Mixed-Valence Tetrametallic Iridium Chains.

Neutral [X-{Ir2 }-{Ir2 }-X] (X=Cl, Br, SCN, I) and dicationic [L-{Ir2 }-{Ir2 }-L]2+ (L=MeCN, Me2 CO) tetrametallic iridium chains made by connecting two dinuclear {Ir2 } units ({Ir2 }=[Ir2 (µ-OPy)2 (CO)4 ], OPy=2-pyridonate) by an iridium-iridium bond are described. The complexes exhibit fractional averaged oxidation states of +1.5 and electronic delocalization along the metallic chain. While the axial ligands do not significantly affect the metal-metal bond lengths, the metallic chain has a significant impact on the iridium-L/X bond distances. The complexes show free rotation around the unsupported iridium-iridium bond in solution, with a low-energy transition state for the chloride chain. The absorption spectra of these complexes show characteristic bands at 438-504 nm, which can be fine-tuned by varying the terminal capping ligands.

Kinetics of response to iloprost evaluated by laser speckle contrast analysis in systemic sclerosis.

OBJECTIVE: Iloprost (ILO) is recommended for the treatment of systemic sclerosis (SSc) microangiopathy, but there is no common consensus on its optimal dosage. The aim of this study is to evaluate the kinetics of response to ILO administered in a daily outpatient scheme in SSc subjects using laser speckle contrast analysis (LASCA). METHOD: Adult SSc patients in stable therapy with ILO administered for 6 h for 2 consecutive days every 4 weeks were enrolled. Peripheral finger perfusion was assessed by LASCA. Each patient underwent five LASCA evaluations: before and after each day of ILO (D1pre, D1post, D2pre, and D2post) and after 4 weeks (D30). RESULTS: Twenty-seven SSc patients (77.8% female, mean age 61.5 years) were enrolled. LASCA showed an increase in perfusion at the end of each ILO course, but on the second day (both D1pre vs D2pre and D2pre vs D2post) the increase was no longer significant in half of the fingers. Moreover, compared to D1post, at the beginning of the second ILO day most of the fingers had already shown a significant reduction in perfusion. After 1 month, there were no statistically significant differences between the perfusion values of D1pre and D30. CONCLUSION: This LASCA study highlights the transience of the vasoactive effect of ILO, with a perfusion benefit that is completely lost after 1 month. The brevity of the perfusion effect of ILO and the use of LASCA are elements to consider in the design of future SSc trials to determine the optimal ILO dosage.

Kikuchi-Fujimoto Disease and COVID-19 vaccination: pharmacovigilance approach.

Summary: Background. Kikuchi-Fujimoto Disease (KFD) or histiocytic necrotizing lymphadenitys is a rare disorder characterized by subacute necrotizing regional lymphadenopathy. It is usually presented as painful cervical nodes and associated with fever, headache, night sweats, nausea, vomiting and sore throat. Etiology of KFD is still unclear, two theories have been proposed: infections and autoimmune origin. Due to recent reports of KFD related to COVID-19 vaccination, the novelty of the mechanism of these vaccines and the immunomodulated role of both matters, a literature and adverse event databases review was carried out in order to shed light on the relationship between these two matters. Methods. A search in the Spanish and the European adverse events databases (FEDRA and Eudravigilance) was performed. Search criteria were any drug and the diagnosis "Histiocytic necrotizing lymphadenitis" according to the Medical Dictionary for Medical Activities version 25.0. All adverse events registered as June 2, 2022, were included. Results. FEDRA encompassed two KFD reports, one related to a mRNA COVID-19 vaccine. Eudravigilance included a total of 62 KFD cases, 14 of them associated to COVID-19 vaccines and eight to other vaccines. Conclusions. Pharmacovigilance is of utter importance in detecting adverse events caused by new vaccines. More research is needed to establish a final connection between KFD and COVD-19 vaccines, but due to the physiopathology of the condition, how vaccines stimulate the immune system and the high number of reported KFD cases with vaccines given its rare incidence, it is plausible to think that both entities are related.

Beamline simulations using monochromators with high d-spacing crystals.

