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The aim of this study was to determine the potential cognitive impairment associated with motor disability in a group of children attending regular schools and to analyze whether there were different cognitive profiles according to the type of motor disability they presented. The study had 87 participants, 31 healthy and 56 with three types of motor disability: Neuromuscular Diseases (NMD Group), Cerebral Palsy-Hemiparesis (CP- HPx Group) and Cerebral Palsy-Diplegia (CP-DP). Ages ranged from 6 to 18 years and they had medium and medium-high socioeconomic and cultural levels. All participants attended regular state-funded and independent schools in an inclusive modality. The neuropsychological assessment included the following cognitive domains: processing speed, working memory, verbal and visual episodic memory, language, visuo-perception and constructive praxis and executive functioning. A second analysis was performed with the groups with CP: one based on the severity of gross motor impairment (GMFCS-E&R scale) and the other based on the levels of manual dexterity (MACS scale). ANCOVAs were performed controlling for age and processing speed in the three analyses. The group with CP-HPx was shown to be the most cognitively impaired of the three groups, with significant deficits in visuo-perception, verbal working memory, and visuo-spatial memory. Subjects with greater gross motor dysfunction (GMFCS-E&R) did not show the greatest cognitive impairment, while those with worse manual dexterity (MACS) exhibited greater cognitive impairment. Children and adolescents with motor disabilities, a priori cognitively normal, present different levels of cognitive impairment. This should be considered when planning educational adaptations for this infant-juvenile population. [ABSTRACT FROM AUTHOR]

Impaired mitochondrial function and an increased number of mutations in mitochondrial DNA (mtDNA) has been found in brains of patients with late-onset Alzheimer's disease (LOAD). The TFAM-gene encodes the mitochondrial transcription factor A, a protein that controls the transcription, replication, damage sensing, and repair of mtDNA. TFAM is on human chromosome region 10q21.1, where a locus for LOAD has been mapped. Our objective was to determine the role of TFAM-gene variation in the risk of LOAD. The seven TFAM coding exons were analysed through single strand conformation analysis and direct sequencing in a cohort of Spanish LOAD-patients and healthy controls. We found four common polymorphisms, two in the flanquing intronic and two in the coding sequences. Polymorphism rs1937 (+35 G/C) was the only missense change (S12T). Genotyping of this polymorphism in 300 LOAD-patients and 183 healthy controls showed a significantly higher frequency of GG-homozygotes in the patients (92% vs. 86%; p=0.04; OR=1.91, 95%CI=1.02-3.50). This suggests that S12 is a risk factor for LOAD in our population. In conclusion, rare variants (mutations) in the TFAM gene were not found in LOAD-patients, but the S12T polymorphism was a moderate risk factor for LOAD in our population. [ABSTRACT FROM AUTHOR]

Neural crest cells are a dynamic migratory stem cell population that differentiates into a plethora of cell-types, including cells of the peripheral nervous system, endocrine cells, melanocytes, and cranio-facial bone and cartilage. In addition, neural crest cells are directly involved in various human health complications (tumors, heart valve malformations, cleft lip or palate). Despite their relevance little is known about the origin and induction of neural crest cells. (a) To analyze the participation of Wnt molecules during neural crest induction, and (b) to initiate studies of the earliest events in neural crest induction in gastrulating embryos. In vivo and in vitro inhibition and activation of Wnt and BMP signaling pathways, immunohistochemistry and RNA in situ hybridization. We have found that Wnt molecules are required and sufficient for neural crest cell induction. We also have found that unlike BMP4, a previously identified neural crest inducer, Wnt signals can induce neural crest cells in the absence of certain additives. In order to study earlier events in neural crest induction we have sought the expression of known neural crest markers during progressively earlier stages. We have identified the expression and requirement of Pax7 for neural crest formation during gastrulation. We also identified an earlier epiblast domain containing cells that generate neural crest cells when cultured in isolation under neural conditions. Taken together, these data suggest that neural crest specification is initiated during gastrulation and that Pax7 plays a critical role in its development. Multiple events account for the formation of neural crest cells in the chick embryo, along with previously identified BMP signals, Wnt signals seem also critical for the formation of neural crest cells. The transcription factor Pax7 is an early marker of the origin of neural crest cells in early gastrulating chick embryos, and its function is required for the formation of neural crest cells in different locations. [ABSTRACT FROM AUTHOR]

A mathematical concept, n-tuples are originally applied to medicinal chemistry, especially with the creation of scaffold diversity inspired by the hybridisation of different commercial drugs with cytarabine, a synthetic arabinonucleoside derived from two marine natural products, spongouridine and spongothymidine. The new methodology explores the virtual chemical-factorial combination of different commercial drugs (immunosuppressant, antibiotic, antiemetic, anti-inflammatory, and anticancer) with the anticancer drug cytarabine. Real chemical combinations were designed and synthesised for 8-duples, obtaining a small representative library of interesting organic molecules to be biologically tested as proof of concept. The synthesised library contains classical molecular properties regarding the Lipinski rules and/or beyond rules of five (bRo5) and is represented by the covalent combination of the anticancer drug cytarabine with ibuprofen, flurbiprofen, folic acid, sulfasalazine, ciprofloxacin, bortezomib, and methotrexate. The insertion of specific nomenclature could be implemented into artificial intelligence algorithms in order to enhance the efficiency of drug-hunting programs. The novel methodology has proven useful for the straightforward synthesis of most of the theoretically proposed duples and, in principle, could be extended to any other central drug.

