A retrospective study of ketamine administration and the development of acute or post-traumatic stress disorder in 274 war-wounded soldiers.

The objective of this study was to explore whether ketamine prevents or exacerbates acute or post-traumatic stress disorders in military trauma patients. We conducted a retrospective study of a database from the French Military Health Service, including all soldiers surviving a war injury in Afghanistan (2010-2012). The diagnosis of post-traumatic stress disorder was made by a psychiatrist and patients were analysed according to the presence or absence of this condition. Analysis included the following covariables: age; sex; acute stress disorder; blast injury; associated fatality; brain injury; traumatic amputation; Glasgow coma scale; injury severity score; administered drugs; number of surgical procedures; physical, neurosensory or aesthetic sequelae; and the development chronic pain. Covariables related to post-traumatic and acute stress disorders with a p ≤ 0.10 were included in a multivariable logistic regression model. The data from 450 soldiers were identified; 399 survived, of which 274 were analysed. Among these, 98 (36%) suffered from post-traumatic stress disorder and 89 (32%) had received ketamine. Fifty-four patients (55%) in the post-traumatic stress disorder group received ketamine vs. 35 (20%) in the no PTSD group (p < 0.001). The 89 injured soldiers who received ketamine had a median (IQR [range]) injury severity score of 5 (3-13 [1-26]) vs. 3 (2-4 [1-6] in the 185 patients who did not (p < 0.001). At multivariable analysis, only acute stress disorder and total number of surgical procedures were independently associated with the development of post-traumatic stress disorder. In this retrospective study, ketamine administration was not a risk factor for the development of post-traumatic stress disorder in the military trauma setting.

Computer-predicted peptides that mimic discontinuous epitopes on the A2 domain of factor VIII.

Development of antibodies (Abs) against factor VIII (FVIII) is a severe complication of haemophilia A treatment. Recent publications suggest that domain specificity of anti-FVIII antibodies, particularly during immune tolerance induction (ITI), might be related to the outcome of the treatment. Obtaining suitable tools for a fine mapping of discontinuous epitopes could thus be helpful. The aim of this study was to map discontinuous epitopes on FVIII A2 domain using a new epitope prediction functionality of the PEPOP bioinformatics tool and a peptide inhibition assay based on the Luminex technology. We predicted, selected and synthesized 40 peptides mimicking discontinuous epitopes on the A2 domain of FVIII. A new inhibition assays using Luminex technology was performed to identify peptides able to inhibit the binding of anti-A2 Abs to A2 domain. We identified two peptides (IFKKLYHVWTKEVG and LYSRRLPKGVKHFD) able to block the binding of anti-A2 allo-antibodies to this domain. The three-dimensional representation of these two peptides on the A2 domain revealed that they are localized on a limited region of A2. We also confirmed that residues 484-508 of the A2 domain define an antigenic site. We suggest that dissection of the antibody response during ITI using synthetic peptide epitopes could provide important information for the management of patients with inhibitors.

Preexisting autoantibodies as predictor of immune related adverse events (irAEs) for advanced solid tumors treated with immune checkpoint inhibitors (ICIs).