Monochromators for synchrotron radiation beamlines typically use perfect crystals for the hard X-ray regime and gratings for soft X-rays. There is an intermediate range, typically 1-3 keV (tender X-rays), which common perfect crystals have difficulties covering and gratings have low efficiency, although some less common crystals with high d-spacing could be suitable. To evaluate the suitability of these crystals for a particular beamline, it is useful to evaluate the crystals' performance using tools such as ray-tracing. However, simulations for double-crystal monochromators are only available for the most used crystals such as Si, Ge or diamond. Here, an upgrade of the SHADOW ray-tracing code and complementary tools in the OASYS suite are presented to simulate high d-spacing crystals with arbitrary, and sometimes complex, structures such as beryl, YB66, muscovite, etc. Isotropic and anisotropic temperature factors are also considered. The YB66 crystal with 1936 atomic sites in the unit cell is simulated, and its applicability for tender X-ray monochromators is discussed in the context of new low-emittance storage rings.

Ocular and systemic toxicity of high-dose intravitreal topotecan in rabbits: Implications for retinoblastoma treatment.

Although many more eyes of children with retinoblastoma are salvaged now compared to just 10 years ago, the control of vitreous seeding remains a challenge. The introduction of intravitreal injection of melphalan has enabled more eyes to be salvaged safely but with definite retinal toxicity. Intensive treatment with high-dose intravitreal topotecan may be a strategy to control tumor burden because of its cell cycle-dependent cytotoxicity and the proven safety in humans. Therefore, we evaluated the ocular and systemic safety of repeated high-dose intravitreal injections of topotecan in rabbits. Systemic and ocular toxicity was assessed in non-tumor-bearing rabbits after four weekly injections of three doses of topotecan (10 µg, 25 µg, and 50 µg) or vehicle alone. Animals were evaluated weekly for general and ophthalmic clinical status. One week after the last injection, vitreous and plasma samples were collected for drug quantification and the enucleated eyes were subjected to histological assessment. Weight, hair loss, or changes in hematologic values were absent during the study period across all animal groups. Eyes injected with all topotecan doses or vehicle showed no signs of anterior segment inflammation, clinical or histologic evidence of damage to the retina, and ERG parameters remained unaltered throughout the study. Vitreous and plasma topotecan lactone concentrations were undetectable. Four weekly intravitreal injections of topotecan up to 50 µg in the animal model or a 100 µg human equivalent dose were not toxic for the rabbit eye. High doses of topotecan may show promising translation to the clinic for the management of difficult-to-treat retinoblastoma vitreous seeds.

Evaluation of the concomitant use of oral preventive treatments and onabotulinumtoxinA in chronic migraine: the PREVENBOX study.

BACKGROUND AND PURPOSE: OnabotulinumtoxinA is an effective preventive treatment for chronic migraine (CM). In CM, in addition to a reduction in headache frequency, a decreased reliance on oral prophylactics is also indicative of treatment effectiveness. This study aimed to quantify the change in the use of oral prophylactics after treatment with onabotulinumtoxinA in patients with CM. METHODS: This was a retrospective, multicentric, cross-sectional study. Patients with CM (International Classification of Headache Disorders-3beta) that had been treated with onabotulinumtoxinA were enrolled consecutively. We collected parameters related to each patient's pre-treatment situation, as well as their current situation, focusing on frequency and intensity of migraine, number of oral prophylactics and the respective cycle of onabotulinumtoxinA. Univariate and logistic regression analyses were performed. RESULTS: We included 542 patients, 90.0% of whom were taking oral preventive treatments. During treatment with onabotulinumtoxinA, 47.8% withdrew at least one prophylactic and 41.6% stopped using oral prophylactics altogether. Factors associated with a reduction or cessation of oral prophylactics were >50% improvement in frequency and intensity, remission to episodic migraine, use of topiramate as an initial treatment, increased number of infiltrations and shorter chronification period (P < 0.05). The multivariate analysis showed that a chronification period <20 months, more than five cycles of onabotulinumtoxinA, >50% improvement in pain intensity and topiramate as an initial treatment were predictors of a reduction in oral prophylactics (area under the curve, 70.3%; P < 0.001). CONCLUSIONS: Our study demonstrated the efficacy and safety of onabotulinumtoxinA. This treatment reduced the use of oral prophylactics. Withdrawal of oral prophylactics was most likely to occur after five cycles of treatment.