An unprecedented transition metal free [2,3]-sigmatropic rearrangement involving stabilized sulfur ylides and allenoates has been thoroughly established. The scope and utility of this reaction have been extensively studied resulting in C-C bond formation under mild conditions with greater than 20 examples reported. A highlight of the work is the simple and fully operational process that does not involve the use of carbenes or the associated hazardous and sensitive reagents. The reaction can be performed at room temperature and using an open flask. Interestingly, the new C-C bond formation reaction is gram scalable, and the obtained isomers are readily separable, affording interesting building blocks that can be used in the preparation of complex molecules.

We report the green synthesis of silver nanoparticles (AgNPs) by using daisy petals ( Bellis perennis ), leek ( Allium porrum ) and garlic skin ( Allium sativum ) as reducing agents and water as solvent. AgNPs are obtained with high monodispersity, spherical shapes and size ranging from 5 to 35 nm and characterized by UV-Vis and TEM techniques. The obtained yields in AgNPs are in concordance with the total phenolic content of each plant. We also study the incorporation of AgNPs in combination with the red algae Pyropia columbina extracts (PCE) into cosmetic formulations and analyze their combined effect as photoprotective agents. Moreover, we carry out the inclusion of the PCE containing mycosporine-like amino acids (MAAs), which are strong UV-absorbing and antioxidant compounds, into β-cyclodextrin (βCD) and p NIPAM nanoparticles and analyze stability and release. The thermoresponsive polymer is grown by free radical polymerization using N -isopropylacrylamide (NIPAM) as the monomer, N,N '-methylenebisacrylamide (BIS) as the cross-linker, and 2,2'-azobis(2-methylpropionamidene) (V50) as the initiator, while βCD complex is prepared by heating in water. We evaluate the nanoparticle and βCD complex formation by UV-Vis and FT-IR, and NMR spectroscopies, respectively, and the nanoparticles' morphology, including particle size, by TEM. The cosmetic formulations are subsequently subjected to accelerated stability tests and photoprotective analyses: a synergistic effect in the combination of AgNPs and PCE in photoprotection was found. It is not related to a UV screen effect but to the antioxidant activity, having potential against photoaging.

The etiology of oculo-auriculo-vertebral spectrum (OAVS) is not well established. About half of patients show a positive family history. The etiology of familiar cases is unclear but appears genetically heterogeneous. This motivated us to report a case of OAVS with microtia, ptosis, facial microsomy, and fusion of vertebral bodies associated with a novel genetic etiology, including a deletion at 1p36.12-13. This case report expands on the genetic etiology of OAVS. Furthermore, it also expands the clinical manifestations of patients with interstitial deletions of the de 1p36.12-13 region.

The bengamides comprise an interesting family of natural products isolated from sponges belonging to the prolific Jaspidae family. Their outstanding antitumor properties, coupled with their unique mechanism of action and unprecedented molecular structures, have prompted an intense research activity directed towards their total syntheses, analogue design, and biological evaluations for their development as new anticancer agents. Together with these biological studies in cancer research, in recent years, the bengamides have been identified as potential antibiotics by their impressive biological activities against various drug-resistant bacteria such as Mycobacterium tuberculosis and Staphylococcus aureus . This review reports on the new advances in the chemistry and biology of the bengamides during the last years, paying special attention to their development as promising new antibiotics. Thus, the evolution of the bengamides from their initial exploration as antitumor agents up to their current status as antibiotics is described in detail, highlighting the manifold value of these marine natural products as valid hits in medicinal chemistry.

Modification of gold substrates with a stable, uniform and ultrathin layer of biocompatible materials is of tremendous interest for the development of bio-devices. We present the fabrication of hybrid systems consisting of triangular prism gold nanoparticles (Au@NTPs) covalently covered with tripod-shaped oligo(p-phenylenes) featuring trifluoromethyl groups. Their synthesis is accomplished using a biphenyl boronic ester as the key compound. Au@NTPs were prepared through a seedless procedure using 3-butenoic acid and benzyldimethyl ammonium chloride, and modified with aminothiol groups. Coverage of this amine-modified gold substrate with a self-assembled monolayer (SAM) of tripod-shaped molecules is carried out in ethanolic solution. The hybrid system avoids up to 70 % of protein corona formation, and allows unspecific attachment for bulky adsorbates, providing an optimal biosensing platform. Chemical composition and morphology are analyzed by transmission electron microscopy (TEM), UV-visible spectroscopy and field emission scanning electron microscopy (FESEM)., (© 2022 The Authors. Published by Wiley-VCH GmbH.)