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are now standard of care in many cancers. They can generate immune-related adverse events (irAEs), but no biomarkers are available to identify patients who are more likely to develop irAEs. We assess the association between pre-existing autoantibodies and occurrence of irAEs. PATIENTS AND METHODS: We prospectively collected data from consecutive patients receiving ICIs for advanced cancers, in a single center between May 2015 and July 2021. Autoantibodies testing was performed before ICIs initiation including AntiNeutrophil Cytoplasmic Antibodies, Antinuclear Antibodies, Rheumatoid Factor anti-Thyroid Peroxidase and anti-Thyroglobulin. We analyzed the associations of pre-existing autoantibodies with onset, severity, time to irAEs and with survival outcomes. RESULTS: Of the 221 patients included, most had renal cell carcinoma (n = 99; 45%) or lung carcinoma (n = 90; 41%). Grade ≥2 irAEs were more frequent among patients with pre-existing autoantibodies: 64 (50%) vs. 20 (22%) patients (Odds-Ratio= 3.5 [95% CI=1.8-6.8]; p < 0.001) in the positive vs negative group, respectively. irAEs occurred earlier in the positive group with a median time interval between ICI initiation and irAE of 13 weeks (IQR = 8.8-21.6) vs. 28.5 weeks (IQR=10.6-55.1) in the negative group (p = 0.01). Twelve patients (9.4%) experienced multiple (≥2) irAEs in the positive group vs. 2 (2%) in the negative group (OR = 4.5 [95% CI: 0.98-36], p = 0.04). After a median follow-up of 25 months, median PFS and OS were significantly longer among patients experiencing irAE (p = 0.00034 and p = 0.016, respectively). CONCLUSION: The presence of pre-existing autoantibodies is significantly associated with the occurrence of grade ≥2 irAEs, with earlier and multiple irAEs in patients treated with ICIs.

Marginally stable current sheets in collisionless magnetic reconnection.

Noncollisional current sheets that form during the nonlinear development of spontaneous magnetic reconnection are characterized by a small thickness, of the order of the electron skin depth. They can become unstable to the formation of plasmoids, which allows the magnetic reconnection process to reach high reconnection rates. In this work, we investigate the marginal stability conditions for the development of plasmoids when the forming current sheet is purely collisionless and in the presence of a strong guide field. We analyze the geometry that characterizes the reconnecting current sheet, and what promotes its elongation. Once the reconnecting current sheet is formed, we identify the regimes for which it is plasmoid unstable. Our study shows that plasmoids can be obtained, in this context, from current sheets with an aspect ratio much smaller than in the collisional regime, and that the plasma flow channel of the marginally stable current layers maintains an inverse aspect ratio of 0.1.

Immunotherapy in older patients with cancer.

Ageing implicates a remodeling of our immune system, which is a consequence of the physiological senescence of our cells and tissues coupled with environmental factors and chronic antigen exposure. An immune system that senesces includes more differentiated cells with accumulation of highly differentiated CD4 and CD8 T cells. The pool of naive T cells decreases with the exponential thymic involution induced by age. Differentiated T cells have similar, if not higher, functional capacities but scarce studies are looking at the impact of senescence among specific T cells. After a stimulation, other immune cells (monocytes, dendritic cells and NK) are functionally altered during ageing. It is as if the immune system was more efficient at the basal level, but less efficient after a stimulation in the old compared to young people, likely due to less reserve. Concerning the clinical impact, older people are more prone to certain pathogens and their clinical manifestations differ from the younger people. Severe flu and VZV reactivation are more frequent with an altered cellular response to vaccination. Vaccination failure can have detrimental consequences in people presenting frailty criteria. Old people frailty is majored by their comorbidities and diseases like cancer. Thus, chemotherapies are employed with circumspection in older patients. The use of anti-PD-1/PD-L1 immunotherapies is therefore attractive, because of less side effects with a better response compared to chemotherapy. Old persons inclusion is lacking in current studies and clinical trials. Some subgroups or pooled analyses confirm the gain in response without increased toxicities in older patients but their inclusion criteria differ from the real-life practice. Specific studies focusing on this population are needed because of the increasing cancer incidence with age and the overall ageing of the population.

Distal Fibular Reconstruction Using Iliac Grafting and Emslie-Vidal's Ligamentoplasty after Exeresis of Single Renal Carcinoma Metastasis.

