Inhibition of adenylyl cyclase 8 prevents the upregulation of Orai1 channel, which improves cardiac function after myocardial infarction.

The upregulation of Orai1 and subsequent store-operated Ca2+ entry (SOCE) has been associated with adverse cardiac remodeling and heart failure (HF). However, the mechanism underlying Orai1 upregulation and its role in myocardial infarction remains unclear. Our study investigated the role of Orai1 in activating adenylyl cyclase 8 (AC8) and cyclic AMP (cAMP) response element-binding protein (CREB), as well as its contribution to cardiac dysfunction induced by ischemia and reperfusion (I/R). We found that I/R evoked an increase in the expression of Orai1 and AC8 in rats' hearts, resulting in a substantial rise in diastolic Ca2+ concentration ([Ca2+]i), and reduced ventricular contractions. The expression of Orai1 and AC8 was also increased in ventricular biopsies of post-ischemic HF patients. Mechanistically, we demonstrate that I/R activation of Orai1 stimulated AC8, which produced cAMP and phosphorylated CREB. Subsequently, p-CREB activated the ORAI1 promoter, resulting in Orai1 upregulation and SOCE exacerbation. Intramyocardial administration of AAV9 carrying AC8 short hairpin RNA decreased the expression of AC8, Orai1 and CREB, which restored diastolic [Ca2+]i and improved cardiac contraction. Therefore, our data suggests that the axis composed by Orai1/AC8/CREB plays a critical role in I/R-induced cardiac dysfunction, representing a potential new therapeutic target to limit the progression of the disease toward HF.

Crystal, Solution, and Computational Study of the Structure of Ortho-Lithium N,N-Diisopropyl-P,P-Diphenylphosphinothioic Amide.

The first crystal structure of an ortho-lithium phosphinothioic amide complexed with tetramethylethylenediamine 12 is reported. The complex consists of a spirane in which the spiro-lithium is N,N- and C,S-chelated by the diamine and organophosphorus ligands, respectively. The analogous ortho anion 14 obtained by Sn(IV)/Li transmetallation in THF has also been synthesized. Nuclear magnetic resonance study of both anions showed that they exist as monomers in solution and are involved in dynamic processes including the restricted rotation around the P-N bond. 14 is converted at room temperature by nucleophilic cyclization to the dearomatized anion 15, which evolves after a few hours to the benzophosphindole sulfide 16. Density functional theory calculations supported the aggregation state in solution and were used to explore the conformational space of anion 12, the mechanism of ortho-lithiation directed by P(X)-N (X=O, S) groups, and the mechanism of formation of 15.

Effects of maternal modafinil treatment on fetal development and neonatal growth parameters - a multicenter case series of the European Network of Teratology Information Services (ENTIS).

OBJECTIVE: In recent years, safety concerns about modafinil exposure during pregnancy have emerged. In particular, increased risks for major congenital anomalies (MCA) and impaired fetal growth were reported, although study results were conflicting. Our investigation aims to examine previously reported safety signals. METHOD: Multicenter case series based on data from 18 Teratology Information Services from 12 countries. Modafinil exposed pregnancies with an estimated date of birth before August 2019 were included in this study. For prospectively ascertained pregnancies, cumulative incidences of pregnancy outcomes, rate of nonchromosomal MCA in first trimester exposed pregnancies and percentiles of neonatal/infant weight and head circumference (HC) were calculated. Potential dose-dependent effects on fetal growth were explored by linear regression models. Retrospectively ascertained cases were screened for pattern of MCA and other adverse events. RESULTS: One hundred and seventy-five prospectively ascertained cases were included, of which 173 were exposed at least during the first trimester. Cumulative incidences for live birth, spontaneous abortion and elective termination of pregnancy were 76.9% (95% CI, 68.0%-84.8%), 9.3% (95% CI, 5.0%-16.9%), and 13.9% (95% CI, 8.1%-23.1%), respectively. Nonchromosomal MCA was present in 3/150 live births, corresponding to an MCA rate of 2.0% (95%CI, 0.6%-6.1%), none were reported in pregnancy losses. Compared to reference standards, birth weight (BW) tended to be lower and neonatal HC to be smaller in exposed newborns (data available for 144 and 73 of 153 live births, respectively). In nonadjusted linear regression models, each 100 mg increase of average dosage per pregnancy day was associated with a decrease in standard deviation score (SDS) of -0.28 SDS (95% CI, -0.45 to -0.10) for BW and of -0.28 SDS (95% CI, -0.56 to 0.01) for HC. Screening of 22 retrospectively reported cases did not reveal any specific pattern of MCA or other adverse outcomes. CONCLUSION: The results do not indicate an increased risk of MCA after in utero exposure to modafinil, but a tendency toward lower BW and reduced neonatal HC. However, these findings should be regarded as preliminary. Until further studies allow for a definite conclusion, modafinil should not be used during pregnancy.