Patients with different autoimmune inflammatory diseases (AIID) on biological therapy are at risk of pneumococcal disease. Adults with inflammatory arthropathies, connective tissue diseases, psoriasis, or inflammatory bowel disease on biological therapy such as anti-TNFα, rituximab, tocilizumab, abatacept, or anakinra were included in this study. Patients completed a protocol combining the pneumococcal vaccines PCV13 and PPV23. Immune response against pneumococcal serotypes 1, 3, 7F, 14, 19A, and 19F were assessed evaluating functional antibodies by an opsonophagocytosis killing assay (OPKA). In this study, 182 patients with AIID completed the sequential vaccination protocol. Patients on etanercept tended to achieve OPKA titers against a larger number of serotypes than the rest of patients on other biological therapies, while adalimumab was associated to a lower number of serotypes with OPKA titers. Rituximab was not associated with a worse response when compared with the rest of biological agents. Not glucocorticoids, nor synthetic disease-modifying antirheumatic drugs, interfered with the immune response. OPKA titers against serotype 3 which is one of the most prevalent, was obtained in 44% of patients, increasing up to 58% in those on etanercept. Hence, almost 50% of patients on biological therapy achieved functional antibodies after the administration of a complete pneumococcal vaccination protocol.

We study the nonequilibrium diffusive release of electroneutral molecular cargo encapsulated inside hollow hydrogel nanoparticles. We propose a theoretical model that includes osmotic, steric, and short-range polymer-cargo attractions to determine the effective cargo-hydrogel interaction, u eff *, and the effective diffusion coefficient of the cargo inside the polymer network, D eff *. Using dynamical density functional theory (DDFT), we investigate the scaling of the characteristic release time, τ 1/2 , with the key parameters involved in the process, namely, u eff *, D eff *, and the swelling ratio. This effort represents a full study of the problem, covering a broad range of cargo sizes and providing predictions for repulsive and attractive polymer shells. Our calculations show that the release time through repulsive polymer networks scales with q 2 e βu eff * / D eff * for β u eff * ≫ 1. In this case, the cargo molecules are excluded from the shell of the hydrogel. For attractive shells, the polymer retains the cargo molecules on its internal surface and its interior, and the release time grows exponentially with the attraction strength. The DDFT calculations are compared to an analytical model for the mean first passage time, which provides an excellent quantitative description of the kinetics for both repulsive and attractive shells without fitting parameters. Finally, we apply the method to reproduce experimental results on the release of paclitaxel from hollow poly(4-vinylpyridine) nanoparticles and find that the slow release of the drug can be explained in terms of the strong binding attraction between the drug and the polymer.

To evaluate the response to hepatitis B virus (HBV) vaccine in patients on biological therapy. Adults with autoimmune inflammatory diseases on biological therapy such as anti-TNFα, rituximab, tocilizumab, abatacept, or anakinra were included. Hepatitis B surface antibody (anti-HBs) was measured by ELISA before and after vaccination. Seroconversion was considered when an anti-HBs titer > 10 mIU/mL was achieved. The effect of treatment on the immunoprotective state was studied. The response was compared with that obtained in patients on synthetic disease modifying anti-rheumatic drugs (DMARDs) and healthy controls. A total of 187 patients on biologicals, 48 on synthetic DMARDs, and 49 on healthy controls were analyzed. More than 80% of patients on biologics responded to the vaccine but required more boosters and second vaccine series. Patients who achieved seroconversion were younger than those who did not (47.10 ± 12.99 vs. 53.18 ± 10.54 years, p = 0.012). Being on etanercept or golimumab was associated with seroconversion, while being on rituximab was not. Seroconversion was achieved in 93.75% of patients on synthetic DMARDs and 97.96% of healthy controls. The seroconversion rate in the biologics group was lower than in the synthetic DMARD group (p = 0.043) and tended to be lower than in the healthy group (p = 0.056). In patients on biological therapy, a high rate of HBV vaccine response can be achieved when a complete vaccination schedule is administered. Vaccination while not on biological agents reduces the requirement for boosters and revaccination. Key points: • Patients on biological therapy can achieve high rates of immune response to HBV vaccine when complete vaccination schedules are administered. • However, to achieve such a high seroconversion rate, more boosters and second vaccination series are required. • This supports the proposal already made to provide HBV vaccination to all patients with an autoimmune inflammatory disease after the diagnosis is made and not when the use of a biological treatment is under consideration.

