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1.  Utility of testing for apraxia and associated features in dementia 
Existing literature suggests that the presence or absence of apraxia and associated parietal deficits may be clinically relevant in differential diagnosis of dementia syndromes.
This study investigated the profile of these features in Alzheimer's disease (AD) and frontotemporal dementia (FTD) spectrum disorders, at first presentation.
Retrospective case note analysis was undertaken in 111 patients who presented to the Oxford Cognitive Disorders Clinic, Oxford, UK, including 29 amnestic AD, 12 posterior cortical atrophy (PCA), 12 logopenic primary progressive aphasia (lvPPA), 20 behavioural variant FTD (bvFTD), 7 non-fluent variant PPA (nfvPPA), 6 semantic variant PPA (svPPA) and 25 patients with subjective cognitive impairment (SCI). The clinical features of interest were: limb apraxia, apraxia of speech (AOS), and left parietal symptoms of dyslexia, dysgraphia, and dyscalculia.
The prevalence of limb apraxia was highest in PCA, amnestic AD, lvPPA and nfvPPA. AOS was only observed in nfvPPA. Associated parietal features were more prevalent in AD spectrum than FTD spectrum disorders. Group comparisons between key differential diagnostic challenges showed that lvPPA and nfvPPA could be significantly differentiated on the presence of left parietal features and AOS, and amnestic AD could be differentiated from bvFTD, svPPA and SCI by limb apraxia. Regression analysis showed that limb apraxia could successfully differentiate between AD and FTLD spectrum disorders with 83% accuracy.
Disease-specific profiles of limb apraxia and associated deficits can be observed. FTD and AD spectrum disorders can be difficult to differentiate due to overlapping cognitive symptoms, and measures of apraxia, in particular, appear to be a promising discriminator.
PMCID: PMC5099316  PMID: 27251676
2.  The Dartmouth Center for Cancer Nanotechnology Excellence: magnetic hyperthermia 
Nanomedicine (London, England)  2015;10(11):1685-1692.
The Dartmouth Center for Cancer Nanotechnology Excellence – one of nine funded by the National Cancer Institute as part of the Alliance for Nanotechnology in Cancer – focuses on the use of magnetic nanoparticles for cancer diagnostics and hyperthermia therapy. It brings together a diverse team of engineers and biomedical researchers with expertise in nanomaterials, molecular targeting, advanced biomedical imaging and translational in vivo studies. The goal of successfully treating cancer is being approached by developing nanoparticles, conjugating them with Fabs, hyperthermia treatment, immunotherapy and sensing treatment response.
PMCID: PMC4493741  PMID: 26080693
immunotherapy; magnetic hyperthermia; magnetic nanoparticles
3.  Microemulsion Synthesis of Iron Core/Iron Oxide Shell Magnetic Nanoparticles and Their Physicochemical Properties 
Iron magnetic nanoparticles were synthesized under an inert atmosphere via the reaction between FeCl3 and NaBH4 in droplets of water in a microemulsion consisting of octane with cetyl trimethylammonium bromide and butanol as surfactants. A thin Fe3O4 layer was produced on the iron nanoparticles using slow, controlled oxidation at room temperature. A silica shell was deposited on the Fe3O4 using 3-aminopropyltrimethoxysilane following the method of Zhang et al. [Mater. Sci. Eng. C 30 (2010) 92–97]. The structure and chemistry of the resulting nanoparticles were studied using variety of methods and their magnetic properties were determined. The diameter of the iron core was typically 8–16 nm, while the thickness of the Fe3O4 shell was 2–3 nm. The presence of the silica layer was confirmed using Fourier transform infra-red spectroscopy and the number of NH2-groups on each nanoparticle was determined based on colorimetric tests using ortho-phthalaldehyde.