Introduction. Restoring lateral ankle stability following distal resection of the fibula is a difficult procedure for which several surgical techniques have been proposed. Each of these techniques has potential drawbacks. This report presents a new option for fibular reconstruction. Case Study. We report the case of a 68-year-old male with evolving pain in the left ankle throughout the past 3 months. Three years prior to consultation, he underwent left nephrectomy for clear-cell adenocarcinoma. A swelling on the external side of the left ankle was noticed upon clinical examination, with no signs of inflammation. The ankle was stable with normal mobility. Radiographic examination revealed a 4 cm lytic lesion on the lateral malleolus with internal and external cortical damages as well as invasion of the soft tissues. Neither lower peroneotibial nor tibiotarsial joints were invaded. Needle biopsy confirmed the presence of metastatic renal clear-cell adenocarcinoma. Consequently, large exeresis of this single metastasis was indicated while preserving functional integrity of the ankle. Following block resection of the distal fibula including the lower tibioperoneal joint, a bicortical autograft was positioned to abut against the external side of the talus. Emslie-Vidal's ligamentoplasty procedure was performed with half of the short peroneal passed under the pedal flexor, then in the bone abutment, and finally through a calcaneal bone tunnel. Peroneus muscles were stabilized using a fragment sampled from the Achilles tendon. Pain decreased in 3 months, and the ankle was stable with normal functionality at a 5-year follow-up. Discussion. Reconstruction of the lateral ankle following fibular resection is possible by reconstructing the external facet of the malleolus using an autograft associated with Emslie-Vidal's ligamentoplasty procedure, hence stabilizing both tibiotalar and subtalar joints. This surgical procedure allowed the patient to return to his daily activities with neither instability nor evolution towards short-term tibiotalar arthrosis.

Immunodiagnosis of human neurocysticercosis using a synthetic peptide selected by phage-display.

The usefulness of a synthetic peptide in the serodiagnosis of Taenia solium human neurocysticercosis (NC) has been evaluated. Phage-displayed peptides were screened with human antibodies to scolex protein antigen from cysticercus cellulosae (SPACc). One clone was found to interact specifically with anti-SPACc IgGs. The corresponding synthetic peptide was found to be recognized in ELISA by NC patient's sera. The study was carried out with sera from 28 confirmed NC patients, 13 control sera and 73 sera from patients suffering from other infectious diseases. A 93% sensibility and a 94.3% specificity was achieved. Figures of 89% and 31.4% of sensibility and specificity were obtained in a SPACc-based ELISA. Immunoblotting of SPACc with anti-peptide antibodies revealed a single band of approximately 45 kDa in 1D and four 45 kDa isoforms in 2D-gel electrophoresis. A strong and specific immunostaining in the fibers beneath the suckers, at the base of the rostellum, and in the tissue surrounding the scolex of cysticerci was observed by immunomicroscopy. Our results show that a peptide-based immunodiagnostic of neurocisticercosis can be envisioned.

Mount pinatubo aerosols, chlorofluorocarbons, and ozone depletion.

The injection into the stratosphere of large quantities of sulfur during the June 1991 eruption of Mount Pinatubo (Philippines) and the subsequent formation of sulfate aerosol particles have generated a number of perturbations in the atmosphere with potential effects on the Earth's climate. Changes in the solar and infrared radiation budget caused by the eruption should produce a cooling of the troposphere and a warming of the lower stratosphere. These changes could affect atmospheric circulation. In addition, heterogeneous chemical reactions on the surface of sulfate aerosol particles render the ozone molecules more vulnerable to atmospheric chlorine and hence to man-made chlorofluorocarbons.

Therapeutic cancer vaccine: building the future from lessons of the past.

Anti-cancer vaccines have raised many hopes from the start of immunotherapy but have not yet been clinically successful. The few positive results of anti-cancer vaccines have been observed in clinical situations of low tumor burden or preneoplastic lesions. Several new concepts and new results reposition this therapeutic approach in the field of immunotherapy. Indeed, cancers that respond to anti-PD-1/PD-L1 (20-30%) are those that are infiltrated by anti-tumor T cells with an inflammatory infiltrate. However, 70% of cancers do not appear to have an anti-tumor immune reaction in the tumor microenvironment. To induce this anti-tumor immunity, therapeutic combinations between vaccines and anti-PD-1/PD-L1 are being evaluated. In addition, the identification of neoepitopes against which the immune system is less tolerated is giving rise to a new enthusiasm by the first clinical results of the vaccine including these neoepitopes in humans. The ability of anti-cancer vaccines to induce a population of anti-tumor T cells called memory resident T cells that play an important role in immunosurveillance is also a new criterion to consider in the design of therapeutic vaccines.