Background and Objectives: Influenza vaccine is recommended for patients with autoimmune inflammatory rheumatic diseases who receive biological therapy. To evaluate if biological therapy impairs immunization after seasonal influenza vaccine., Material and Methods: Patients with inflammatory arthopathies, psoriasis, inflammatory bowel disease or connective tissue diseases who were receiving or were going to initiate biological therapy were included and vaccinated during 2014-2015 influenza season. ELISA was used to measure influenza antigen A and B antibodies, before and after vaccination. Demographic parameters, diagnosis and kind of treatment were recorded and their influence on the final serological status against influenza was studied., Results: 253 subjects were analyzed. After vaccination, 77% of participants presented detectable antibodies against antigen A and 50.6% of them had detectable antibodies against antigen B. Final seropositivity rate against antigen B antibodies increased from baseline (50.6% vs 43.5%, p<0.001). Anti-TNF drugs were associated with better response and rituximab with the worst (79.2% vs 55.0% for final seropositivity against antigen A, p=0.020). Vaccine response in the rituximab group tended to improve when the interval between the drug administration and the vaccination was at least 12 weeks (seropositivity rate 80.0% in those with the longer interval vs 25.0% in the other group, p=0.054)., Conclusions: Among the patients on biological therapy vaccinated against influenza, anti-TNF therapy was identified as a predictive factor of final seropositivity. Rituximab presented a lower rate of final seropositivity, which could be increased with an accurate administration schedule., (Copyright © 2019 Elsevier España, S.L.U. All rights reserved.)

Following the track of the useful titanocene [Ti(η 5 -C 5 H 5 ) 2 Cl] reagent in organic synthesis, the related half-sandwich titanium(III) derivatives [Ti(η 5 -C 5 R 5 )Cl 2 ] are receiving increasing attention in radical chemistry of many catalyzed transformations. However, the structure of the active titanium(III) species remains unknown in the literature. Herein, we describe the synthesis, crystal structure, and electronic structure of titanium(III) aggregates of composition [{Ti(η 5 -C 5 Me 5 )Cl 2 } n ]. The thermolysis of [Ti(η 5 -C 5 Me 5 )Cl 2 Me] (1) in benzene or hexane at 180 °C results in the clean formation of [{Ti(η 5 -C 5 Me 5 )Cl(μ-Cl)} 2 ] (2), methane, and ethene. The treatment of 1 with excess pinacolborane in hexane at 65 °C leads to a mixture of 2 and the paramagnetic trimer [{Ti(η 5 -C 5 Me 5 )(μ-Cl) 2 } 3 ] (3). The X-ray crystal structures of compounds 2 and 3 show Ti-Ti distances of 3.267(1) and 3.219(12) Å, respectively. Computational studies (CASPT2//CASSCF and BS DFT methods) for dimer 2 reveal a singlet ground state and a relatively large singlet-triplet energy gap. Nuclear magnetic resonance spectroscopy of 2 in aromatic hydrocarbon solutions and DFT calculations for several [{Ti(η 5 -C 5 Me 5 )Cl 2 } n ] aggregates are consistent with the existence of an equilibrium between the diamagnetic dimer [{Ti(η 5 -C 5 Me 5 )Cl(μ-Cl)} 2 ] and a paramagnetic tetramer [{Ti(η 5 -C 5 Me 5 )(μ-Cl) 2 } 4 ] in solution. In contrast, complex 2 readily dissolves in tetrahydrofuran to give a green-blue solution from which blue crystals of the mononuclear adduct [Ti(η 5 -C 5 Me 5 )Cl 2 (thf)] (4) were grown.

Until now, few cases of partial trisomy of 3q due to segregation error of parental balanced translocation and segregation of a duplicated deficient product resulting from parental pericentric inversion have been reported so far. Only five cases of chromosomal insertion malsegregation involving 3q region are available yet, thus making it relatively rare. In this case report, we are presenting a unique case of discontinuous partial trisomy of 3q26.1-q28 region which resulted from a segregation error of two insertions involving 3q26.1 to 3q27.3 and 3q28 regions with ~21Mb and ~2Mb sizes, respectively. The maternally inherited insertion was cytogenetically characterized as der(8)(8pter→8p22::3q26→3q27.3::3q28→3q28::8p22→8qter) and the patient's major clinical features involved Dandy Walker malformation, sub-aortic ventricular septal defect, upslanting palpebral fissures, clinodactyly, hirsutism, and prominent forehead. Besides, a review of the literature involving cases with similar chromosomal imbalances and cases with "3q-duplication syndrome" is also provided., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A new type of chiral sulfonium salts that are characterized by a bicyclic system has been designed and synthesized from α-amino acids. Their corresponding ylides, which were prepared by basic treatment of the sulfonium salts, reacted smoothly with a broad array of simple and chiral aldehydes to provide trans-epoxy amides in reasonable to very good yields and excellent stereoselectivities (>98%). The obtained epoxy amides were found to be useful as synthetic building blocks. Thus, they were reduced into their corresponding epoxy alcohols and subjected to oxirane-ring-opening reactions with different types of nucleophiles., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The National Commission of Rheumatology has developed a satisfaction survey for residents concerning their training period. 37% of the 176 invited to participate answered the survey. 71% said they were satisfied or very satisfied with the influence of the assistance activities during their training. 38% were dissatisfied or very dissatisfied with supervision by staff. 39% were dissatisfied or very dissatisfied with their training in polarized light microscopy. 52% said no regular meetings were structured to monitor their training. 66% said that there had been no effective evaluation of their training. 39% were dissatisfied or very dissatisfied on the tools they were given to publish at their teaching unit. Overall satisfaction on classroom training for residents of Rheumatology is high. There are opportunities for improvement relating to training in certain techniques, monitoring and evaluation of the training period and training in research skills., (Copyright © 2011 Elsevier España, S.L. All rights reserved.)

