The Specific Copper(II) Chelator TDMQ20 Is Efficient for the Treatment of Wilson's Disease in Mice.

(1) Background: In patients with Wilson's disease, the deficiency of the copper carrier ATP7B causes the accumulation of copper in the liver, brain and various other organs. Lifelong treatment is therefore mandatory, using copper chelators to increase the excretion of copper and to avoid life-threatening damage. The clinically used reference drug, D-penicillamine, exhibit numerous adverse effects, especially a frequent severe and irreversible neurological worsening, mainly due to its lack of metal selectivity; (2) Methods: A new tetradentate ligand based on an 8-aminoquinoline entity, named TDMQ20, which is highly selective for copper compared with other metal ions, is evaluated in "toxic milk" TX mice as an oral treatment of this Wilson's disease murine model; (3) Results: The concentration of copper in the liver of "toxic milk" TX mice decreased and the fecal excretion of copper increased upon oral treatment with TDMQ20. Both effects are dose-dependent, and more pronounced than those of D-penicillamine; (4) Conclusions: The TDMQ20 copper chelator is more efficient than the reference drug D-penicillamine for the treatment of a Wilson's disease murine model. Pharmacological data obtained with TDMQ20 on the TX mouse model strongly support the selection of this ligand as a drug candidate for this genetic disease.

GDU-952, a novel AhR agonist ameliorates skin barrier abnormalities and immune dysfunction in DNFB-induced atopic dermatitis in mice.

The aryl hydrocarbon receptor (AhR) is widely expressed in the skin. It controls immune-mediated skin responses to various external environmental signals, promote terminal differentiation of epidermal keratinocytes and participates the maintenance of the skin barrier function. As a therapeutic target, AhR activation modulates many diseases progression driven by immune/inflammatory processes such as atopic dermatitis (AD) and psoriasis. In this study, we revealed that GDU-952 is a novel AhR agonist, which is able to decreases IgE serum levels, to inhibit pro-inflammatory cytokines such as IL-6 and TNF-α and to induce immunoregulatory effects through restoring Th1/Th2 immune balance and promoting CD4+FOXP3+regulatory T (Treg) populations in AD skin lesions. Furthermore, GDU-952 can strengthen the skin barrier function through upregulating epidermal differentiation-related and tight junction proteins. This may alleviate AD symptoms, such as dermatitis scores, epidermal hyperplasia and mast cell infiltration. These results offer a rationale for further preclinical/clinical studies to evaluate the possible use of GDU-952 in the management of AD.

Hybrid molecules based on an emodin scaffold. Synthesis and activity against SARS-CoV-2 and Plasmodium.

Since the Covid-19 epidemic, it has been clear that the availability of small and affordable drugs that are able to efficiently control viral infections in humans is still a challenge in medicinal chemistry. The synthesis and biological activities of a series of hybrid molecules that combine an emodin moiety and other structural moieties expected to act as possible synergistic pharmacophores in a single molecule were studied. Emodin has been reported to block the entry of the SARS-CoV-2 virus into human cells and might also inhibit cytokine production, resulting in the reduction of pulmonary injury induced by SARS-CoV-2. The pharmacophore associated with emodin was either a polyamine residue (emodin-PA series), a choice driven by the fact that a natural alkyl PA like spermine and spermidine play regulatory roles in immune cell functions, or a diphenylmethylpiperazine derivative of the norchlorcyclizine series (emoxyzine series). In fact, diphenylmethylpiperazine antagonists of the H1 histamine receptor display activity against several viruses by multiple interrelated mechanisms. In the emoxyzine series, the most potent drug against SARS-CoV-2 was (R)-emoxyzine-2, with an EC50 value = 1.9 µM, which is in the same range as that of the reference drug remdesivir. However, the selectivity index was rather low, indicating that the dissociation of antiviral potency and cytotoxicity remains a challenge. In addition, since emodin was also reported to be a relatively high-affinity inhibitor of the virulence regulator FIKK kinase from the malaria parasite Plasmodium vivax, the antimalarial activity of the synthesized hybrid compounds has been evaluated. However, these molecules cannot efficiently compete with the currently used antimalarial drugs.

