Biomedical subjects

David Mann

Publications and source records attributed to David Mann.

At least 19 recordsLinked to original sources

PubMed2011

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

ATP-Binding Cassette Transporters↗

PubMed2006

Effects of cardiac resynchronization therapy with or without a defibrillator on survival and hospitalizations in patients with New York Heart Association class IV heart failure.

BACKGROUND: Cardiac resynchronization therapy (CRT) alone or combined with an implantable defibrillator (CRT-D) has been shown to improve exercise capacity and quality of life and to reduce heart failure (HF) hospitalizations and mortality in patients with New York Heart Association (NYHA) class III and IV HF. There is concern that the device procedure may destabilize these very ill class IV patients. We sought to examine the outcomes of NYHA class IV patients enrolled in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial to assess the potential benefits of CRT and CRT-D. METHODS AND RESULTS: The COMPANION trial randomized 1520 patients with NYHA class III and IV HF to optimal medical therapy, CRT, or CRT-D. In the class IV patients (n=217), the primary end point of time to death or hospitalization for any cause was significantly improved by both CRT (hazard ratio [HR], 0.64; 95% CI, 0.43 to 0.94; P=0.02) and CRT-D (HR, 0.62; 95% CI, 0.42 to 0.90; P=0.01). Time to all-cause death and HF hospitalization was also significantly improved in both CRT (HR, 0.57; 95% CI, 0.37 to 0.87; P=0.01) and CRT-D (HR, 0.49; 95% CI, 0.32 to 0.75; P=0.001) Time to all-cause death trended to an improvement in both CRT (HR, 0.67; 95% CI, 0.41 to 1.10; P=0.11) and CRT-D (HR, 0.63; 95% CI, 0.39 to 1.03; P=0.06). Time to sudden death appeared to be significantly reduced in the CRT-D group (HR, 0.27; 95% CI, 0.08 to 0.90; P=0.03). There was a nonsignificant reduction in time to HF deaths for both CRT (HR, 0.68; 95% CI, 0.34 to 1.37; P=0.28) and CRT-D (HR, 0.79; 95% CI, 0.41 to 1.52; P=0.48). CONCLUSIONS: CRT and CRT-D significantly improve time to all-cause mortality and hospitalizations in NYHA class IV patients, with a trend for improved mortality. These devices should be considered in ambulatory NYHA class IV HF patients similar to those enrolled in COMPANION.

Aged↗

PubMed2006

Sequence analysis of all identified open reading frames on the frontal temporal dementia haplotype on chromosome 3 fails to identify unique coding variants except in CHMP2B.

A segregating splice site mutation in the CHMP2B gene has been shown in the single Danish family which has been reported to show linkage between dementia and chromosome 3 markers. Despite extensive analysis, no other segregating mutations have been found in other kindreds, although some point variants have been found both in sporadic cases and in controls. We recently found a premature stop codon in a person without dementia and this led us to investigate whether the splice site mutation in the Danish kindred did not explain the disease, but rather was hitchhiking on the segregating disease haplotype. We determined to test this possibility by sequencing every other gene on the haplotype in a case from the kindred. We did not find any other unique variants. The implications of these findings for the likely mode of pathogenesis of frontal temporal dementia are discussed.

Base Sequence↗

PubMed2006

FeCo/graphitic-shell nanocrystals as advanced magnetic-resonance-imaging and near-infrared agents.

Nanocrystals with advanced magnetic or optical properties have been actively pursued for potential biological applications, including integrated imaging, diagnosis and therapy. Among various magnetic nanocrystals, FeCo has superior magnetic properties, but it has yet to be explored owing to the problems of easy oxidation and potential toxicity. Previously, FeCo nanocrystals with multilayered graphitic carbon, pyrolytic carbon or inert metals have been obtained, but not in the single-shelled, discrete, chemically functionalized and water-soluble forms desired for biological applications. Here, we present a scalable chemical vapour deposition method to synthesize FeCo/single-graphitic-shell nanocrystals that are soluble and stable in water solutions. We explore the multiple functionalities of these core-shell materials by characterizing the magnetic properties of the FeCo core and near-infrared optical absorbance of the single-layered graphitic shell. The nanocrystals exhibit ultra-high saturation magnetization, r1 and r2 relaxivities and high optical absorbance in the near-infrared region. Mesenchymal stem cells are able to internalize these nanoparticles, showing high negative-contrast enhancement in magnetic-resonance imaging (MRI). Preliminary in vivo experiments achieve long-lasting positive-contrast enhancement for vascular MRI in rabbits. These results point to the potential of using these nanocrystals for integrated diagnosis and therapeutic (photothermal-ablation) applications.