A series of titanium-group 3/lanthanide metal complexes have been prepared by reaction of [{Ti(η(5)-C(5)Me(5))(μ-NH)}(3)(μ(3)-N)] (1) with halide, triflate, or amido derivatives of the rare-earth metals. Treatment of 1 with metal halide complexes [MCl(3)(thf)(n)] or metal trifluoromethanesulfonate derivatives [M(O(3)SCF(3))(3)] at room temperature affords the cube-type adducts [X(3)M{(μ(3)-NH)(3)Ti(3)(η(5)-C(5)Me(5))(3)(μ(3)-N)}] (X = Cl, M = Sc (2), Y (3), La (4), Sm (5), Er (6), Lu (7); X = OTf, M = Y (8), Sm (9), Er (10)). Treatment of yttrium (3) and lanthanum (4) halide complexes with 3 equiv of lithium 2,6-dimethylphenoxido [LiOAr] produces the aryloxido complexes [(ArO)(3)M{(μ(3)-NH)(3)Ti(3)(η(5)-C(5)Me(5))(3)(μ(3)-N)}] (M = Y (11), La (12)). Complex 1 reacts with 0.5 equiv of rare-earth bis(trimethylsilyl)amido derivatives [M{N(SiMe(3))(2)}(3)] in toluene at 85-180 °C to afford the corner-shared double-cube nitrido compounds [M(μ(3)-N)(3)(μ(3)-NH)(3){Ti(3)(η(5)-C(5)Me(5))(3)(μ(3)-N)}(2)] (M = Sc (13), Y (14), La (15), Sm (16), Eu (17), Er (18), Lu (19)) via NH(SiMe(3))(2) elimination. A single-cube intermediate [{(Me(3)Si)(2)N}Sc{(μ(3)-N)(2)(μ(3)-NH)Ti(3)(η(5)-C(5)Me(5))(3)(μ(3)-N)}] (20) was obtained by the treatment of 1 with 1 equiv of the scandium bis(trimethylsilyl)amido derivative [Sc{N(SiMe(3))(2)}(3)]. The X-ray crystal structures of 2, 7, 11, 14, 15, and 19 have been determined. The thermal decomposition in the solid state of double-cube nitrido complexes 14, 15, and 18 has been investigated by thermogravimetric analysis (TGA) and differential thermal analysis (DTA) measurements, as well as by pyrolysis experiments at 1100 °C under different atmospheres (Ar, H(2)/N(2), NH(3)) for the yttrium complex 14.

Gleason-type chiral auxiliaries were used for the synthesis of a novel class of sulfonium salts, obtained via methylation of the sulfide with Meerwein's salt. The salts were reacted with aldehydes under basic conditions to provide epoxy amides, which were reduced to their corresponding epoxy alcohols in excellent enantiomeric excesses. Interestingly, it was feasible to synthesize both enantiomeric epoxy alcohols depending on which of the sulfonium salts, prepared from L-amino acids (6 and 9 from L-valine or 15 and 16 from L-serine) was employed., (© 2011 American Chemical Society)

The National Rheumatology Board is responsible for postgraduate formation in rheumatology. Herein we present the new criteria for accreditation of teaching units. These criterion contemplate four domains, namely: structure, clinical work, teaching and research. Each domain is divided in subdomains and items. Some of them are of an obligatory nature. This document serves as reference for future applications. The document may be reviewed in the future., (Copyright © 2010 Elsevier España, S.L. All rights reserved.)

Brugada syndrome is characterized by right bundle branch block and ST-segment elevation in the right precordial ECG leads. Familial transmission is frequent and approximately 25% of cases exhibit mutations in the SCN5A gene. We analyzed the sequence of this gene in 25 Spanish patients with Brugada syndrome. In 4 (16%), we found mutations that had not previously been described: three were amino acid changes (i.e. Ala2>Thr, Ala735>Thr and Val1340>Ile) and one was an intron mutation that affected messenger RNA processing (i.e. IVS18-1G>A). These four patients had relatives who were also mutation carriers, several of whom had normal ECGs, even on flecainide challenge. Our study suggests that genetic analysis could be helpful in the presymptomatic diagnosis of Brugada syndrome, but may be less useful for stratifying the risk of adverse events.

