Incidence and prevalence of upper-extremity musculoskeletal disorders. A systematic appraisal of the literature

BACKGROUND: A systematic appraisal of the worldwide incidence and prevalence rates of UEDs available in scientific literature was executed to gauge the range of these estimates in various countries and to determine whether the rates are increasing in time. METHODS: Studies that recruited at least 500 people, collected data by using questionnaires, interviews and/or physical examinations, and reported incidence or prevalence rates of the whole upper-extremity including neck, were included. RESULTS: No studies were found with regard to the incidence of UEDs and 13 studies that reported prevalence rates of UEDs were included. The point prevalence ranged from 1.6–53%; the 12-months prevalence ranged from 2.3–41%. One study reported on the lifetime prevalence (29%). We did not find evidence of a clear increasing or decreasing pattern over time. The case definitions for UEDs used in the studies, differed enormously. Therefore, it was not possible to pool the data. CONCLUSION: There are substantial differences in reported prevalence rates on UEDs. Main reason for this is the absence of a universally accepted way of labelling or defining UEDs. If we want to make progress in this field, the first requirement is to agree on unambiguous terminology and classification of EUDs

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Germline selection shapes human mitochondrial DNA diversity.

Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.NIHR, Wellcome Trust, MRC, Genomics Englan

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Experimental and theoretical comparison between M(cp)Cl3Ln systems of NbIV and MoIV (cp = η-C5H5)

International audienceThe controlled sodium reduction of Nb(cp)Cl 4 L (cp = η-C 5 H 5 ; L = PMe 3 , PMe 2 Ph or PMePh 2 ) or Nb(η-C 5 Me 5 )Cl 4 in the presence of PMe 3 afforded the mononuclear 15-electron complexes Nb(cp)Cl 3 L and Nb(η-C 5 Me 5 )Cl 3 (PMe 3 ), respectively. Reduction of Nb(cp)Cl 4 in the presence of an excess of L for PMe 2 Ph and PMePh 2 afforded solids that contain mainly the 17-electron Nb(cp)Cl 3 L 2 species but are contaminated by the mono-L derivatives. A UV/VIS investigation of the solution equilibrium between Nb(cp)Cl 3 (PMe 2 Ph) 2 and Nb(cp)Cl 3 (PMe 2 Ph) plus free PMe 2 Ph afforded an enthalpy of 19.0 ± 1.6 kcal mol -1 and an entropy of 45 ± 5 cal K -1 mol -1 for the ligand dissociation process. A comparative study of the equilibrium between Mo(cp)Cl 3 (PMe 2 Ph) 2 and Mo(cp)Cl 3 (PMe 2 Ph) plus free PMe 2 Ph cannot be carried out because the equilibration is too slow at room temperature and because of thermal decomposition with ring loss at high temperature. Theoretical calculations at the second-order Møller-Plesset perturbation (MP2) level on the M(cp)Cl 3 (PH 3 ) n (M = Nb or Mo, n = 1 or 2) model systems afforded geometries in good agreement with experimental examples. The calculated PH 3 dissociation energy for M = Nb of 21.3 kcal mol -1 is in good agreement with experiment. For M = Mo, the more saturated complex is stabilized by 32.8 kcal mol -1 relative to the excited 1 A′ state and by 23.5 kcal mol -1 relative to the ground 3 A″ state. Therefore, the regain of pairing energy upon PH 3 dissociation from Mo(cp)Cl 3 (PH 3 ) 2 provides a calculated stabilization for the 16-electron monophosphine complex of 9.3 kcal mol -1 . The observed variations of bonding parameters upon metal change from Nb to Mo and a natural population analysis suggest that the main reason for a greater Mo–PH 3 bonding interaction is the greater extent of both M–P σ bonding and π back bonding for the d 2 metal relative to the d 1 metal

Spin State Change in Organometallic Reactions. Experimental and MP2 Theoretical Studies of the Thermodynamics and Kinetics of the CO and N 2 Addition to Spin Triplet Cp*MoCl(PMe 3 ) 2