Smoking during pregnancy: changes and associated risk factors in Spain, 1980-2016.

BACKGROUND: Trends for maternal smoking rates have varied substantially across industrialized countries. The objective was to describe how the prevalence of maternal smoking evolved in Spain during 1980-2016. METHODS: Data came from the Spanish Collaborative Study of Congenital Malformations. Our sample consisted of 40 934 mothers of newborns with no congenital defects from hospitals all across Spain. We estimated change points in trend and the mean annual change in smoking prevalence using 'joinpoint' regression. Relevant potential factors (age, country of birth, education, parity, planned pregnancy and alcohol consumption) were examined using multivariate logistic regression. RESULTS: Maternal smoking prevalence in 1980 and 2016 were 14.3% (95% confidence interval [CI]: 11.9-17.0) and 20.4% (95% CI: 15.9-25.8). We identified four periods with distinct trends: a sharp increase during the 80s, a plateau during the 90s, a decrease starting in 2000 and a slowdown of such decrease from 2009 on. Smoking was significantly higher among young women, Spain-born, with low education, unplanned pregnancy, and alcohol consumption. CONCLUSIONS: Currently in Spain maternal smoking remains very high. Tobacco consumption trend showed an increase during the 80s, a plateau during the 90s, and a reduction in the 2000s. Several sociodemographic and behavioural factors were associated to greater likelihood of smoking.

A Multicountry Analysis of Prevalence and Mortality among Neonates and Children with Bladder Exstrophy.

OBJECTIVE: Bladder exstrophy (BE) is a rare but severe birth defect affecting the lower abdominal wall and genitourinary system. The objective of the study is to examine the total prevalence, trends in prevalence, and age-specific mortality among individuals with BE. STUDY DESIGN: We conducted a retrospective cohort study. Data were analyzed from 20 birth defects surveillance programs, members of the International Clearinghouse for Birth Defects Surveillance and Research in 16 countries. Live births, stillbirths, and elective terminations of pregnancy for fetal anomaly (ETOPFA) diagnosed with BE from 1974 to 2014. Pooled and program-specific prevalence of BE per 100,000 total births was calculated. The 95% confidence intervals (CI) for prevalence were estimated using Poisson approximation of binomial distribution. Time trends in prevalence of BE from 2000 to 2014 were examined using Poisson regression. Proportion of deaths among BE cases was calculated on the day of birth, day 2 to 6, day 7 to 27, day 28 to 364, 1 to 4 years, and ≥5 years. Mortality analysis was stratified by isolated, multiple, and syndromic case status. RESULTS: The pooled total prevalence of BE was 2.58 per 100,000 total births (95% CI = 2.40, 2.78) for study years 1974 to 2014. Prevalence varied over time with a decreasing trend from 2000 to 2014. The first-week mortality proportion was 3.5, 17.3, and 14.6% among isolated, multiple, and syndromic BE cases, respectively. The majority of first-week mortality occurred on the first day of life among isolated, multiple, and syndromic BE cases. The proportion of first-week deaths was higher among cases reported from programs in Latin America where ETOPFA services were not available. CONCLUSIONS: Prevalence of BE varied by program and showed a decreasing trend from 2000 to -2014. Mortality is a concern among multiple and syndromic cases, and a high proportion of deaths among cases occurred during the first week of life. KEY POINTS: · Total prevalence of BE was 2.58 per 100,000 births.. · Prevalence decreased from 2000 to 2014.. · The first-week mortality was 9.3%..

Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder.

Pathogenic hemizygous or heterozygous mutations in the IQSEC2 gene cause X-linked intellectual developmental disorder-1 (XLID1), characterized by a variable phenotype including developmental delay, intellectual disability, epilepsy, hypotonia, autism, microcephaly and stereotypies. It affects both males and females typically through loss of function in males and haploinsufficiency in heterozygous females. Females are generally less affected than males. Two novel unrelated cases, one male and one female, with de novo IQSEC2 variants were detected by trio-based whole exome sequencing. The female case had a previously undescribed frameshift mutation (NM_001111125:c.3300dup; p.Met1101Tyrfs*5), and the male showed an intronic variant in intron 6, with a previously unknown effect (NM_001111125:c.2459+21C>T). IQSEC2 gene expression study revealed that this intronic variant created an alternative donor splicing site and an aberrant product, with the inclusion of 19bp, confirming the pathogenic effect of the intron variant. Moreover, a strong reduction in the expression of the long, but also the short IQSEC2 isoforms, was detected in the male correlating with a more severe phenotype, while the female case showed no decreased expression of the short isoform, and milder effects of the disease. This suggests that the abnormal expression levels of the different IQSEC2 transcripts could be implicated in the severity of disease manifestations.

De novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects.

Disruption of the autism susceptibility candidate 2 (AUTS2) gene through genomic rearrangements, copy number variations (CNVs), and intragenic deletions and mutations, has been recurrently involved in syndromic forms of developmental delay and intellectual disability, known as AUTS2 syndrome. The AUTS2 gene plays an important role in regulation of neuronal migration, and when altered, associates with a variable phenotype from severely to mildly affected patients. The more severe phenotypes significantly correlate with the presence of defects affecting the C-terminus part of the gene. This article reports a new patient with a syndromic neurodevelopmental disorder, who presents a deletion of 30 nucleotides in the exon 9 of the AUTS2 gene. Importantly, this deletion includes the transcription start site for the AUTS2 short transcript isoform, which has an important role in brain development. Gene expression analysis of AUTS2 full-length and short isoforms revealed that the deletion found in this patient causes a remarkable reduction in the expression level, not only of the short isoform, but also of the full AUTS2 transcripts. This report adds more evidence for the role of mutated AUTS2 short transcripts in the development of a severe phenotype in the AUTS2 syndrome.

Urocortin Role in Ischemia Cardioprotection and the Adverse Cardiac Remodeling.

Despite the considerable progress in strategies of myocardial protection, ischemic heart diseases (IHD) and consequent heart failure (HF) remain the main cause of mortality worldwide. Several procedures are used routinely to guarantee the prompt and successful reestablishment of blood flow to preserve the myocardial viability of infarcted hearts from ischemia injuries. However, ischemic heart reperfusion/revascularization triggers additional damages that occur when oxygen-rich blood re-enters the vulnerable myocardial tissue, which is a phenomenon known as ischemia and reperfusion (I/R) syndrome. Complications of I/R injuries provoke the adverse cardiac remodeling, involving inflammation, mishandling of Ca2+ homeostasis, apoptotic genes activation, cardiac myocytes loss, etc., which often progress toward HF. Therefore, there is an urgent need to develop new cardioprotective therapies for IHD and HF. Compelling evidence from animal studies and pilot clinical trials in HF patients suggest that urocortin (Ucn) isoforms, which are peptides associated with stress and belonging to the corticotropin releasing factor family, have promising potential to improve cardiovascular functions by targeting many signaling pathways at different molecular levels. This review highlights the current knowledge on the role of urocortin isoforms in cardioprotection, focusing on its acute and long-term effects.

Applicability of high-resolution NMR in combination with chemometrics for the compositional analysis and quality control of spices and plant-derived condiments.

Over the last years, the consumption of spices and plant-derived condiments has increased considerably, owing to new culinary trends. Unfortunately, the current marketing channels make them highly vulnerable to adulteration and food fraud. High-resolution nuclear magnetic resonance (NMR) is a powerful tool for the compositional study of spices and plant-derived condiments. It allows the chemical characterization of a wide range of polar and non-polar metabolites, and provides unique structural information not available by other techniques. The chemometric-based analysis of NMR 'fingerprints' has been used to discriminate samples according to species and geographical origin and to detect adulterations, among other applications. The comprehensive identification and quantification of marker compounds can be achieved even in complex mixtures, demonstrating a great potential for high-throughtput quality control applications. © 2020 Society of Chemical Industry.

Expanding the genotypic and phenotypic spectrum of severe serine biosynthesis disorders.

Serine biosynthesis disorders comprise a spectrum of very rare autosomal recessive inborn errors of metabolism with wide phenotypic variability. Neu-Laxova syndrome represents the most severe expression and is characterized by multiple congenital anomalies and pre- or perinatal lethality. Here, we present the mutation spectrum and a detailed phenotypic analysis in 15 unrelated families with severe types of serine biosynthesis disorders. We identified likely disease-causing variants in the PHGDH and PSAT1 genes, several of which have not been reported previously. Phenotype analysis and a comprehensive review of the literature corroborates the evidence that serine biosynthesis disorders represent a continuum with varying degrees of phenotypic expression and suggest that even gradual differences at the severe end of the spectrum may be correlated with particular genotypes. We postulate that the individual residual enzyme activity of mutant proteins is the major determinant of the phenotypic variability, but further functional studies are needed to explore effects at the enzyme protein level.