A new type of chiral sulfur ylides has been synthesized and their reactivities against carbonyl compounds tested, showing a high degree of stereoselectivity in the formation of trans epoxy amides under very mild reaction conditions.

Aim: Endothelin-1 (ET-1) promotes vasoconstriction and cell proliferation, and has been implicated in hypertension and coronary artery disease. Our aim was to analyse the role of the ET-1 gene (EDN1) in the risk for atherosclerosis/myocardial infarction (MI) in a population with smoking as the prevalent risk factor., Methods: The study included 316 patients with early onset MI (<55 years old). All were male with at least one diseased coronary vessel. Denaturing high performance liquid chromatography (DHPLC), single-strand conformation analysis (SSCA), and direct sequencing were used to search for DNA variants in the five EDN1 exons and the promoter region. To determine the association of EDN1 polymorphisms with MI, we genotyped the patients and controls (n=350) and compared the allele and genotype frequencies between groups., Results: We found six common nucleotide changes: -1394 (T/G) and -974 C/A (promoter), +120 ins/del A (exon 1, 5' UTR), 568 A/G (exon 3, E106E), 844 G/T (exon 5, K198N), and 1617 T/C (exon 5, 3' UTR). No rare EDN1-variants specific to the MIpatients were found. None of the EDN1 polymorphisms were significantly associated with early-onset MI in our population. The two promoter polymorphisms were in linkage disequilibrium with K198N, but no haplotype was associated with MI risk., Conclusions: In our population, the EDN1 variation did not contribute to early-onset MI.

Several heterometallic nitrido complexes were prepared by reaction of the imido-nitrido titanium complex [{Ti(eta(5)-C(5)Me(5))(mu-NH)}(3)(mu(3)-N)] (1) with amido derivatives of Group 13-15 elements. Treatment of 1 with bis(trimethylsilyl)amido [M{N(SiMe(3))(2)}(3)] derivatives of aluminum, gallium, or indium in toluene at 150-190 degrees C affords the single-cube amidoaluminum complex [{(Me(3)Si)(2)N}Al{(mu(3)-N)(2)(mu(3)-NH)Ti(3)(eta(5)-C(5)Me(5))(3)(mu(3)-N)}] (2) or the corner-shared double-cube compounds [M(mu(3)-N)(3)(mu(3)-NH)(3){Ti(3)(eta(5)-C(5)Me(5))(3)(mu(3)-N)}(2)] [M = Ga (3), In (4)]. Complexes 3 and 4 were also obtained by treatment of 1 with the trialkyl derivatives [M(CH(2)SiMe(3))(3)] (M = Ga, In) at high temperatures. The analogous reaction of 1 with [{Ga(NMe(2))(3)}(2)] at 110 degrees C leads to [{Ga(mu(3)-N)(2)(mu(3)-NH)Ti(3)(eta(5)-C(5)Me(5))(3)(mu(3)-N)}(2)] (5), in which two [GaTi(3)N(4)] cube-type moieties are linked through a gallium-gallium bond. Complex 1 reacts with one equivalent of germanium, tin, or lead bis(trimethylsilyl)amido derivatives [M{N(SiMe(3))(2)}(2)] in toluene at room temperature to give cube-type complexes [M{(mu(3)-N)(2)(mu(3)-NH)Ti(3)(eta(5)-C(5)Me(5))(3)(mu(3)-N)}] [M = Ge (6), Sn (7), Pb (8)]. Monitoring the reaction of 1 with [Sn{N(SiMe(3))(2)}(2)] and [Sn(C(5)H(5))(2)] by NMR spectroscopy allows the identification of intermediates [RSn{(mu(3)-N)(mu(3)-NH)(2)Ti(3)(eta(5)-C(5)Me(5))(3)(mu(3)-N)}] [R = N(SiMe(3))(2) (9), C(5)H(5) (10)] in the formation of 7. Addition of one equivalent of the metalloligand 1 to a solution of lead derivative 8 or the treatment of 1 with a half equivalent of [Pb{N(SiMe(3))(2)}(2)] afford the corner-shared double-cube compound [Pb(mu(3)-N)(2)(mu(3)-NH)(4){Ti(3)(eta(5)-C(5)Me(5))(3)(mu(3)-N)}(2)] (11). Analogous antimony and bismuth derivatives [M(mu(3)-N)(3)(mu(3)-NH)(3){Ti(3)(eta(5)-C(5)Me(5))(3)(mu(3)-N)}(2)] [M = Sb (12), Bi (13)] were obtained through the reaction of 1 with the tris(dimethylamido) reagents [M(NMe(2))(3)]. Treatment of 1 with [AlCl(2){N(SiMe(3))(2)}(OEt(2))] affords the precipitation of the singular aluminum-titanium square-pyramidal aggregate [{{(Me(3)Si)(2)N}Cl(3)Al(2)}(mu(3)-N)(mu(3)-NH)(2){Ti(3)(eta(5)-C(5)Me(5))(3)(mu-Cl)(mu(3)-N)}] (14). The X-ray crystal structures of 5, 11, 13, 14, and [AlCl{N(SiMe(3))(2)}(2)] were determined.