Design, synthesis and evaluation of novel pyrimidinylaminothiophene derivatives as FGFR1 inhibitors against human glioblastoma multiforme.

Vascular endothelial growth factor receptors (VEGFRs) have emerged as the most promising anti-angiogenic therapeutic targets for the treatment of recurrent glioblastomas (GBM). However, anti-VEGF treatments led to the high proportion of non-responder patients or non lasting clinical response and the tumor progression to the greater malignant stage. To overcome these problems, there is an utmost need to develop innovative anti-angiogenic therapies. In this study, we report the development of a series of new FGFR1 inhibitors. Among them, compound 4i was able to potently inhibit FGFR1 kinase activities both in vitro and in vivo. This compound displayed strong anti-angiogenic activity in HUVECs and anti-tumor growth and anti-invasion effects in U-87MG cell line. These results emphasize the importance of FGFR1-mediated signaling pathways in GBM and reveal that pharmacological inhibition of FGFR1 can enhance the anti-tumoral, anti-angiogenic and anti-metastatic efficiency against GBM. These data support targeting of FGFR1 as a novel anti-angiogenic strategy and highlight the potential of compound 4i as a promising anti-angiogenic and anti-metastatic candidate for GBM therapy.

Gluteal Propeller Perforator Flaps: A Paradigm Shift in Abdominoperineal Amputation Reconstruction.

Abdominoperineal amputation (AAP) is a gold standard procedure treating advanced abdominal and pelvic cancers. The defect resulting from this extensive surgery must be reconstructed to avoid complications, such as infection, dehiscence, delayed healing, or even death. Several approaches can be chosen depending on the patient. Muscle-based reconstructions are a reliable solution but are responsible for additional morbidity for these fragile patients. We present and discuss our experience in AAP reconstruction using gluteal-artery-based propeller perforator flaps (G-PPF) in a case series. Between January 2017 and March 2021, 20 patients received G-PPF reconstruction in two centers. Either superior gluteal artery (SGAP)- or inferior artery (IGAP)-based perforator flaps were performed depending on the best configuration. Preoperative, intraoperative, and postoperative data were collected. A total of 23 G-PPF were performed-12 SGAP and 11 IGAP flaps. Final defect coverage was achieved in 100% of cases. Eleven patients experienced at least one complication (55%), amongst whom six patients (30%) had delayed healing, and three patients (15%) had at least one flap complication. One patient underwent a new surgery at 4 months for a perineal abscess under the flap, and three patients died from disease recurrence. Gluteal-artery-based propeller perforator flaps are an effective and modern surgical procedure for AAP reconstruction. Their mechanic properties, in addition to their low morbidity, make them an optimal technique for this purpose; however, technical skills are needed, and closer surveillance with patient compliance is critical to ensure success. G-PPF should be widely used in specialized centers and considered a modern alternative to muscle-based reconstructions.

Distribution in Rat Blood and Brain of TDMQ20, a Copper Chelator Designed as a Drug-Candidate for Alzheimer's Disease.

(1) Background: TDMQ20 is a specific regulator of copper homeostasis in the brain, able to inhibit cognitive impairment in the early stages of Alzheimer's disease (AD) in mouse models of AD. To promote the further development of this drug-candidate, preliminary data on the pharmacokinetics of TDMQ20 in a mammal model have been collected. Since TDMQ20 should be administered orally, its absorption by the gastrointestinal tract was evaluated by comparison of blood concentrations after administration by oral and IV routes, and its ability to reach its target (the brain) was confirmed by comparison between blood and brain concentrations after oral administration. (2) Methods: plasmatic and brain concentrations of the drug after oral or intravenous treatment of rats at pharmacologically relevant doses were determined as a function of time. (3) Results: oral absorption of TDMQ20 was rapid and bioavailability was high (66% and 86% for males and females, respectively). The drug accumulated in the brain for several hours (brain-plasma ratio 3 h after oral administration = 2.6), and was then efficiently cleared. (4) Conclusions: these data confirm that TDMQ20 efficiently crosses the brain-blood barrier and is a relevant drug-candidate to treat AD.