Genetic diversity and population structure of Culex modestus across Europe: does recent appearance in the United Kingdom reveal a tendency for geographical spread?

In mainland Europe, the mosquito species Culex modestus Ficalbi (1890) is a bridge vector for West Nile virus (WNV) from its natural bird-mosquito cycle to mammals. The present study assessed the genetic diversity of Cx. modestus, as well as related Culex species, using the mitochondrial COI DNA barcoding region and compared this with the population structure across Europe. A haplotype network was mapped to determine genealogical relationships among specimens. The intraspecific genetic diversity within individual Culex species was below 2%, whereas the interspecific genetic divergence varied from 2.99% to 13.74%. In total, 76 haplotypes were identified among 198 sequences. A median-joining network determined from 198 COI sequences identified two major lineages that were separated by at least four mutation steps. A high level of intraspecific genetic diversity was not detected in Cx. modestus in samples submitted from different European populations, which indicates that morphologically identified specimens represent a single species and not a species complex. Therefore, it is deduced that different populations of Cx. modestus will show a similar potential to transmit WNV, lending support to concerns that the population present in southeast England represents a risk of transmission to humans.

Inner-Sphere Oxygen Activation Promoting Outer-Sphere Nucleophilic Attack on Olefins.

Alkoxylation and hydroxylation reactions of 1,5-cyclooctadiene (cod) in an iridium complex with alcohols and water promoted by the reduction of oxygen to hydrogen peroxide are described. The exo configuration of the OH/OR groups in the products agrees with nucleophilic attack at the external face of the olefin as the key step. The reactions also require the presence of a coordinating protic acid (such as picolinic acid (Hpic)) and involve the participation of a cationic diolefin iridium(III) complex, [Ir(cod)(pic)2 ]+ , which has been isolated. Independently, this cation is also involved in easy alkoxy group exchange reactions, which are very unusual for organic ethers. DFT studies on the mechanism of olefin alkoxylation mediated by oxygen show a low-energy proton-coupled electron-transfer step connecting a superoxide-iridium(II) complex with hydroperoxide-iridium(III) intermediates, rather than peroxide complexes. Accordingly, a more complex reaction, with up to four different products, occurred upon reacting the diolefin-peroxide iridium(III) complex with Hpic. Moreover, such hydroperoxide intermediates are the origin of the regio- and stereoselectivity of the hydroxylation/alkoxylation reactions. If this protocol is applied to the diolefin-rhodium(I) complex [Rh(pic)(cod)], free alkyl ethers ORC8 H11 (R=Me, Et) resulted, and the reaction is enantioselective if a chiral amino acid, such as l-proline, is used instead of Hpic.

Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders. OBJECTIVES: To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC. METHODS: We conducted RNA-Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies. RESULTS: Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in situ analyses validated the RNA-Seq data. In addition, enzyme-linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB. CONCLUSIONS: Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury-sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS. What's already known about this topic? Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three genodermatoses with high predisposition to cancer development. Although their causal genetic mutations mainly affect epithelia, the dermal microenvironment likely contributes to the physiopathology of these disorders. What does this study add? We disclose a large overlapping transcription profile between XPC, KS and RDEB fibroblasts that points towards an activated phenotype with high matrix-synthetic capacity. This common signature seems to be independent of the primary causal deficiency, but reflects an underlying derangement of the extracellular matrix via transforming growth factor-ß signalling activation and oxidative state imbalance. What is the translational message? This study broadens the current knowledge about the pathology of these diseases and highlights new targets and biomarkers for effective therapeutic intervention. It is suggested that high levels of circulating periostin could represent a potential biomarker in RDEB.

N-acetyl-cysteine blunts 6-hydroxydopamine- and L-buthionine-sulfoximine-induced apoptosis in human mesenchymal stromal cells.