International audienceThe first comparative kinetic study of the addition of the isolobal and isosteric CO and N2 ligands to a spin triplet organometallic compound, i.e. Cp*MoCl(PMe3)2, is reported. A fast and quantitative addition process occurred when interacting Cp*MoCl(PMe3)2 with CO, which is followed by a subsequent slower process involving PMe3 replacement and formation of Cp*MoCl(CO)2(PMe3). The N2 addition, on the other hand, is much slower and proceeds incompletely to an equilibrium position. The temperature dependence of this equilibrium gives the parameters for the reaction ΔH = −22.8 ± 2.1 kcal/mol and ΔS = −67 ± 7 cal·mol-1·K-1. The activation parameters for the CO addition are ΔH⧧ = 5.0 ± 0.3 kcal/mol and ΔS⧧ = −35 ± 4 cal·mol-1·K-1, while the activation parameters for the N2 addition are ΔH⧧ = 14.0 ± 1.0 kcal/mol and ΔS⧧ = −20 ± 3 kcal/mol. Extrapolation of the rates to 25 °C indicates a difference of more than three orders of magnitude:  kCO = 29 ± 3 M-1 s-1 and kN2 = 0.014 ± 0.001 M-1 s-1. Theoretical calculations with full geometry optimization at the MP2 level have been carried out on the model systems CpMoCl(PH3)2 + L (L = CO or N2), the calculated energetics of the system being in agreement with experiment. The 16-electron CpMoCl(PH3)2 molecule is found to be more stable in the spin triplet state, the excited 1A‘ state being 10.9 kcal/mol higher in energy. The Mo−L bond formation is calculated to be exothermic by 27.9 kcal/mol for L = N2 and by 60.0 kcal/mol for L = CO. Calculations along the L addition coordinate show an initial ligand rearrangement related barrier for both the spin singlet and the spin triplet surfaces. After overcoming this barrier, the spin singlet curve descends in energy earlier for the CO vs the N2 addition as expected from greater diffuseness of the CO donor and acceptor orbitals. As the N2 ligand continues to approach the metal, the 3A‘‘ surface becomes increasingly repulsive whereas the addition of CO leads to an attractive interaction and a bound triplet state

Structure of the 17-electron Cp*MoCl2(dppe): an unexpected trans geometry in the solid state

International audienceCompound Cp*MoCl2(dppe) crystallizes in the monoclinic space group P21/c, a=16.9063(10), b=11.0118(8), c=18.6128(14) Å, β=111.713(6)°, V=3219.3(4) Å3, Z=4, Dcalc=1.445 Mg m−3, μ(Mo Kα)=0.698 mm−1, R1=0.0448, wR2=0.0906 for all data, R1=0.0337, wR2=0.0839 for 4754 data with I>2σ(I). The geometry of the compound is a four-legged piano stool as typically found for this class of compounds, but the dppe ligand occupies relative trans position whereas the previously reported CpMoBr2(dppe) has the more common cis geometry. EPR spectroscopic investigations indicate that a mixture of isomers is present in solution and that the relative amounts of the isomers are both solvent and temperature dependent

Theoretical Study of the 15- and 17-Electron Structures of Cyclopentadienylchromium(III) and Cyclopentadienylmolybdenum(III) Complexes. Dichloride and Dimethyl Compounds

International audienceThe structure and the energetics of the model systems CpMX2(PH3) + PH3 ⇄ CpMX2(PH3)2 (Cp = cyclopentadienyl; M = Cr, Mo; X = Cl, CH3) are studied by performing Møller−Plesset second order (MP2) and density functional theory (DFT) calculations. Extended basis sets are employed in the geometry optimizations. The results indicate that the structural preference can be traced back to the competition between electron pairing stabilization and M−P bond dissociation energy along the spin doublet surface. At all levels of calculation, the energy splitting, a measure of the cost of pairing the electron during the promotion process from the quartet ground state to the excited doublet state for CpCrX2(PH3), is found to be on average 15−20 kcal/mol greater than the energy gain associated with the formation of the new Cr−PH3 bond along the spin doublet surface. For the analogous Mo chloride system the reverse appears to be true, the products with higher coordination being energetically favored by 10−12 kcal/mol. These data are in agreement with experimental evidence