Objective: Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular disease that may not always be related to the presence of traditional cardiovascular risk factors. The aim of this study was to determine if anti-cyclic citrullinated peptide (anti-CCP) antibodies are associated with cardiovascular disease in patients with RA., Methods: Anti-CCP antibodies were determined by enzyme-linked immunosorbent assay in the earliest serum sample available from 937 patients with a diagnosis of RA. We studied the relationship between anti-CCP antibodies with traditional cardiovascular risk factors and cardiovascular events., Results: We found positive anti-CCP antibodies (>25 units/ml) in 672 patients (71.7%). There was no association between the anti-CCP antibodies and cardiovascular risk factors such as smoking, hypertension, dyslipidemia, being overweight, or diabetes mellitus. However, patients who had positive anti-CCP antibodies experienced more frequent ischemic heart disease (6.5% versus 2.6%; odds ratio [OR] 2.58, 95% confidence interval [95% CI] 1.17-5.65) and had higher mortality rates (11.2% versus 6.8%; OR 1.72, 95% CI 1.01-2.91). Similar results were obtained when we considered anti-CCP titers 20-fold higher (>500 units/ml). Multivariable analysis showed that ischemic heart disease is independently associated with positive anti-CCP antibodies (OR 2.8, 95% CI 1.19-6.56; P = 0.009)., Conclusion: Anti-CCP antibodies in patients with RA are independently associated with the development of ischemic heart disease.

Background: Gitelman's syndrome (GS) is caused by mutations in the SLC12A3. Most of the mutations are rare, making it difficult to establish a genotype-phenotype correlation. Although GS is a recessive disorder, some patients also have an affected parent, suggesting a dominant inheritance., Methods: We sequenced the 26 coding exons of SLC12A3 in a family in which the proband and her father had a late onset GS. We obtained cDNA of the 2 patients and analyzed the effect of a mutation on pre-mRNA splicing., Results: The 2 patients were homozygous for a nucleotide change in the last nucleotide of exon 15: c.1925 G>A. The mother was a heterozygous carrier for this putative mutation. Amplification of cDNA with primers for exons 14-17 was negative, suggesting that this mutation affected the splicing and promoted mRNA degradation through nonsense-mediated decay., Conclusions: We report a family with 2 patients with late onset GS and homozygous for a mutation in the last nucleotide of exon 15. Our study shows that homozygosity for this mutation resulted in a significant loss of normal SLC12A3 transcript., (Copyright 2009 S. Karger AG, Basel.)

Introduction and Objectives: Mutation of a sarcomeric gene is the most frequent cause of hypertrophic cardiomyopathy. For each such gene, however, previous studies have reported a range of different mutation frequencies, and clinical manifestations have been highly heterogeneous, both of which limit the use of genetic information in clinical practice. Our aim was to determine the frequency of mutations in the sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in a cohort of Spanish patients with hypertrophic cardiomyopathy., Methods: We used sequencing to analyze the coding regions of these five genes in 120 patients (29% with a family history) and investigated how the patient phenotype varied with the gene mutated., Results: In total, 32 patients were found to have mutations: 10 in MYH7 (8%), 20 in MYBPC3 (16%), 2 in TNNT2, 1 in TPM1 and none in TNNI3. Overall, 61% of mutations had not been described before. Two patients had two mutations (i.e., double mutants). There was no difference in the mean age at diagnosis or the extent of the hypertrophy between those with MYH7 mutations and those with MYBPC3 mutations., Conclusions: Some 26% of patients had a mutation in one of the five sarcomeric genes investigated. More than half of the mutations had not been described before. The MYBPC3 gene was the most frequently mutated, followed by MYH7. No phenotypic differences were observed between carriers of the various mutations, which makes it difficult to use genetic information to stratify risk in these patients.

A new approach to the stereoselective synthesis of polypropionate-type frameworks is reported utilizing reactions of amide-stabilized sulfur ylides with chiral aldehydes. To establish a new strategy for macrolide fragment synthesis, the stereoselectivity of these reactions in the construction of epoxy amides was the most important aspect of this study. In this aspect, we found a strong influence of the protecting groups employed in the starting aldehydes upon the stereochemical outcome of their reactions with the sulfur ylide 1. Thus, numerous aldehydes showed remarkable stereofacial differentiation, providing a major diastereoisomer, in contrast to others that displayed a poor or no stereoselectivity. Despite the difficulties encountered for some cases with respect to their diastereomeric yields, we were able to prepare various stereotetrads and stereopentads, thus enhancing the synthetic value of this new methodology for the preparation of typical polypropionate frameworks found in many natural products, in particular the macrolide class of antibiotics.