Heterozygous pathogenic variants in GLI1 are a common finding in isolated postaxial polydactyly A/B.

Postaxial polydactyly (PAP) is a frequent limb malformation consisting in the duplication of the fifth digit of the hand or foot. Morphologically, this condition is divided into type A and B, with PAP-B corresponding to a more rudimentary extra-digit. Recently, biallelic truncating variants in the transcription factor GLI1 were reported to be associated with a recessive disorder, which in addition to PAP-A, may include syndromic features. Moreover, two heterozygous subjects carrying only one inactive copy of GLI1 were also identified with PAP. Herein, we aimed to determine the level of involvement of GLI1 in isolated PAP, a condition previously established to be autosomal dominantly inherited with incomplete penetrance. We analyzed the coding region of GLI1 in 95 independent probands with nonsyndromic PAP and found 11.57% of these subjects with single heterozygous pathogenic variants in this gene. The detected variants lead to premature termination codons or result in amino acid changes in the DNA-binding domain of GLI1 that diminish its transactivation activity. Family segregation analysis of these variants was consistent with dominant inheritance with incomplete penetrance. We conclude that heterozygous changes in GLI1 underlie a significant proportion of sporadic or familial cases of isolated PAP-A/B.

Identification of adjuvants in plant protection products applying a suspect screening workflow based on orthogonal techniques.

In this study, the identification of adjuvants (surfactants and solvents) in quizalofop-p-ethyl plant protection products (PPPs) was carried out by applying nuclear magnetic resonance (NMR), ultra-high-performance liquid chromatography (UHPLC) and gas chromatography (GC), both coupled to high-resolution mass spectrometry (HRMS), and using a suspect analysis approach. NMR provided a rapid and global overview of the composition of the studied samples and supported the tentative identification of the glycol ether family, commonly employed as surfactants, and 2-ethyl-1-butanol. UHPLC-HRMS was used for characterization of the glycol polymer surfactants, while GC-HRMS was used to obtain information about volatile organic compounds (benzene or naphthalene derivates) present in the PPPs. A total of nine adjuvants were characterized in the tested PPPs, belonging to naphthalene, benzene, sulphate and fatty acid esters of glycerol families. In addition, the estimation of compound concentrations was carried out using GC(LC)-HRMS, and finally, these concentration levels were related to their toxicity values.

Effect of oocyte morphology on post-warming survival and embryo development in vitrified autologous oocytes.

RESEARCH QUESTION: Does the presence of dysmorphisms affect post-warming survival and embryo development in vitrified autologous oocytes? DESIGN: A retrospective study comparing post-warming survival, fertilization and embryo development between morphologically normal (n = 269) and dysmorphic oocytes (n = 147). RESULTS: The survival rate was 81.4% in the morphologically normal oocytes and 87.1% in the dysmorphic oocyte group (OR 1.53; 95% CI 0.86 to 2.72). The fertilization rate was 69.9 versus 66.4% (OR 0.85; 95% CI 0.53 to 1.36), the proportion of good-quality embryos on day 3 was 30.3% versus 32.0% (OR 1.08; 95% CI 0.59 to 1.97) and the blastocyst formation rate was 54.5% versus 60.5% (OR 1.27; 95% CI 0.60 to 2.72) for the morphologically normal and the dysmorphic oocytes group, respectively. No statistical differences were found when the number and type of dysmorphism were analysed. CONCLUSION: Oocyte dysmorphisms did not seem to affect survival, fertilization and embryo development in vitrified autologous oocytes, and yielded comparable results to the morphologically normal oocytes.

Changes in Alcohol Intake During Pregnancy in Spain, 1980 to 2014.

