monitoring of the reactions revealed that ClSA and DHBA underwent photobleaching after developing a temporarily featureless absorbance between 300 and 500 nm. Measurement of OH radicals using terephtalic acid as a probe showed that OH radicals were generated with an average rate of 7 × 10-9 M s-1 and a total cumulated concentration of 10-3 M, corresponding to ∼ 5-fold the initial concentration of DHBA. Furthermore, TOC analysis indicated that significant mineralization (51-90%) occurred. These findings are consistent with the formation of light induced secondary OH (LIS-OH) precursors such as featureless long wavelength absorbing compounds as well as non-absorbing hydroperoxides. The formation of LIS-OH illustrated here may also take place in the aqueous photodegradation of other substituted phenols likely present in dissolved organic matter and humic substructures, it deserves to be studied in more details.

[Suprasellar arachnoid cyst associated with syringomyelia. Case report]. / Kyste arachnoïdien suprasellaire et cavité syringomyélique. A propos d'un cas.

We present a case of suprasellar arachnoid cyst which was revealed by visual impairement and hypopituitarism. Neuroradiological imaging showed the peculiar association of the suprasellar cyst with cerebellar tonsillar herniation and a large asymptomatic cervical syringomyelic cavity. Surgical treatment of the suprasellar cyst allowed the reduction of both the cyst and the syrinx. A common pathophysiological mechanism of these lesions is discussed. We suggest the possibility that an initial obstruction of the basal cisterns caused the suprasellar cyst formation which led to medullar cavity formation.

[Clinical aspects and treatment of dural-spinal arteriovenous fistulas with perimedullary venous drainage. 10 cases]. / Aspects cliniques et traitement des fistules artério-veineuses durales rachidiennes à drainage veineux périmédullaire. A propos de 10 observations.

BACKGROUND AND PURPOSE: Spinal dural arteriovenous fistulas (SDAVF) are rare but represent the most frequent spinal arteriovenous malformation. Their clinical manifestations are well known, but their management can still be discussed between surgery and endovascular treatment. The purpose of this study is to emphasize the pre-eminence of surgical management for posterior and postero-lateral fistulas, which are the most common location of the malformation. METHODS: We report a consecutive series of 10 patients with SDAVF treated between July, 1995 and July, 1997. Results are compared with other series of the literature. RESULTS: Clinical manifestations were not specific and the diagnosis was established in most cases only one year after the onset of symptoms, as a progressive myelopathy. Low back pain was present in 4 patients, with pseudo-radicular pain in the lower limbs suggesting spinal degenerative disease in 3 cases. At the time of diagnosis, 8 patients had permanent motor weakness of the lower limbs, usually associated with hypesthesia and sphincterial dysfunction (7 cases). In all cases, the diagnosis was established using MRI. In most cases, the intradural draining spinal veins were also visible on MRI images. The location of the SDAVF was always precised by angiography, and was located between T5 and L1 in our series. Seven patients were successfully operated on, with surgical interruption of the intradural draining vein. Three patients underwent an endovascular treatment, but two of them were operated on later, as control angiography showed recurrence of the SDAVF. The clinical status of patients always improved after treatment, but recovery was incomplete in patients with severe and long lasting neurological deficit. CONCLUSIONS: Surgical interruption of the intradural draining vein is a safe and effective method of treatment of SDAVF, especially for posterior and postero-lateral fistulas. Endovascular treatment is recommended for anterior locations of SDAVF.

[Chronic subdural hematoma in patients over 80 years of age]. / L'hématome sous-dural chronique chez les patients de plus de 80 ans.

Eighty cases of chronic subdural haematomas (SDH) in elderly patients (over 80 year-old) are reported retrospectively. The estimated incidence of the disease is 17 cases per 10(5) per year. The main presenting symptoms were confusion and impaired mentation. Surgical treatment was performed in all patients. Biological disorders deserved particular attention in the elderly SDH population. Complications occurred in 10% of patients, and recurrence of SDH was noted in 5% of patients. After their hospital discharge, 85% of patients returned to their previous neurological status. In this study, the age of patients did not appear to be a poor prognostic factor.

[Congenital clubfoot. Analysis of 260 cases followed from birth]. / Pied bot varus équin congénital. Analyse de 260 cas suivis depuis la naissance.

INTRODUCTION: This study is a critical analysis of the results in a homogeneous series of 260 cases of congenital clubfoot followed from birth. MATERIAL AND METHODS: This series of congenital club feet was divided in 2 groups: the stiff forms (144 cases) and the supple forms (116 cases). Daily physical therapy and Denis Brown's splints were begun from the first examination. This method did not allow full correction of deformations in 213 cases. A posterior medial surgical release was performed. Its importance depended on the criteria of radio-clinical analysis before surgery. 46 feet were operated twice. RESULTS: Follow up averaged 7 years. 39 per cent of patients had completed growth, only 18 per cent of feet were not operated. With the surgical treatment, the results were ""very good'' and ""good'' in 75.1 per cent of cases, according to an analysis using Seringe's criteria. 21 per cent were operated again, on an average between 3 and 8 years, with poorer results than at first surgery. DISCUSSION: The quality of the results depends on the quality of the functional treatment. Poor control of equinism with Denis-Brown splints can be corrected by using Seringe's articulated splints or by a series of plaster casts. CONCLUSION: Many technical factors influence the results. The quality of post-operative contention is stressed.