Animals↗

PubMed2006

Selective etching of metallic carbon nanotubes by gas-phase reaction.

Metallic and semiconducting carbon nanotubes generally coexist in as-grown materials. We present a gas-phase plasma hydrocarbonation reaction to selectively etch and gasify metallic nanotubes, retaining the semiconducting nanotubes in near-pristine form. With this process, 100% of purely semiconducting nanotubes were obtained and connected in parallel for high-current transistors. The diameter- and metallicity-dependent "dry" chemical etching approach is scalable and compatible with existing semiconductor processing for future integrated circuits.

Journal Article↗

PubMed2006

TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

Ubiquitin-positive tau-negative neuronal cytoplasmic inclusions and dystrophic neurites are common pathological features in frontotemporal lobar degeneration (FTLD) with or without symptoms of motor neuron disease and in amyotrophic lateral sclerosis (ALS). Using biochemical and immunohistochemical analyses, we have identified a TAR DNA-binding protein of 43 kDa (TDP-43), a nuclear factor that functions in regulating transcription and alternative splicing, as a component of these structures in FTLD. Furthermore, skein-like inclusions, neuronal intranuclear inclusions, and glial inclusions in the spinal cord of ALS patients are also positive for TDP-43. Dephosphorylation treatment of the sarkosyl insoluble fraction has shown that abnormal phosphorylation takes place in accumulated TDP-43. The common occurrence of intracellular accumulations of TDP-43 supports the hypothesis that these disorders represent a clinicopathological entity of a single disease, and suggests that they can be newly classified as a proteinopathy of TDP-43.

Aged↗

PubMed2006

Biomechanical and clinical evaluation of a novel technique for surgical repair of spondylolysis in adolescents.

STUDY DESIGN: A biomechanical comparison of a novel spondylolysis repair technique method to established spondylolysis repair constructs accompanied by a case series of 5 adolescent patients with spondylolysis treated with this technique. OBJECTIVES: To provide retrospective data on these patients treated with an intralaminar link construct, as well as present comparative biomechanical data on this construct and that of an intact spine, lytic spine, and known methods of repair. SUMMARY OF BACKGROUND DATA: Spondylolysis is a unilateral or bilateral defect in the pars interarticularis, and most commonly occurs at L5 and less frequently at L4. Surgical treatment may be indicated in patients with persistent pain and impairment despite conservative treatment. Unlike posterolateral fusion, direct pars repairs may benefit adolescents by sparing motion segments. METHODS: Biomechanical testing of 5 cadaver lumbar spines was completed to provide comparative biomechanical data on this intralaminar link construct, and that of an intact spine, destabilized spondylolytic spine, Scott wiring technique, pedicle screw-cable system, and the pedicle screw-rod-hook constructs. There were 5 adolescent patients with spondylolysis treated with multiaxial pedicle screws, with a modular linkage that passes beneath the spinous process of the same segment. RESULTS: Biomechanical evaluation of the intralaminar link construct showed the least displacement (across pars defect) followed by the pedicle screw-rod-hook system, Scott wiring, and, finally, the pedicle screw-cable system. Interbody flexion and extension stiffness was highest for pedicle screw-rod-hook followed by normal, intralaminar link construct, Scott wiring, pedicle screw-cable system, and, finally, the destabilized spine. Interbody torsional stiffness was highest for pedicle screw-rod-hook followed by intralaminar link construct, normal, pedicle screw-cable system, Scott wiring, and lytic spine. Retrospective follow-up (average 4.6 years) of patients showed complete radiographic healing or pain relief in all 5 patients. There was 1 patient with solid healing of L3 spondylolysis who later had onset pain despite evidence of solid fusion on computerized tomographic images. In this patient, pain resolved after implant removal. CONCLUSIONS: Biomechanical evaluation of the intralaminar link construct showed excellent stability of a spondylolytic defect in comparison to established methods. Clinical follow-up of this method reflects the results of biomechanical testing with excellent clinical results.

Adolescent↗

PubMed2006

Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.

Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years. A large proportion of FTD patients (35-50%) have a family history of dementia, consistent with a strong genetic component to the disease. In 1998, mutations in the gene encoding the microtubule-associated protein tau (MAPT) were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17). The neuropathology of patients with defined MAPT mutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau. However, in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21 (D17S1787-D17S806), mutations in MAPT have not been found and the patients consistently lack tau-immunoreactive inclusion pathology. In contrast, these patients have ubiquitin (ub)-immunoreactive neuronal cytoplasmic inclusions and characteristic lentiform ub-immunoreactive neuronal intranuclear inclusions. Here we demonstrate that in these families, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles. PGRN is located 1.7 Mb centromeric of MAPT on chromosome 17q21.31 and encodes a 68.5-kDa secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation. PGRN has also been strongly linked to tumorigenesis. Moreover, PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt-Jakob disease, motor neuron disease and Alzheimer's disease. Our results identify mutations in PGRN as a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival.