Median Nerve Entrapment after Supracondylar Humeral Fracture in a Young Child.

Median nerve entrapment after supracondylar humeral fracture in children is rare. We report a case of Gartland type III supracondylar humeral fracture complicated by an entrapment of the median nerve following closed reduction and percutaneous pinning in a 5-year-old child. The diagnosis of entrapment was made 14 months post injury following progressive motor and sensory palsy. Resection and end-to-end suture were performed, leading to complete sensory and motor recovery eight months later. This nerve complication is often unnoticed and should be suspected systematically before and after reduction of all displaced supracondylar humeral fracture in children. The indication of resection-suture or nerve graft depends on the entrapment and the delay of the palsy.

Reactivity profile of anti-factor VIII antibodies with designed synthetic peptides mimicking epitopes of the C2 and a1 domains.

Antibodies (Abs) that block factor VIII (FVIII) activity occur in hemophilia A patients treated with FVIII replacement therapy and severely impair treatment. In this work, we designed and synthesized ten peptides whose sequences are found in putative epitopes at the surface of a1 and C2 domains of the FVIII molecule. These peptides were screened for their ability to inhibit the binding of anti-FVIII Abs from plasmas of hemophilia A patients to FVIII. All peptides were efficient in inhibiting anti-FVIII Abs in plasma from patients with inhibitors, with however different efficiencies. It was found that each tested patient's plasma had a different profile of reactivity with peptides, consistent with an individual anti-FVIII Ab specificity. The profile of recognized peptides was also changing during the treatment of the patients. Three peptides were used in an affinity chromatography assay to attempt to remove anti-FVIII Abs from patients' plasma. Anti-FVIII IgGs were significantly captured by the peptide-Sepharose affinity matrixes as assessed by enzyme-linked immunosorbent assay. However, due to the low level of Abs in the plasma samples, other methods (Chromogenic and Bethesda assays) were not sensitive enough to properly detect the reduction of inhibitors.

Association of calpain-10 polymorphisms with type 2 diabetes in the Tunisian population.

BACKGROUND: Genome-wide analyses of the genetic predisposition to type 2 diabetes mellitus (T2DM) in different isolates and populations have identified regions of interest called non insulin-dependent diabetes mellitus (NIDDM) 1, 2, 3 and 4. At the NIDDM1 locus (2q37.3), calpain-10 (CAPN10) encodes for a ubiquitously expressed protease implicated in the two fundamental pathophysiological aspects of T2DM. This is a report of the results of a study of the association of four CAPN10 polymorphisms with T2DM in the Tunisian population. PARTICIPANTS AND METHODS: A total of 222 T2DM patients with a diabetes duration of 10 years or more and 206 healthy controls were enrolled to analyze the frequency distribution of four CAPN10 polymorphisms (UCSNP-43, UCSNP-19, UCSNP-110 and UCSNP-63) using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in the Tunisian population. We also investigated the association of T2DM with different haplotypes and haplotype combinations. RESULTS: Only the A allele of UCSNP-43 showed an association with T2DM (odds ratio, OR=1.86). We also identified a novel combination of haplotypes (121/221) defined by three polymorphisms (UCNSP-43, -19 and -63) that is associated with an increased risk of T2DM (OR=2.38). CONCLUSION: In this study involving the Tunisian population, we identified genetic variants within CAPN10 that are linked with T2DM and a novel haplotype combination, 121/221, associated with an increased susceptibility to T2DM.

Risk genotypes and haplotypes of the GLUT1 gene for type 2 diabetic nephropathy in the Tunisian population.