Proteomics Evidence of the Role of TDMQ20 in the Cholinergic System and Synaptic Transmission in a Mouse Model of Alzheimer's Disease.

The interaction between copper ions and amyloid peptide Aß has been reported to be involved in Alzheimer's disease (AD) pathology. Based on copper coordination biochemistry, we designed specific copper chelators [tetradentate monoquinolines (TDMQs)] in order to regulate copper homeostasis in the AD brain and inhibit the deleterious oxidative stress catalyzed by copper-Aß complexes. We previously reported that TDMQ20, a highly selective copper chelator selected as a drug candidate, was able to extract copper from the Cu-Aß1-16 complex and restore cognitive and behavioral deficits in AD mouse models. For a better understanding of the mechanism of action of TDMQ20, we decided to investigate the change of profile of proteins expressed in 5xFAD mice after an oral treatment of TDMQ20 (dose = 10 mg/kg, once every two days for 3 months, in total 45 times). Clioquinol (CQ), a non-specific chelator, has been used as a comparator. Here, we report the proteomic alterations in the cortex of 5xFAD mice using iTRAQ (isobaric tags for relative and absolute quantification) proteomics technology. The results indicated that 178 differentially expressed proteins (DEPs) have been identified in the AD mouse group with respect to wild type (WT) animals (AD/WT). After treatment by TDMQ20, 35 DEPs were found common in AD/WT and TDMQ20/AD groups in an opposite change manner (up- or down-regulated, respectively). In addition, among the 35 DEPs mentioned above, 10 common target proteins have been identified in AD/WT, TDMQ20/AD, and CQ/AD groups, among which 3 target proteins were successfully validated by western blot analysis. In particular, the expression levels of ChAT and CHRM4 are significantly increased upon TDMQ20 treatment with respect to 5xFAD mice, while CQ did not significantly change the expression of these proteins. Our study suggests the involvement of the copper chelator TDMQ20 on the cholinergic system, a feature that may explain the improved cognitive and behavioral performance in AD mice upon oral treatment of TDMQ20.

Synthesis and Antimalarial Activities of New Hybrid Atokel Molecules.

The currently spreading resistance of the malaria parasite Plasmodium falciparum to artemisinin-based combination therapies makes an urgent need for new efficient drugs. Aiming to kill artemisinin-resistant Plasmodium, a series of novel hybrid drugs named Atokels were synthesized and characterized. Atokels are based on an 8-amino- or 8-hydroxyquinoline entity covalently bound to a 1,4-naphthoquinone through a polyamine linker. These drugs have been designed to target the parasite mitochondrion by their naphthoquinone moiety reminiscent of the antimalarial drug atovaquone, and to trigger a damaging oxidative stress due to their ability to chelate metal ions in order to generate redox active complexes in situ. The most effective Atokel drug shown a promising antimalarial activity (IC50 =622 nm on an artemisinin-resistant P. falciparum strain) and no cytotoxicity at 50 µm indicating a specific antiplasmodial mode of action.

How to Define a Nanozyme.

Over the past 15 years, many articles have considered "nanozymes" as ferromagnetic nanoparticles having an "intrinsic peroxidase-like activity" in the presence of hydrogen peroxide. However, the definition and the catalytic activity of these nanozymes have been questioned. The present Perspective reports the main criteria that are essential to classify a nanoparticle as a nanozyme. It is important to consider that not all nanoparticles able to generate hydroxyl radicals in the presence of hydrogen peroxide without catalytic activity can be registered as nanozymes.