Parkinson disease (PD) is characterized by the loss of dopaminergic (DAergic) neurons linked to environmental toxicants that cause oxidative stress (OS). The aim of this investigation was to establish the molecular response of human mesenchymal stroma cells (MSCs) depleted of glutathione (GSH) by the specific inhibitor L-buthionine-sulfoximine (BSO) to 6-hydroxydopamine (6-OHDA) and/or N-acetylcysteine (NAC) co-treatment. We found that treatment with BSO (10 mM) plus 6-OHDA (200 µM) induced apoptosis in MSCs through an oxidative stress (OS) mechanism involving H2O2, reflected by the detection of dichlorofluorescein-positive (DCF+) cells and oxidation of DJ-1 Cys106-SH into DJ-1 Cys106-SO3; an almost complete reduction in glutathione peroxidase 1 (GPX1) expression; activation of the transcription factor c-JUN, the pro-apoptotic protein BAX and BH-3-only protein PUMA; loss of mitochondrial membrane potential (∆Ψm); activation of the protease caspase-3 (CASP3) and apoptosis-inducing factor (AIF); chromatin condensation; and DNA fragmentation. Strikingly, co-treatment of MSCs with NAC (5 mM) and BSO + 6-OHDA significantly reduced the expression of OS and cell death markers but were unable to restore the expression of GPX1 compared to the expression in untreated or treated cells with NAC only. These findings highlighted the importance of the maintenance of the GSH-dependent (e.g., GPX1, GSH synthesis) and -independent (e.g., ROS scavenger molecules and thiol reducing activity) antioxidant systems (e.g., NAC) in the protection of MSCs from detrimental stress stimuli, thereby increasing the survival of stromal cells.

[Child psychiatry interventions in patients with 22q11 deletion syndrome: From treatment to prevention]. / Prise en charge pédopsychiatrique des patients présentant un syndrome microdélétionnel 22q11.2 : du soin à la prévention.

22q11.2DS is one of the more frequent genetic syndromes associated to psychiatric symptoms. It has been associated to an increased risk to develop schizophrenia in adolescence or early adulthood. However, psychiatric symptoms appear early on, and should be recognized as soon as possible by child psychiatrists in order to improve the present well-being of children and their family, and to prevent further risks of developing severe and chronic psychiatric diseases later on. In this paper, we present a review of the recent literature concerning the 22q11.2DS syndrome focused on the risk factors that may be associated to an increased risk of psychotic transition. We advocate for the development of systematic specialized child psychiatry consultations for these patients, included in networks with geneticists, adult psychiatrists, and family associations, in order to improve their psychiatric prognosis and to support the development of translational research.

Trends of maxillofacial trauma: An update from the prospective register of a multicenter study in emergency services of Chile.

BACKGROUND: Determine the behavior of the maxillofacial trauma of adults treated in 3 tertiary care centers in the central zone of Chile. MATERIAL AND METHODS: descriptive, cross-sectional, multicenter study, based on the prospective records of maxillofacial trauma cases attended between May 2016 and April 2017 by dental and maxillofacial clinical teams of Adult Emergency Units of hospitals Dr. Sótero del Río (metropolitan region), Carlos Van Buren and Dr. Gustavo Fricke (region V). Age, sex, date of occurrence, type of trauma according to ICD-10, etiology, legal medical prognosis and associated injuries were recorded, stratifying by sex and age. Chi square and unpaired Wilcoxon tests were used to compare by groups. RESULTS: 2.485 cases and 3.285 injuries were investigated. The male: female ratio was 1.7: 1 with age under 30 predominant, followed by older adults. Variability was observed in the yearly, weekly and daily presentation. The highest frequencies were in January and September, weekends and at night. The main etiologies were violence (42.3%), falls (13.1%) and road traffic crashes (12.9%) with differences by age and sex (p <0.05). 31,9% of the injuries occurred in hard tissue, being fractures in nasal bones predominant (S02.2). CONCLUSIONS: the profile of the maxillofacial trauma in Chile seems to be mixed by age, affecting young people and the elderly. The male sex predominates; the main cause, which varies by age group, is violence. Their surveillance is possible from hospital emergency records.

Activating a Peroxo Ligand for C-O Bond Formation.