Background: The cyclophilin A (CypA)-cyclosporine (CsA) complex promotes immune response. The variation at the CypA gene could explain CsA-pharmacokinetics and clinical outcomes among CsA-treated patients., Methods: The study included 290 kidney transplanted patients (65% male; mean age 51 +/- 15 yr), treated with CsA. The five CypA- exons and the promoter region were analysed through single-strand conformation analysis, denaturing high performance liquid chromatography, and direct sequencing. The effect of a promoter polymorphism (-11 G/C) on gene expression was analysed in cell-cultures., Results: We found two polymorphisms in the promoter (-11 G/C) and exon 1 (+36 G/A). Genotype frequencies did not differ between patients according to their pharmacokinetics status. In vitro studies showed that -11 G/C affected gene expression. The -11 G allele was significantly associated with clinical nephrotoxicity (p = 0.006). The strongest predictors for nephrotoxicity were a donor age > or =55 yr, and the promoter GG + GC genotypes., Conclusions: Our work suggests that a CypA-promoter polymorphism (-11 G/C) could be associated with clinical nephrotoxicity. Replication of this study in other populations is necessary to define the role of CypA-variants in the main clinical outcomes among CsA-treated kidney-transplanted patients.

Treatment of [{TiCp*(mu-NH)} 3(mu 3-N)] ( 1; Cp* = eta (5)-C 5Me 5) with yttrium and erbium halide complexes [MCl 3(THF) 3.5] and [MCpCl 2(THF) 3] (Cp = eta (5)-C 5H 5) gives cube-type adducts [Cl 3M{(mu 3-NH) 3Ti 3Cp* 3(mu 3-N)}] and [CpCl 2M{(mu 3-NH) 3Ti 3Cp* 3(mu 3-N)}]. An analogous reaction of 1 with [{MCp 2Cl} 2] in toluene affords [Cp 3M(mu-Cl)ClCpM{(mu 3-NH) 3Ti 3Cp* 3(mu 3-N)}] (M = Y, Er).

We report the results of a study carried out in 825 young football club members, all of whom underwent screening for hypertrophic cardiomyopathy using a 12-lead ECG. Echocardiographic assessment was performed in only those with positive ECG results, as defined by the European Society of Cardiology. Echocardiography proved necessary in 61 (7%) individuals with positive ECG findings, of whom 7 had echocardiographic findings indicative of left ventricular hypertrophy: five were in the "gray zone", 1 was judged to have athlete's heart, and one had been diagnosed with hypertrophic cardiomyopathy. In all these cases, ECG showed repolarization abnormalities, and 4 satisfied criteria for left ventricular hypertrophy.

Mitochondrial function is necessary to supply the energy required for cell metabolism. Mutations/polymorphisms in mitochondrial DNA (mtDNA) have been implicated in Parkinson's disease (PD). The mitochondrial transcription factor A (TFAM) controls the transcription of mtDNA and regulates the mtDNA-copy number, thus being important for maintaining ATP production. TFAM dysfunction may also be involved in PD, and TFAM gene mutations/polymorphisms could contribute to the risk of developing PD. We searched for gene variants in the seven TFAM-exons in a total of 250 PD-patients. We found five common polymorphisms, and only one was a missense change (S12T in exon 1). Genotype and allele frequencies did not differ between patients and healthy controls (n=225) for the five polymorphisms. Our work suggests that TFAM-variants did not contribute to the risk of developing PD.

The synthesis of the polypropionate chain of Streptovaricin U (1) is described utilizing a new approach for the stereoselective synthesis of the macrolide-type antibiotics via sulfur ylides.

Polymorphisms at different genes have been proposed as determinants of the risk for developing late-onset Alzheimer's disease (LOAD). Among the several candidate genes are those that encode proteins involved in neuronal degeneration/survival. Studies of primary neuronal cultures supported that members of the myocyte enhancing factor-2 (MEF2) family of transcription factors have an anti-apoptotic effect, regulating the expression of proteins involved in neuronal survival and differentiation. We analysed the MEF2A gene in a total of 357 patients (mean age 72 years, range 60-97 years). Among others, a Pro279Leu in exon 8 and a polyglutamine (CAG) repeat polymorphisms in exon 12 were found. These variants were also genotyped in 495 healthy controls (>50 years old), and the frequencies were statistically compared. Eight patients were 279L (six P/L and two L/L), compared to only one control (2% vs. 0.2%; p=0.004, OR=11.32). There was a significantly higher frequency of 279L-carriers among APOE epsilon4+ (7/154=4.5%), compared to epsilon4- (1/203) (p=0.02). In conclusion, our work suggests that the variation at the MEF2A gene could be involved in the risk of developing LOAD. Because MEF2 has been related with neuronal survival, and the 279L allele has been related with a reduction in the transcriptional activation activity of MEF2A, the effect of this allele could be mediated through a down-regulation of antiapoptotic genes.