Comparison of alternative arterial anastomosis site during liver transplantation when the recipient's hepatic artery is unusable.

Background: Few studies have analyzed outcomes of liver transplantation (LT) when the recipient hepatic artery (HA) was not usable. Methods: We retrospectively evaluated the outcomes of LT performed using the different alternative sites to HA. Results: Between 2002 and 2017, 1,677 LT were performed in our institution among which 141 (8.4%) with unusable recipient HA were analyzed. Four groups were defined according to the site of anastomosis: the splenic artery (SA group, n=26), coeliac trunk (CT group, n=12), aorta using or not the donor's vessel (Ao group, n=91) and aorta using a vascular prosthesis (Ao-P group, n=12) as conduit. The median number of intraoperative red blood cell transfusions was significantly increased in the Ao and Ao-P groups (5, 5, 8.5 and 16 for SA, CT, Ao and Ao-P group respectively, P=0.002), as well as fresh frozen plasma (4.5, 2.5, 10, 17 for the SA, CT, Ao and Ao-P groups respectively, P=0.001). Hospitalization duration was also significantly increased in the Ao and Ao-P groups (15, 16, 24, 26.5 days for the SA, CT, Ao and Ao-P groups respectively, P<0.001). The occurrence of early allograft dysfunction (EAD) (P=0.07) or arterial complications (P=0.26) was not statistically different. Level of factor V, INR, bilirubin and creatinine during the 7th postoperative days (POD) was significantly improved in the SA group. No difference was observed regarding graft (P=0.18) and patient (P=0.16) survival. Conclusions: In case of unusable HA, intraoperative and postoperative outcomes are improved when using the SA or CT compared to aorta.

Does baseline quality of life predict the occurrence of complications in resectable esophageal cancer?

BACKGROUND: The aim of this study was to assess the impact of baseline health related quality of life (HRQOL) on the occurrence of postoperative complications and death in patients with resectable esophageal cancer. METHODS: Existing data from a prospective, multicenter, open label, randomized, controlled phase III trial comparing hybrid versus open esophagectomy in patients with resectable esophageal cancer from 2009 to 2012 in France were used. A Cox regression model was used to assess the prognostic value of the baseline HRQOL score on the occurrence of major complications (MC), and major pulmonary complications (MPC) at 30 days post-surgery, as well as on 1-year postoperative overall survival (OS). RESULTS: Every 10-point increase in the baseline role functioning score was associated with a 14% reduction in the risk of MC, while every 10-point increase in fatigue or pain score was associated with an 18% increase in the risk of MC. Similarly, higher scores on fatigue and pain were associated with a higher risk of MPC. Compared with the hybrid procedure, patients undergoing open esophagectomy had a significantly higher risk of MC and MPC. Patients diagnosed with esophageal adenocarcinoma were at significantly lower risk of MC or MPC compared to patients with esophageal squamous cell carcinoma. Higher pain (HR = 1.23, p = 0.035) and insomnia (HR = 1.16, P = 0.031) scores were associated with increased 1-year OS. CONCLUSION: Fatigue, pain, insomnia, and squamous cell pathology were indicators of poor prognosis, and that the presence of these findings might possibly change the management plan towards other forms of treatment and warrant close attention.

Associations between the severity of medical and surgical complications and perception of surgeon empathy in esophageal and gastric cancer patients.