Dioxygen activation for effective C-O bond formation in the coordination sphere of a metal is a long-standing challenge in chemistry for which the design of catalysts for oxygenations is slowed down by the complicated, and sometimes poorly understood, mechanistic panorama. In this context, olefin-peroxide complexes could be valuable models for the study of such reactions. Herein, we showcase the isolation of rare "Ir(cod)(peroxide)" complexes (cod=1,5-cyclooctadiene) from reactions with oxygen, and then the activation of the peroxide ligand for O-O bond cleavage and C-O bond formation by transfer of a hydrogen atom through proton transfer/electron transfer reactions to give 2-iradaoxetane complexes and water. 2,4,6-Trimethylphenol, 1,4-hydroquinone, and 1,4-cyclohexadiene were used as hydrogen atom donors. These reactions can be key steps in the oxy-functionalization of olefins with oxygen, and they constitute a novel mechanistic pathway for iridium, whose full reaction profile is supported by DFT calculations.

PARKIN overexpression in human mesenchymal stromal cells from Wharton's jelly suppresses 6-hydroxydopamine-induced apoptosis: Potential therapeutic strategy in Parkinson's disease.

BACKGROUND AIMS: Stem cell transplantation is an excellent option for regenerative or replacement therapy. However, deleterious microenvironmental and endogenous factors (e.g., oxidative stress) compromise ongoing graft survival and longevity. Therefore, (transient or stable) genetically modified cells may be reasonably thought to resist oxidative stress-induced damage. Genetic engineering of mesenchymal stromal cells (MSCs) obtained from Wharton's jelly tissue may offer some therapeutic potential. PARKIN is a multifunctional ubiquitin ligase able to protect dopaminergic cells against stress-related signaling. We, therefore, evaluated the effect of the neurotoxicant 6-hydroxydopamine (6-OHDA) on regulated cell death signaling in MSCs and investigated whether overexpression of PARKIN in MSCs was capable of modulating the effect of 6-OHDA. METHODS: We transiently transfected Wharton's jelly-derived MSCs with an mCherry-PARKIN vector using the Lipofectamine LTX method. Naïve MSCs and MSCs overexpressing PARKIN were exposed to increasing concentrations of 6-OHDA. We used light and fluorescence microscopy, flow cytometry, immunocytochemistry staining, in-cell Western and Western blot analysis. RESULTS: After 12-24 h of 6-OHDA exposure, we detected dichlorofluorescein (DCF)-positive cells (80%) indicative of reactive oxygen species (H2O2) production, reduced cell viability (40-50%), decreased mitochondrial membrane potential (ΔΨm, ~35-45%), DNA fragmentation (18-30%), and G1-arrested cell cycle in the MSCs. 6-OHDA exposure increased the expression of the transcription factor c-JUN, increased the expression of the mitochondria maintenance Phosphatase and tensin homologue-induced putative kinase 1 (PINK1) protein and increased the expression of pro-apoptotic PUMA, caspase-3 and apoptosis-inducing factor (AIF). 6-OHDA exposure also significantly augmented the oxidation of the oxidative stress sensor, DJ-1. Overexpression of PARKIN in MSCs not only significantly reduced the expression of cell death and oxidative stress markers but also significantly reduced DCF-positive cells (~50% reduction). DISCUSSION: 6-OHDA induced apoptosis in MSCs via generation of H2O2, activation of c-JUN and PUMA, mitochondrial depolarization and nuclei fragmentation. Our findings suggest that PARKIN protects MSCs against 6-OHDA toxicity by partly interacting with H2O2, reducing the expression of c-JUN, PUMA, AIF and caspase-3, and maintaining the mitochondrial ΔΨm.

Impact of mutations within the [Fe-S] cluster or the lipoic acid biosynthesis pathways on mitochondrial protein expression profiles in fibroblasts from patients.