Cell Survival↗

PubMed2006

Characterization of Abeta11-40/42 peptide deposition in Alzheimer's disease and young Down's syndrome brains: implication of N-terminally truncated Abeta species in the pathogenesis of Alzheimer's disease.

Senile plaques (SPs), one of two defining lesions of Alzheimer's disease (AD), are composed of a mixture of full-length Abeta1-40/42, and N- or C-terminally truncated Abeta peptides, including Abeta11-40/42. Sequential proteolysis of amyloid precursor protein (APP) by beta- and gamma-secretases produces Abeta1-40/42, but beta-site APP-cleaving enzyme 1 (BACE1), the major beta-secretase, also generates Abeta11-40/42, and BACE1 overexpression in cultured cells results primarily in secretion of Abeta11-40/42. The ratio of Abeta11-40/42 to Abeta1-40/42 depends on the ratio of BACE1 to APP, and Abeta11-40/42 can be generated from both full-length APP and its carboxy-terminal fragment (C99). Here, we investigated the role of Abeta11-40/42 in the pathogenesis of AD and Down's syndrome (DS) brains. We demonstrated significant amount of Abeta11-42 in DS brains by Western blots. While pyroAbeta11-42-modified Abeta species existed predominantly in mature SP cores in AD brain sections, both unmodified free Abeta11-40 and pyro-modified Abeta11-40 are detected in vascular amyloid deposits by immunohistochemistry. Using novel ELISAs for quantifying free Abeta11-40/42 and pyroAbeta11-40/42, we showed that insoluble Abeta11-42 predominated in extracts of AD and DS brains. This is the first systematic study of Abeta11-40/42 in neurodegenerative Abeta amyloidosis implicating Abeta11-40/42 in SP formation of AD and DS brains. The detection of Abeta11-42 in young DS brain suggests an early role for this N-terminally truncated Abeta peptide in the pathogenesis of SPs in AD and DS.

Adolescent↗

PubMed2006

Hydrogenation and hydrocarbonation and etching of single-walled carbon nanotubes.

We present a systematic experimental investigation of the reactions between hydrogen plasma and single-walled carbon nanotubes (SWNTs) at various temperatures. Microscopy, infrared (IR) and Raman spectroscopy, and electrical transport measurements are carried out to investigate the properties of SWNTs after hydrogenation. Structural deformations, drastically reduced electrical conductance, and an increased semiconducting nature of SWNTs upon sidewall hydrogenation are observed. These changes are reversible upon thermal annealing at 500 degrees C via dehydrogenation. Harsh plasma or high temperature reactions lead to etching of nanotubes likely via hydrocarbonation. Smaller SWNTs are markedly less stable against hydrocarbonation than larger tubes. The results are fundamental and may have implications to basic and practical applications including hydrogen storage, sensing, band gap engineering for novel electronics, and new methods of manipulation, functionalization, and etching of nanotubes.

Journal Article↗

PubMed2006

Association study of the Ubiquilin gene with Alzheimer's disease.

Recently, the ubiquilin 1 gene has been proposed as a major candidate gene for AD. Here, we have investigated the potential impact of the UBQ-8i polymorphism (rs12344615) within this gene on the risk of developing AD. No association of this polymorphism with the disease was observed in a large French case-control population. Furthermore, no relationship between this polymorphism and Abeta load or degree of neurofibrillary degeneration in the brains of 114 patients with AD was detected.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Thermally and molecularly stimulated relaxation of hot phonons in suspended carbon nanotubes.

The high-bias electrical transport properties of suspended metallic single-walled carbon nanotubes (SWNTs) are investigated at various temperatures in vacuum, in various gases, and when coated with molecular solids. It is revealed that nonequilibrium optical phonon effects in suspended nanotubes decrease as the ambient temperature increases. Gas molecules surrounding suspended SWNTs assist the relaxation of hot phonons and afford enhanced current flow along nanotubes. Molecular solids of carbon dioxide frozen onto suspended SWNTs quench the nonequilibrium phonon effect. The discovery of strong environmental effects on high current transport in nanotubes is important to high performance nanoelectronics applications of 1D nanowires in general.

Journal Article↗

PubMed2006

CHMP2B mutations are not a common cause of frontotemporal lobar degeneration.