OBJECTIVE: To assess the impact of global physician empathy and its three subdimensions (establishing rapport, emotional and cognitive processes) on the severity of postoperative complications in a sample of cancer patients. METHODS: We retrospectively analyzed data on 256 patients with esogastric cancer from the French national FREGAT database. Empathy and its subdimensions were assessed using the patient-reported CARE scale and the severity of medical and surgical complications was reported with the Clavien-Dindo classification system. The usual covariates were included in multinomial logistic regression analyses. RESULTS: Physician empathy predicted the odds of reporting major complications. When patients perceived high empathy, they were less likely to report major complications compared to no complications (OR = .95, 95% CI = [.91-.99], p = .029). Among the three dimensions, only "establishing rapport" (OR = .84, 95% CI = [.73-.98], p = .019) and the "emotional process" (OR = .85, 95% CI = [.74-.98], p = .022) predicted major complications. CONCLUSIONS: Physician empathy is essential before surgery. Further research is needed to understand the mechanisms associating empathy with health outcomes in cancer. Physicians should be trained to establish good rapport with patients, especially in the preoperative period.

Limited Resection Versus Pancreaticoduodenectomy for Duodenal Gastrointestinal Stromal Tumors? Enucleation Interferes in the Debate: A European Multicenter Retrospective Cohort Study.

BACKGROUND: The optimal surgical procedure for duodenal gastrointestinal stromal tumors (D-GISTs) remains poorly defined. Pancreaticoduodenectomy (PD) allows for a wide resection but is associated with a high morbidity rate. OBJECTIVES: The aim of this study was to compare the short- and long-term outcomes of PD versus limited resection (LR) for D-GISTs and to evaluate the role of tumor enucleation (EN). METHODS: In this retrospective European multicenter cohort study, 100 patients who underwent resection for D-GIST between 2001 and 2013 were compared between PD (n = 19) and LR (n = 81). LR included segmental duodenectomy (n = 47), wedge resection (n = 21), or EN (n = 13). The primary objective was to evaluate disease-free survival (DFS) between the groups, while the secondary objectives were to analyze the overall morbidity and mortality, radicality of resection, and 5-year overall survival (OS) and recurrence rates between groups. Furthermore, the short- and long-term outcomes of EN were evaluated. RESULTS: Baseline characteristics were comparable between the PD and LR groups, except for a more frequent D2 tumor location in the PD group (68.3% vs. 29.6%; p = 0.016). Postoperative morbidity was higher after PD (68.4% vs. 23.5%; p < 0.001). OS (p = 0.70) and DFS (p = 0.64) were comparable after adjustment for D2 location and adjuvant therapy rate. EN was performed more in American Society of Anesthesiologists (ASA) stage III/IV patients with tumors < 5 cm and was associated with a 5-year OS rate of 84.6%, without any disease recurrences. CONCLUSIONS: For D-GISTs, LR should be the procedure of choice due to lower morbidity and similar oncological outcomes compared with PD. In selected patients, EN appears to be associated with equivalent short- and long-term outcomes. Based on these results, a surgical treatment algorithm is proposed.

Perforator-Based Intercostal Artery Muscle Flap: A Novel Approach for the Treatment of Tracheoesophageal or Bronchoesophageal Fistulas.

SUMMARY: Postoperative tracheoesophageal or bronchoesophageal fistulas represent a major surgical challenge. The authors report the description of an original perforator-based intercostal artery muscle flap, aiming to cover all types of intrathoracic fistulas, from any location, in difficult cases such as postoperative fistulas after esophagectomy in an irradiated field. Between June of 2016 and January of 2019, eight male patients were treated with a perforator-based intercostal artery muscle flap. All had previous surgery for esophageal cancer and developed a tracheoesophageal or bronchoesophageal fistula during the perioperative course. The mean patient age was 55.9 ± 8.8 years. All patients received neoadjuvant chemotherapy and seven received neoadjuvant radiation therapy. A perforator-based intercostal artery muscle flap, with a mean skin paddle size of 9.86 × 5 cm, was harvested. The median operative time was 426.50 minutes. The tracheoesophageal or bronchoesophageal fistula was successfully and definitively occluded in three patients; two patients experienced recurrence; and one patient underwent re operation. At 1 year, five patients were alive (62.5 percent), and among them, three (37.5 percent) were free from any intrathoracic complications. Three patients died, because of massive digestive bleeding, mesenteric ischemia, and multiorgan failure, respectively. The perforator-based intercostal artery muscle flap, like the Taylor flap in abdominoperineal reconstruction, could become a workhorse flap for all intrathoracic reconstructions, as it can always be harvested, even if a previous thoracotomy has ruined most of the options. This surgical technique, easily feasible, reliable, and reproducible, became our first option for all postoperative tracheoesophageal or bronchoesophageal fistula patients during the postoperative course following esophagectomy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Five-Year Survival Outcomes of Hybrid Minimally Invasive Esophagectomy in Esophageal Cancer: Results of the MIRO Randomized Clinical Trial.