BACKGROUND: Even small amounts of alcohol consumed during pregnancy can have adverse effects on the embryo and the fetus. We estimated how alcohol intake among pregnant women in Spain changed between 1980 and 2014, and identified factors associated with alcohol use. METHODS: Data came from the Spanish Collaborative Study of Congenital Malformations (ECEMC). The sample includes ECEMC's control mothers, 40,268 pregnant women from all regions of Spain. We classified alcohol consumption during pregnancy into 3 categories: no consumption; sporadic consumption of small amounts of alcohol; and regular consumption, or sporadic but in large quantities including drunkenness. Independent variables included sociodemographic factors, planned/unplanned pregnancy, maternal chronic diseases, gestational diabetes, and tobacco and illegal drug use during pregnancy. Trend analyses were performed using data from 1980 to 2014. The multinomial logistic regression models designed to identify associated factors differentiated between 2 periods: 1994 to 2004 and 2005 to 2014. RESULTS: Prevalence of alcohol consumption declined from 29.6% (95% CI: 27.1 to 32.2) in 1980 to 5.4% (95% CI: 3.7 to 7.6) in 2014, mostly due to the reduction in regular intake. This decline was especially acute between 1980 and 1994. Sporadic and regular consumption increased among women working outside the home, born outside Spain, those whose pregnancy was unplanned, and those reporting using tobacco or other drugs. Comparing 1994 to 2004 versus 2005 to 2014, a stronger association was observed between regular alcohol consumption and tobacco consumption in the latter period (interaction p = 0.003). CONCLUSIONS: Alcohol consumption among expectant mothers has declined substantially in the last 35 years. However, it is worth highlighting the significant and substantial associations between alcohol use and consumption of tobacco, which have become stronger in the most recent years.

Analysis of Mortality among Neonates and Children with Spina Bifida: An International Registry-Based Study, 2001-2012.

BACKGROUND: Medical advancements have resulted in better survival and life expectancy among those with spina bifida, but a significantly increased risk of perinatal and postnatal mortality for individuals with spina bifida remains. OBJECTIVES: To examine stillbirth and infant and child mortality among those affected by spina bifida using data from multiple countries. METHODS: We conducted an observational study, using data from 24 population- and hospital-based surveillance registries in 18 countries contributing as members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). Cases of spina bifida that resulted in livebirths or stillbirths from 20 weeks' gestation or elective termination of pregnancy for fetal anomaly (ETOPFA) were included. Among liveborn spina bifida cases, we calculated mortality at different ages as number of deaths among liveborn cases divided by total number of liveborn cases with spina bifida. As a secondary outcome measure, we estimated the prevalence of spina bifida per 10 000 total births. The 95% confidence interval for the prevalence estimate was estimated using the Poisson approximation of binomial distribution. RESULTS: Between years 2001 and 2012, the overall first-week mortality proportion was 6.9% (95% CI 6.3, 7.7) and was lower in programmes operating in countries with policies that allowed ETOPFA compared with their counterparts (5.9% vs. 8.4%). The majority of first-week mortality occurred on the first day of life. In programmes where information on long-term mortality was available through linkage to administrative databases, survival at 5 years of age was 90%-96% in Europe, and 86%-96% in North America. CONCLUSIONS: Our multi-country study showed a high proportion of stillbirth and infant and child deaths among those with spina bifida. Effective folic acid interventions could prevent many cases of spina bifida, thereby preventing associated childhood morbidity and mortality.

Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.

Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding.

Orai1 and TRPC1 Proteins Co-localize with CaV1.2 Channels to Form a Signal Complex in Vascular Smooth Muscle Cells.

Voltage-dependent CaV1.2 L-type Ca2+ channels (LTCC) are the main route for calcium entry in vascular smooth muscle cells (VSMC). Several studies have also determined the relevant role of store-operated Ca2+ channels (SOCC) in vascular tone regulation. Nevertheless, the role of Orai1- and TRPC1-dependent SOCC in vascular tone regulation and their possible interaction with CaV1.2 are still unknown. The current study sought to characterize the co-activation of SOCC and LTCC upon stimulation by agonists, and to determine the possible crosstalk between Orai1, TRPC1, and CaV1.2. Aorta rings and isolated VSMC obtained from wild type or smooth muscle-selective conditional CaV1.2 knock-out (CaV1.2KO) mice were used to study vascular contractility, intracellular Ca2+ mobilization, and distribution of ion channels. We found that serotonin (5-HT) or store depletion with thapsigargin (TG) enhanced intracellular free Ca2+ concentration ([Ca2+]i) and stimulated aorta contraction. These responses were sensitive to LTCC and SOCC inhibitors. Also, 5-HT- and TG-induced responses were significantly attenuated in CaV1.2KO mice. Furthermore, hyperpolarization induced with cromakalim or valinomycin significantly reduced both 5-HT and TG responses, whereas these responses were enhanced with LTCC agonist Bay-K-8644. Interestingly, in situ proximity ligation assay revealed that CaV1.2 interacts with Orai1 and TRPC1 in untreated VSMC. These interactions enhanced significantly after stimulation of cells with 5-HT and TG. Therefore, these data indicate for the first time a functional interaction between Orai1, TRPC1, and CaV1.2 channels in VSMC, confirming that upon agonist stimulation, vessel contraction involves Ca2+ entry due to co-activation of Orai1- and TRPC1-dependent SOCC and LTCC.