OBJECTIVE: Diabetic nephropathy (DN) is a long-term complication of both type 1 and type 2 diabetes. Genetic studies on DN have been of little help so far, since several genetic association studies have shown conflicting results. Here we report the findings of a case-control study on five SNPs in the glucose transporter 1 (GLUT1) gene. The study investigated the association of five GLUT1 genotypes and haplotypes with DN. RESEARCH DESIGN AND METHODS: All subjects, 126 DN (cases) and 273 type 2 diabetes (controls), were genotyped using the polymerase chain reaction restriction fragment length polymorphism. RESULTS: The TT and the AA genotypes of the Haell and Enh2 SNP1, increased the risk of DN. The study also identified CGT as the highest risk haplotype (4.4-fold) followed by CAT with an increased risk of DN of 2.6-fold. CONCLUSIONS: The GLUT1 gene confers susceptibility to DN in type 2 diabetes patients in the Tunisian population.

Novel insights on new particle formation derived from a pan-european observing system.

The formation of new atmospheric particles involves an initial step forming stable clusters less than a nanometre in size (<~1 nm), followed by growth into quasi-stable aerosol particles a few nanometres (~1-10 nm) and larger (>~10 nm). Although at times, the same species can be responsible for both processes, it is thought that more generally each step comprises differing chemical contributors. Here, we present a novel analysis of measurements from a unique multi-station ground-based observing system which reveals new insights into continental-scale patterns associated with new particle formation. Statistical cluster analysis of this unique 2-year multi-station dataset comprising size distribution and chemical composition reveals that across Europe, there are different major seasonal trends depending on geographical location, concomitant with diversity in nucleating species while it seems that the growth phase is dominated by organic aerosol formation. The diversity and seasonality of these events requires an advanced observing system to elucidate the key processes and species driving particle formation, along with detecting continental scale changes in aerosol formation into the future.

The Loxtox protein family in Loxosceles intermedia (Mello-Leitão) venom.

We isolated cDNA sequences coding for dermonecrotic/sphingomyelinases factor proteins from the brown spider Loxosceles intermedia, here named Loxtox proteins. The amino acid sequences based on cloned cDNA of several Loxtox proteins revealed at least six distinct groups of proteins expressed in the venom gland. The level of similarity among the toxins varied from 99% to 55%. The finding of several isoforms of Loxtox in the venom of this spider may reflect an evolutionary adaptation for different prey types and reinforces the idea of an efficient mutational mechanism in the venom gland of spiders.

Vascular emergencies in liver trauma.

The use of CT in the diagnosis and management of liver trauma is responsible for the shift from routine surgical versus non-surgical treatment in the management of traumatic liver injuries, even when they are of high grade. The main cause of complication and of death in liver trauma is related to vascular injury. The goal of this review focussed on the vascular complications of liver trauma is to describe the elementary lesions shown by CT in liver trauma including laceration, parenchymal hematoma and contusions, partial devascularisation, subcapsular hematomas, hemoperitoneum, active bleeding, pseudoaneurysm of the hepatic artery, bile leak, and periportal oedema, to illustrate the possible pitfalls in CT diagnosis of liver trauma and to underline the key-points which may absolutely be present in a CT report of liver trauma. Then we will remind the grading system based on the CT features and we will analyze the interest and limitations of such grading systems. Last we will discuss the diagnostic strategy at the early phase in patients with suspected liver trauma according to their clinical conditions and underline the conditions of arterial embolization, and then we will discuss the diagnosis strategy at the delayed phase according to the suspected complications.

Tissue-resident memory T cells play a key role in the efficacy of cancer vaccines.

Resident memory CD8+T cells (TRM) usually defined by the CD103 marker represent a new subset of long-lived memory T cells that remain in the tissues. We directly demonstrate their specific role in cancer vaccine-induced tumor regression. In human, they also seem to play a major role in tumor immunosurveillance.

Functional characterization and epitope analysis of a recombinant dermonecrotic protein from Loxosceles intermedia spider.