Importance: Available data comparing the long-term results of hybrid minimally invasive esophagectomy (HMIE) with that of open esophagectomy are conflicting, with similar or even better results reported for the minimally invasive esophagectomy group. Objective: To evaluate the long-term, 5-year outcomes of HMIE vs open esophagectomy, including overall survival (OS), disease-free survival (DFS), and pattern of disease recurrence, and the potential risk factors associated with these outcomes. Design, Setting, and Participants: This randomized clinical trial is a post hoc follow-up study that analyzes the results of the open-label Multicentre Randomized Controlled Phase III Trial, which enrolled patients from 13 different centers in France and was conducted from October 26, 2009, to April 4, 2012. Eligible patients were 18 to 75 years of age and were diagnosed with resectable cancer of the middle or lower third of the esophagus. After exclusions, patients were randomized to either the HMIE group or the open esophagectomy group. Data analysis was performed on an intention-to-treat basis from November 19, 2019, to December 4, 2020. Interventions: Hybrid minimally invasive esophagectomy (laparoscopic gastric mobilization with open right thoracotomy) was compared with open esophagectomy. Main Outcomes and Measures: The primary end points of this follow-up study were 5-year OS and DFS. The secondary end points were the site of disease recurrence and potential risk factors associated with DFS and OS. Results: A total of 207 patients were randomized, of whom 175 were men (85%), and the median (range) age was 61 (23-78) years. The median follow-up duration was 58.2 (95% CI, 56.5-63.8) months. The 5-year OS was 59% (95% CI, 48%-68%) in the HMIE group and 47% (95% CI, 37%-57%) in the open esophagectomy group (hazard ratio [HR], 0.71; 95% CI, 0.48-1.06). The 5-year DFS was 52% (95% CI, 42%-61%) in the HMIE group vs 44% (95% CI, 34%-53%) in the open esophagectomy group (HR, 0.81; 95% CI, 0.55-1.17). No statistically significant difference in recurrence rate or location was found between groups. In a multivariable analysis, major intraoperative and postoperative complications (HR, 2.21; 95% CI, 1.41-3.45; P < .001) and major pulmonary complications (HR, 1.94; 95% CI, 1.21-3.10; P = .005) were identified as risk factors associated with decreased OS. Similarly, multivariable analysis of DFS identified overall intraoperative and postoperative complications (HR, 1.93; 95% CI, 1.28-2.90; P = .002) and major pulmonary complications (HR, 1.85; 95% CI, 1.19-2.86; P = .006) as risk factors. Conclusions and Relevance: This study found no difference in long-term survival between the HMIE and open esophagectomy groups. Major postoperative overall complications and pulmonary complications appeared to be independent risk factors in decreased OS and DFS, providing additional evidence that HMIE may be associated with improved oncological results compared with open esophagectomy primarily because of a reduction in postoperative complications. Trial Registration: ClinicalTrials.gov Identifier: NCT00937456.

Simultaneous Versus Delayed Resection for Initially Resectable Synchronous Colorectal Cancer Liver Metastases: A Prospective, Open-label, Randomized, Controlled Trial.