Congenital Anomalies: Cluster Detection and Investigation.

This work summarizes the main aspects to be considered around birth defects (or congenital anomalies) clusters. Most birth defects (BD), considered individually, fall into the definition of rare diseases (RD), according to their low frequency. Likewise, many RD are congenital, because their manifestations are present at birth or can be even evident before the delivery. It has been estimated that overall 7.9 million children are born each year with serious BD of genetic or partially genetic origin, and additional hundreds of thousands more are born with serious BD of post-conception origin.A "birth defect cluster" can be defined as an unusual aggregation of cases (grouped in place and time) that is suspected to be greater than expected, even though the expected number may not be known. These clusters are incidents or occurrences that let us turn the challenge of identifying the causal agent(s) involved in the origin of such clusters, into an opportunity to exert primary prevention, and thus achieve the ultimate goal of enabling infants being born healthy. Therefore, any program or system involved in BD surveillance and research should devote part of its activities to detect and investigate clusters, to ensure that such opportunity for primary prevention will be conveniently leveraged. Regardless the type of cluster, there are several phases that must be undertaken sequentially for proper control and the maximum benefit for the population: cluster detection, evaluation and investigation, management, adoption of preventive measures, and communication of the results to the public or target population.

Monitoring Huntington's Disease Mortality across a 30-Year Period: Geographic and Temporal Patterns.

BACKGROUND: Huntington's disease (HD) is a progressive neurodegenerative condition characterized by chorea, dystonia, behavioral disturbances and cognitive decline. The aim of this study is to assess temporal and spatial changes on mortality attributable to HD over 30 years in Spain. METHODS: HD data were extracted from the nationwide mortality registry for the period 1984-2013. Annual and 5-year gender- and age-specific rates adjusted for the standard European population were calculated. Geographic analysis was performed by districts from 1999 through 2013, and then estimated standardized mortality ratios (SMRs) and smoothed SMRs. RESULTS: There were 1,556 HD-related deaths across the study period. An increasing trend in age-adjusted HD mortality was in evidence, specifically from 1994 through 1998. On a year-by-year basis, age-adjusted mortality rates increased from 0.076 per 100,000 population in 1984 to 0.157 in 2013. Geographical differences among districts were evident in specific areas and in the southwest of Spain with a significantly higher HD mortality risk. CONCLUSION: HD mortality rising trends in Spain might be attributable to improvements in diagnosis leading to a rise in prevalence. Geographical variability in HD mortality could be related to regional differences in disease prevalence, health-care disparities, or other factors which call for in-depth assessment in future studies.

C-H Activation in Primary 3-Phenylpropylamines: Synthesis of Seven-Membered Palladacycles through Orthometalation. Stoichiometric Preparation of Benzazepinones and Catalytic Synthesis of Ureas.

The dimeric cyclometalated complexes [Pd2{κ(2)C,N-C6H4CH2CH2C(R)(Me)NH2-2}2(µ-Cl)2] (R = Me (1a), H (1b)) are prepared by reacting 1,1-dimethyl-3-phenylpropylammonium or 1-methyl-3-phenylpropylammonium triflate with Pd(OAc)2 in a 1:1 molar ratio and subsequent treatment with excess NaCl. The mononuclear derivatives [Pd{κ(2)C,N-C6H4CH2CH2C(R)(Me)NH2-2}Cl(L)] (L = PPh3, R = Me (3a), H (3b); L = 4-picoline (4-pic), R = Me (4a), H (4b)) were prepared from 1a,b by splitting the chloro bridges with the neutral ligands L. A conformational analysis of the mononuclear palladacycles in solution has been carried out. Insertion of CO takes place into the Pd-C bond of complexes 1a,b, affording Pd(0) and the tetrahydro-benzazepinone 5a or 5b, which possesses potential pharmacological interest. Additionally, the triflate salt A or B undergoes catalytic carbonylation with CO to afford the corresponding N,N'-dialkylurea, using Pd(OAc)2/Cu(OAc)2, in boiling acetonitrile. The crystal structures of 3a·(1)/2H2O, 3b, 4b·CHCl3, and 5a were determined by X-ray diffraction studies.