PMCID: PMC4633094  PMID: 26549922
microemulsion synthesis; magnetic nanoparticles; Fe/Fe oxide; magnetic properties; size distribution
4.  Antibody-mediated targeting of iron oxide nanoparticles to the folate receptor alpha increases tumor cell association in vitro and in vivo 
Active molecular targeting has become an important aspect of nanoparticle development for oncology indications. Here, we describe molecular targeting of iron oxide nanoparticles (IONPs) to the folate receptor alpha (FOLRα) using an engineered antibody fragment (Ffab). Compared to control nanoparticles targeting the non-relevant botulinum toxin, the Ffab-IONP constructs selectively accumulated on FOLRα-overexpressing cancer cells in vitro, where they exhibited the capacity to internalize into intracellular vesicles. Similarly, Ffab-IONPs homed to FOLRα-positive tumors upon intraperitoneal administration in an orthotopic murine xenograft model of ovarian cancer, whereas negative control particles showed no detectable tumor accumulation. Interestingly, Ffab-IONPs built with custom 120 nm nanoparticles exhibited lower in vitro targeting efficiency when compared to those built with commercially sourced 180 nm nanoparticles. In vivo, however, the two Ffab-IONP platforms achieved equivalent tumor homing, although the smaller 120 nm IONPs were more prone to liver sequestration. Overall, the results show that Ffab-mediated targeting of IONPs yields specific, high-level accumulation within cancer cells, and this fact suggests that Ffab-IONPs could have future utility in ovarian cancer diagnostics and therapy.
PMCID: PMC4388088  PMID: 25878495
nanoparticle targeting; antibody fragment; biodistribution; ovarian cancer
5.  Understanding mNP Hyperthermia for cancer treatment at the cellular scale 
The use of magnetic nanoparticles (mNP’s) to induce local hyperthermia has been emerging in recent years as a promising cancer therapy, in both a stand-alone and combination treatment setting. Studies have shown that cancer cells associate with, internalize, and aggregate mNP’s more preferentially than normal cells. Once the mNP’s are delivered inside the cells, a low frequency (30 kHz–300 kHz) alternating electromagnetic field is used to activate the mNP’s. The nanoparticles absorb the applied field and provide localized heat generation at nano-micron scales. It has been shown experimentally that mNP’s exhibit collective behavior when in close proximity. Although most prevailing mNP heating models assume there is no magnetic interaction between particles, our data suggests that magnetic interaction effects due to mNP aggregation are often significant; In the case of multi-crystal core particles, interaction is guaranteed. To understand the physical phenomena responsible for this effect, we modeled electromagnetic coupling between mNP’s in detail. The computational results are validated using data from the literature as well as measurements obtained in our lab. The computational model presented here is based on a method of moments technique and is used to calculate magnetic field distributions on the nanometer scale, both inside and outside the mNP.
PMCID: PMC4169898  PMID: 25249755
Magnetic nanoparticle; hyperthermia; cancer therapy; magnetic interaction; interparticle interaction; collective behavior; method of auxiliary sources; multi-scale modeling
6.  Development of Novel Magnetic Nanoparticles for Hyperthermia Cancer Therapy 
Proceedings of SPIE  2011;7901:790115-.
Advances in magnetic nanoparticle hyperthermia are opening new doors in cancer therapy. As a standalone or adjuvant therapy this new modality has the opportunity significantly advance thermal medicine. Major advantages of using magnetic magnetite (Fe3O4) nanoparticles are their highly localized power deposition and the fact that the alternating magnetic fields (AMF) used to excite them can penetrate deeply into the body without harmful effect. One limitation, however, which hinders the technology, is the problem of inductive heating of normal tissue by the AMF if the frequency and fields strength are not appropriately matched to the tissue. Restricting AMF amplitude and frequency limits the heat dose which can be selectively applied to cancerous tissue via the magnetic nanoparticle, thus lowering therapeutic effect. In an effort to address this problem, particles with optimized magnetic properties must be developed. Using particles with higher saturation magnetizations and coercivity will enhance hysteresis heating increasing particle power density at milder AMF strengths and frequencies. In this study we used oil in water microemulsions to develop nanoparticles with zero-valent Fe cores and magnetite shells. The superior magnetic properties of zero-valent Fe give these particles the potential for improved SAR over pure magnetite particles. Silane and subsequently dextran have been attached to the particle surface in order to provide a biocompatible surfactant coating. The heating capability of the particles was tested in-vivo using a mouse tumor model. Although we determined that the final stage of synthesis, purification of the dextran coated particles, permits significant corrosion/oxidation of the iron core to hematite, the particles can effectively heat tumor tissue. Improving the purification procedure will allow the generation Fe/Fe3O4 with superior SAR values.