OBJECTIVE: To answer whether synchronous colorectal cancer liver metastases (SLM) should be resected simultaneously with primary cancer or should be delayed. SUMMARY BACKGROUND DATA: Numerous studies have compared both strategies. All were retrospective and conclusions were contradictory. METHODS: Adults with colorectal cancer and resectable SLM were randomly assigned to either simultaneous or delayed resection of the metastases. The primary outcome was the rate of major complications within 60 days following surgery. Secondary outcomes included overall and disease-free survival. RESULTS: A total of 105 patients were recruited. Eighty-five patients (39 and 46 in the simultaneous- and delayed-resection groups, respectively) were analyzed. The percentage of major perioperative complications did not differ between groups (49% and 46% in the simultaneous- and delayed-resection groups, respectively, adjusted OR 0.84, 95% CI 0.35-2.01; P = 0.70, logistic regression). Complications rates were 28% and 13% (P = 0.08, χ2 test) at colorectal site and 15% and 17% (P = 0.80, χ2 test) at liver site, in simultaneous- and delayed-resection groups, respectively. In the delayed-resection group, 8 patients did not reach the liver resection stage, and this was due to disease progression in 6 cases. After 2 years, overall and disease-free survival tended to be improved in simultaneous as compared with delayed-resection groups (P = 0.05), a tendency which persisted for OS after a median follow-up of 47 months. CONCLUSIONS: Complication rates did not appear to differ when colorectal cancer and synchronous liver metastases are resected simultaneously. Delayed resection tended to impair overall survival.

Fatal epidural abscess with meningitis: a rare complication of colorectal surgery.

BACKGROUND: Anastomotic leakage following colorectal surgery remains a frequent complication. We report a rare case of a fatal epidural abscess caused by a colo-epidural fistula complicating a laparoscopic proctectomy. CASE PRESENTATION: A 62 year-old-man presented with weight loss, pelvic sepsis and neurological dysfunction four months after closing of the ileostomy following a laparoscopic proctectomy for a rectal adenocarcinoma one year ago. Cross-sectional imaging confirmed an epidural abscess caused by a chronic colorectal anastomotic leak. Systemic antibiotics and laparotomy with defunctioning pelvic loop colostomy were performed. Unfortunately, this management to control the major spinal infection failed. Epidural decompression and debridement was not possible due to his poor condition and the patient subsequently died. CONCLUSION: Colo-epidural fistula can occur as a consequence of colorectal anastomotic leakage. Prior to frank neurology symptoms and sepsis, patients may present with only a low-grade fever. Without prompt and aggressive management of colo-epidural infection, this severe complication can lead to paraplegia and death.

TDMQ20, a Specific Copper Chelator, Reduces Memory Impairments in Alzheimer's Disease Mouse Models.

Besides targeting amyloid or tau metabolisms, regulation of redox metal ions is a recognized therapeutic target for Alzheimer's disease (AD). Based on the bioinorganic chemistry of copper, we designed specific chelators of copper(II) (TDMQs) insight to regulate copper homeostasis in the brain and to inhibit the deleterious oxidative stress catalyzed by copper-amyloid complexes. An oral treatment by TDMQ20 was able to fully reverse the cognitive and behavioral impairment in three different murine models, two nontransgenic models mimicking the early stage of AD and a transgenic model representing a more advanced stage of AD. To our knowledge, such a comparative study using the same molecule has never been performed. Regular C57BL/6 mice received a single injection of human Cu-Aß1-42 in the lateral ventricles (icv-CuAß) or in the hippocampus (hippo-CuAß). In both cases, mice developed a cognitive impairment similar to that of transgenic 5XFAD mice. Oral administration of TDMQ20 to icv-CuAß or hippo-CuAß mice within a 16-day period resulted in a significant improvement of the cognitive status. The 3-month treatment of transgenic 5XFAD mice with TDMQ20 also resulted in behavioral improvements. The consistent positive pharmacological results obtained using these different AD models correlate well with previously obtained physicochemical data of TDMQ20. The short-term novel object recognition (NOR) test was found particularly relevant to evaluate the rescue of declarative memory impairment. TDMQ20 was also able to reduce the oxidative stress in the mouse cortex. Due to its reliability and facile use, the hippo-CuAß model can be considered as a robust nontransgenic model to evaluate the activity of potential drugs on the early stages of memory deficits.