In the present study the recombinant form (recLiD1) of a dermonecrotic protein present in the Brazilian brown spider Loxosceles intermedia venom was expressed in Escherichia coli cells and purified by reversed-phase HPLC using a C8 Vydac column. About 25.8mg of purified recLiD1 was produced from a litre of bacterial culture. SDS/PAGE and immunoblot analysis of the recombinant protein revealed an apparent molecular weight of 32-35kDa. The later result was confirmed by mass spectrometry (32,758Da). recLiD1 displayed dermonecrotic and platelet aggregation activities which were qualitatively similar to that displayed by the crude L. intermedia venom. However, very low sphingomyelinase D enzymatic activity and complement-dependent haemolytic activities were observed. recLiD1 immunized BALB/c mice developed an antibody response. Anti-recLiD1 antibodies recognized L. intermedia venom in an indirect enzyme-linked immunosorbent assay (ELISA) and cross-reacted with crude venoms from L. intermedia, L. gaucho and L. laeta. An in vivo protection assay carried out 5 weeks after the end of the immunization protocol showed that 75% of the vaccinated mice could resist the challenge by 2.5LD(50) of L. intermedia venom. To characterize epitopes associated with protective antibodies, we prepare sets of immobilized synthetic 15 mer overlapping peptides covering the complete amino acid sequences of the recLiD1. Antibodies revealed one antigenic region in the N-terminal part of the toxin. The amino acid sequence of this epitope was found in several dermonecrotic proteins and some of its residues have been implicated with the active site of the toxin.

Antibodies against synthetic epitopes inhibit the enzymatic activity of mutalysin II, a metalloproteinase from bushmaster snake venom.

Mutalysin II (mut-II), a 22.5kDa zinc endopeptidase isolated from bushmaster (Lachesis muta muta) snake venom, is a direct acting fibrin(ogen)olytic proteinase. It induces monoclonal and polyclonal antibodies which efficiently neutralize the hemorrhagic effect of L. muta and several Bothrops whole venoms. To characterize epitopes of protective antibodies we have used the Spot method of multiple peptide synthesis to prepare 64 overlapping dodecapeptides frameshifted by three residues, covering the complete amino acid sequence of mut-II. The rabbit anti-mut-II antibodies binding pattern to peptides revealed several continuous antigenic regions: one in the N-terminal part, two in the central region and the other in the C-terminal of mut-II. By using homology modelling, a three-dimensional model of mut-II was built which showed that epitopes are surface exposed. Anti-peptide antibodies were raised against three peptides (one representative of each epitope region) covalently coupled as a mixture to keyhole limpet hemocyanin. Purified IgG from the resulting anti- peptide antibodies cross-reacted with mut-II and induced a dose-dependent inhibition of the mut-II catalyzed proteolysis of fibrinogen.

[Cancer immunotherapy: Rational and recent breakthroughs]. / Immunothérapie des cancers : rationnel et avancées récentes.

Cancer immunotherapy has occupied a marginal therapeutic option in cancer despite strong arguments documenting the role of the immune system in controlling the proliferation of cancers. The recent success of immunotherapy results from a change in the past paradigm. From now on, the goal is not only to activate the immune system against tumor, but also to take account of the immunosuppressive tumor microenvironment Among these mechanisms, negative costimulatory molecules (CTLA-4, PD-1, etc.) expressed by T cells in the tumor could explain their lack of effectiveness in inhibiting tumor growth. Blocking these molecules allowed the reactivation of anti-tumor T cells. Clinically, the administration of anti-CTLA-4 antibody (ipilimumab: Yervoy®) was granted marketing authorization for patients with metastatic melanoma. The anti-PD-1 antibodies (nivolumab: Opdivo®, pembrolizumab: Keytruda®) have demonstrated clinical efficacy when compared to the standard therapy in metastatic melanomas, advanced lung cancers and metastatic renal cell carcinoma. In phase I and II clinical trials, other tumors (Hodgkin's disease, head and neck cancers, bladder cancer, gastric cancer, etc.) appear to be responsive to these immunomodulators. These treatments were associated with the occurrence of side effects dominated by autoimmunity predictable by unlocking the breaks exerted by immune system to maintain tolerance against self-antigen. The optimization of therapeutic combination based on these molecules and the search for biomarkers associated with these treatments constitute a challenge for the future for this new therapeutic class of drugs for oncology.