It was reported in 1995 that a large Danish family with familial frontotemporal dementia (FTD) was linked to the pericentromeric region of chromosome 3. It has since been claimed that a mutation in the splice acceptor site of exon 6 of CHMP2B is the pathogenic variant in this family. In order to determine whether CHMP2B mutations are a common cause of disease in patients with frontotemporal lobar degeneration (FTLD) we sequenced all exons and flanking regions of CHMP2B in 141 familial FTLD probands from the USA and UK. We failed to find a single pathogenic variant in any case. Polymorphisms were detected but were present in control samples. We conclude that mutations in CHMP2B are a rare cause of familial FTLD and may be specific to the Danish pedigree.

Dementia↗

PubMed2006

Thermal conductance of an individual single-wall carbon nanotube above room temperature.

The thermal properties of a suspended metallic single-wall carbon nanotube (SWNT) are extracted from its high-bias (I-V) electrical characteristics over the 300-800 K temperature range, achieved by Joule self-heating. The thermal conductance is approximately 2.4 nW/K, and the thermal conductivity is nearly 3500 Wm(-1)K(-1) at room temperature for a SWNT of length 2.6 mum and diameter 1.7 nm. A subtle decrease in thermal conductivity steeper than 1/T is observed at the upper end of the temperature range, which is attributed to second-order three-phonon scattering between two acoustic modes and one optical mode. We discuss sources of uncertainty and propose a simple analytical model for the SWNT thermal conductivity including length and temperature dependence.

Journal Article↗

PubMed2005

Ultra-high-yield growth of vertical single-walled carbon nanotubes: Hidden roles of hydrogen and oxygen.

An oxygen-assisted hydrocarbon chemical vapor deposition method is developed to afford large-scale, highly reproducible, ultra-high-yield growth of vertical single-walled carbon nanotubes (V-SWNTs). It is revealed that reactive hydrogen species, inevitable in hydrocarbon-based growth, are damaging to the formation of sp(2)-like SWNTs in a diameter-dependent manner. The addition of oxygen scavenges H species and provides a powerful control over the C/H ratio to favor SWNT growth. The revelation of the roles played by hydrogen and oxygen leads to a unified and universal optimum-growth condition for SWNTs. Further, a versatile method is developed to form V-SWNT films on any substrate, lifting a major substrate-type limitation for aligned SWNTs.

Journal Article↗

PubMed2005

Negative differential conductance and hot phonons in suspended nanotube molecular wires.

Freely suspended metallic single-walled carbon nanotubes (SWNTs) exhibit reduced current carrying ability compared to those lying on substrates, and striking negative differential conductance at low electric fields. Theoretical analysis reveals significant self-heating effects including electron scattering by hot nonequilibrium optical phonons. Electron transport characteristics under strong self-heating are exploited for the first time to probe the thermal conductivity of individual SWNTs (approximately 3600 W m-1 K-1 at T=300 K) up to approximately 700 K, and reveal a 1/T dependence expected for umklapp phonon scattering at high temperatures.

Journal Article↗

PubMed2005

Association study of the vascular endothelial growth factor gene with the risk of developing Alzheimer's disease.

Numerous observations indicate that cerebrovascular dysfunction contributes to cognitive decline and neurodegeneration in AD. Converging evidence points to a pivotal role for vascular endothelial growth factor (VEGF) in neuronal protection, and the lack of activity of this in neurodegenerative disorders. The VEGF gene is located at 6p21.3, a site several studies have shown to have significant linkage with AD, and a functional polymorphism within the VEGF promoter may alter the risk of developing AD. We assessed the potential impact of this polymorphism on the risk of developing AD in a large French case-control population, and investigated its association with the severity of brain vascular lesions (arteriosclerosis, white matter loss and cerebral amyloid angiopathy) in several brain regions (frontal, temporal, parietal and occipital cortex) in AD. No association of the VEGF promoter polymorphism with the risk of developing AD was observed. No relationship between this polymorphism and vascular pathological changes in AD was detected. Our data indicate that although this polymorphism is functional, it does not confer greater risk for AD, nor modulate the extent of vascular pathology.

Aged↗

PubMed2005

On the origin of preferential growth of semiconducting single-walled carbon nanotubes.

A correlation is observed between the diameters (d) of single-walled carbon nanotubes and the percentages of metallic and semiconducting tubes synthesized at 600 degrees C by plasma-assisted chemical vapor deposition. Small tubes (d approximately 1.1 nm) show semiconductor percentages that are much higher than expected for a random chirality distribution. Density functional theory calculations reveal differences in the heat of formation energies for similar-diameter metallic, quasi-metallic, and semiconducting nanotubes. Semiconducting tubes exhibit the lowest energies and the stabilization scales with approximately 1/d(2). This could be a thermodynamic factor in the preferential growth of small semiconducting nanotubes.

Journal Article↗