End Colostomy With or Without Mesh to Prevent a Parastomal Hernia (GRECCAR 7): A Prospective, Randomized, Double Blinded, Multicentre Trial.

OBJECTIVE: To evaluate whether systematic mesh implantation upon primary colostomy creation was effective to prevent PSH. SUMMARY OF BACKGROUND DATA: Previous randomized trials on prevention of PSH by mesh placement have shown contradictory results. METHODS: This was a prospective, randomized controlled trial in 18 hospitals in France on patients aged ≥18 receiving a first colostomy for an indication other than infection. Participants were randomized by blocks of random size, stratified by center in a 1:1 ratio to colostomy with or without a synthetic, lightweight monofilament mesh. Patients and outcome assessors were blinded to patient group. The primary endpoint was clinically diagnosed PSH rate at 24 months of the intention-to-treat population. This trial was registered at ClinicalTrials.gov, number NCT01380860. RESULTS: From November 2012 to October 2016, 200 patients were enrolled. Finally, 65 patients remained in the no mesh group (Group A) and 70 in the mesh group (Group B) at 24 months with the most common reason for drop-out being death (n = 41). At 24 months, PSH was clinically detected in 28 patients (28%) in Group A and 30 (31%) in Group B [P = 0.77, odds ratio = 1.15 95% confidence interval = (0.62;2.13)]. Stoma-related complications were reported in 32 Group A patients and 37 Group B patients, but no mesh infections. There were no deaths related to mesh insertion. CONCLUSION: We failed to show efficiency of a prophylactic mesh on PSH rate. Placement of a mesh in a retro-muscular position with a central incision to allow colon passage cannot be recommended to prevent PSH. Optimization of mesh location and reinforcement material should be performed.

Hypothermic Oxygenated Perfusion Improves Extended Criteria Donor Liver Graft Function and Reduces Duration of Hospitalization Without Extra Cost: The PERPHO Study.

Few studies have evaluated the efficacy or the cost of hypothermic oxygenated perfusion (HOPE) in the conservation of extended criteria donor (ECD) grafts from donation after brain death (DBD) donors during liver transplantation (LT). We performed a prospective, monocentric study (NCT03376074) designed to evaluate the interest of HOPE for ECD-DBD grafts. For comparison, a control group was selected after propensity score matching among patients who received transplants between 2010 and 2017. Between February and November 2018, the HOPE procedure was used in 25 LTs. Immediately after LT, the median aspartate aminotransferase (AST) level was significantly lower in the HOPE group (724UI versus 1284UI; P = 0.046) as were the alanine aminotransferase (ALT; 392UI versus 720UI; P = 0.01), lactate (2.2 versus 2.7; P = 0.01) There was a significant reduction in intensive care unit stay (3 versus 5 days; P = 0.01) and hospitalization (15 versus 20 days; P = 0.01). The incidence of early allograft dysfunction (EAD; 28% versus 42%; P = 0.22) was similar . A level of AST or ALT in perfusate >800UI was found to be highly predictive of EAD occurrence (areas under the curve, 0.92 and 0.91, respectively). The 12-month graft (88% versus 89.5%; P = 1.00) and patient survival rates (91% versus 91.3%; P = 1.00) were similar. The additional cost of HOPE was estimated at € 5298 per patient. The difference between costs and revenues, from the hospital's perspective, was not different between the HOPE and control groups (respectively, € 3023 versus € 4059]; IC, -€ 5470 and € 8652). HOPE may improve ECD graft function and reduce hospitalization stay without extra cost. These results must be confirmed in a randomized trial.