Lipoic acid (LA) is the cofactor of the E2 subunit of mitochondrial ketoacid dehydrogenases and plays a major role in oxidative decarboxylation. De novo LA biosynthesis is dependent on LIAS activity together with LIPT1 and LIPT2. LIAS is an iron­sulfur (Fe-S) cluster-containing mitochondrial protein, like mitochondrial aconitase (mt-aco) and some subunits of respiratory chain (RC) complexes I, II and III. All of them harbor at least one [Fe-S] cluster and their activity is dependent on the mitochondrial [Fe-S] cluster (ISC) assembly machinery. Disorders in the ISC machinery affect numerous Fe-S proteins and lead to a heterogeneous group of diseases with a wide variety of clinical symptoms and combined enzymatic defects. Here, we present the biochemical profiles of several key mitochondrial [Fe-S]-containing proteins in fibroblasts from 13 patients carrying mutations in genes encoding proteins involved in either the lipoic acid (LIPT1 and LIPT2) or mitochondrial ISC biogenesis (FDX1L, ISCA2, IBA57, NFU1, BOLA3) pathway. Ten of them are new patients described for the first time. We confirm that the fibroblast is a good cellular model to study these deficiencies, except for patients presenting mutations in FDX1L and a muscular clinical phenotype. We find that oxidative phosphorylation can be affected by LA defects in LIPT1 and LIPT2 patients due to excessive oxidative stress or to another mechanism connecting LA and respiratory chain activity. We confirm that NFU1, BOLA3, ISCA2 and IBA57 operate in the maturation of [4Fe-4S] clusters and not in [2Fe-2S] protein maturation. Our work suggests a functional difference between IBA57 and other proteins involved in maturation of [Fe-S] proteins. IBA57 seems to require BOLA3, NFU1 and ISCA2 for its stability and NFU1 requires BOLA3. Finally, our study establishes different biochemical profiles for patients according to their mutated protein.

Further delineation of a rare recessive encephalomyopathy linked to mutations in GFER thanks to data sharing of whole exome sequencing data.

BACKGROUND: Alterations in GFER gene have been associated with progressive mitochondrial myopathy, congenital cataracts, hearing loss, developmental delay, lactic acidosis and respiratory chain deficiency in 3 siblings born to consanguineous Moroccan parents by homozygosity mapping and candidate gene approach (OMIM#613076). Next generation sequencing recently confirmed this association by the finding of compound heterozygous variants in 19-year-old girl with a strikingly similar phenotype, but this ultra-rare entity remains however unknown from most of the scientific community. MATERIALS AND METHODS: Whole exome sequencing was performed as part of a "diagnostic odyssey" for suspected mitochondrial condition in 2 patients, presenting congenital cataracts, progressive encephalomyopathy and hypotrophy and detected unreported compound heterozygous variants in GFER. RESULTS: Thanks to an international data sharing, we found 2 additional patients carrying compound heterozygous variants in GFER. Reverse phenotyping confirmed the phenotypical similarities between the 4 patients. Together with the first literature reports, the review of these 8 cases from 4 unrelated families enables us to better describe this apparently homogeneous disorder, with the clinical and biological stigmata of mitochondrial disease. CONCLUSION: This report highlights the clinical utility of whole exome sequencing and reverse phenotyping for the diagnosis of ultra-rare diseases and underlines the importance of a broad data sharing for accurate clinical delineation of previously unrecognized entities.

Molecular, clinical and neuropsychological study in 31 patients with Kabuki syndrome and KMT2D mutations.

Kabuki syndrome (KS-OMIM 147920) is a rare developmental disease characterized by the association of multiple congenital anomalies and intellectual disability. This study aimed to investigate intellectual performance in children with KS and link the performance to several clinical features and molecular data. We recruited 31 children with KMT2D mutations who were 6 to 16 years old. They all completed the Weschler Intelligence Scale for Children, fourth edition. We calculated all indexes: the Full Scale Intellectual Quotient (FSIQ), Verbal Comprehension Index (VCI), Perceptive Reasoning Index (PRI), Processing Speed Index (PSI), and Working Memory Index (WMI). In addition, molecular data and several clinical symptoms were studied. FSIQ and VCI scores were 10 points lower for patients with a truncating mutation than other types of mutations. In addition, scores for FSIQ, VCI and PRI were lower for children with visual impairment than normal vision. We also identified a discrepancy in indexes characterized by high WMI and VCI and low PRI and PSI. We emphasize the importance of early identification and intensive care of visual disorders in patients with KS and recommend individual assessment of intellectual profile.

Rhodium Complexes Promoting C-O Bond Formation in Reactions with Oxygen: The Role of Superoxo Species.

C-O bond formation in reactions of olefins with oxygen is a long standing challenge in chemistry for which the very complicated-sometimes controversial-mechanistic panorama slows down the design of catalysts for oxygenations. In this regard, the mechanistic details of the oxidation of the complex [Rh(cod)(Ph2 N3 )] (1) (cod=1,5-cyclooctadiene) with oxygen to the unique 2-rhodaoxetane compound [{Rh(OC8 H12 )(Ph2 N3 )}2 ] (2) has been investigated by DFT calculations. The results of this study provide evidences for a novel bimetallic mechanism in which two rhodium atoms redistribute the four electrons involved in the cleavage of the O=O bond. Furthermore, both oxygen atoms are used to create two new C-O bonds in a controlled fashion with 100 % atom economy. The key intermediates that we have found in this process are a mononuclear open-shell triplet superoxo compound, an open-shell singlet "µ-(peroxo)" derivative, and a closed-shell singlet "bis(µ-oxo)" complex. Some of the findings are used to predict the reactions of RhI complexes with oxygen, exemplified by that of the complex [Rh(cod)(OnapyMe2 )] (3). Starting from 3, [{Rh(OC8 H12 )(OnapyMe2 )}2 ] (4) has been prepared and characterized, which represents the second example of a 2-rhodaoxetane compound coming from an oxygenation reaction with oxygen.

FOXO3a and the MAPK p38 are activated by cetuximab to induce cell death and inhibit cell proliferation and their expression predicts cetuximab efficacy in colorectal cancer.

BACKGROUND: Cetuximab, a monoclonal antibody against EGFR used for the treatment of colorectal cancer (CRC), is ineffective in many patients. The aim of this study was to identify the signalling pathways activated by cetuximab in CRC cells and define new biomarker of response. METHODS: We used in vitro, in vivo models and clinical CRC samples to assess the role of p38 and FOXO3a in cetuximab mechanism of action. RESULTS: We show that cetuximab activates the MAPK p38. Specifically, p38 inhibition reduced cetuximab efficacy on cell growth and cell death. At the molecular level, cetuximab activates the transcription factor FOXO3a and promotes its nuclear translocation via p38-mediated phosphorylation, leading to the upregulation of its target genes p27 and BIM and the subsequent induction of apoptosis and inhibition of cell proliferation. Finally, we found that high FOXO3a and p38 expression levels are associated with better response rate and improved outcome in cetuximab-treated patients with CRC harbouring WT KRAS. CONCLUSIONS: We identify FOXO3a as a key mediator of cetuximab mechanism of action in CRC cells and define p38 as its activator in this context. Moreover, high FOXO3a and p38 expression could predict the response to cetuximab in patients with CRC harbouring WT KRAS.

A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome.

Cornelia de Lange syndrome is a multisystemic developmental disorder mainly related to de novo heterozygous NIPBL mutation. Recently, NIPBL somatic mosaicism has been highlighted through buccal cell DNA study in some patients with a negative molecular analysis on leukocyte DNA. Here, we present a series of 38 patients with a Cornelia de Lange syndrome related to a heterozygous NIPBL mutation identified by Sanger sequencing. The diagnosis was based on the following criteria: (i) intrauterine growth retardation and postnatal short stature, (ii) feeding difficulties and/or gastro-oesophageal reflux, (iii) microcephaly, (iv) intellectual disability, and (v) characteristic facial features. We identified 37 novel NIPBL mutations including 34 in leukocytes and 3 in buccal cells only. All mutations shown to have arisen de novo when parent blood samples were available. The present series confirms the difficulty in predicting the phenotype according to the NIPBL mutation. Until now, somatic mosaicism has been observed for 20 cases which do not seem to be consistently associated with a milder phenotype. Besides, several reports support a postzygotic event for those cases. Considering these elements, we recommend a first-line buccal cell DNA analysis in order to improve gene testing sensitivity in Cornelia de Lange syndrome and genetic counselling.