PMCID: PMC3947375  PMID: 24619487
Magnetic Nanoparticle; Ferrofluid; Hyperthermia; Tumor; Cancer; Synthesis
Nano LIFE  2010;1(01n02):10.1142/S1793984410000067.
The activation of magnetic nanoparticles (mNPs) by an alternating magnetic field (AMF) is currently being explored as technique for targeted therapeutic heating of tumors. Various types of superparamagnetic and ferromagnetic particles, with different coatings and targeting agents, allow for tumor site and type specificity. Magnetic nanoparticle hyperthermia is also being studied as an adjuvant to conventional chemotherapy and radiation therapy. This review provides an introduction to some of the relevant biology and materials science involved in the technical development and current and future use of mNP hyperthermia as clinical cancer therapy.
PMCID: PMC3859910  PMID: 24348868
Magnetic nanoparticle; hyperthermia; cancer; tumor
9.  Recessive Mutations in SPTBN2 Implicate β-III Spectrin in Both Cognitive and Motor Development 
PLoS Genetics  2012;8(12):e1003074.
β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5), an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as “Lincoln ataxia,” because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1). In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome.
Author Summary
β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Mutations in β-III spectrin cause spinocerebellar ataxia type 5 (SCA5), sometimes called Lincoln ataxia because it was first described in the relatives of United States President Abraham Lincoln. This is generally an adult-onset progressive cerebellar disorder. Recessive mutations have not previously been described in any of the brain spectrins. We identified a homozygous mutation in SPTBN2, which causes a more severe disorder than SCA5, with a developmental cerebellar ataxia, which is present from childhood; in addition there is marked cognitive impairment. We call this novel condition SPARCA1 (Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1). This condition could be caused by two separate gene mutations; but we show, using a combination of genome-wide mapping, whole-genome sequencing, and detailed behavioural and neuropathological analysis of a β-III spectrin mouse knockout, that both the ataxia and cognitive impairment are caused by the recessive mutations in β-III spectrin. SPARCA1 is one of a family of neuronal spectrinopathies and illustrates the importance of spectrins in brain development and function.
PMCID: PMC3516553  PMID: 23236289
10.  Health improvement for disadvantaged people in Nepal – an evaluation 
An evaluation of progress with participatory approaches for improvement of health knowledge and health experiences of disadvantaged people in eight Districts of Eastern Nepal has been undertaken.
A random selection of Village Development Committees and households, within the eight Districts where participation and a Rights-based Approach had been promoted specifically by local NGOs were compared with similar villages and households in eight Districts where this approach had not been promoted. Information was sought by structured interview and observation by experienced enumerators from both groups of householders. Health knowledge and experiences were compared between the two sets of households. Adjustments were made for demographic confounders.
Complete data sets were available for 628 of the 640 households. Health knowledge and experiences were low for both sets of households. However, health knowledge and experiences were greater in the participatory households compared with the non-participatory households. These differences remained after adjustment for confounders.
The study was designed to evaluate progress with participatory processes delivered by non-governmental organisations over a five year period. Improvements in health knowledge and experiences of disadvantaged people were demonstrated in a consistent and robust manner where interventions had taken place.
PMCID: PMC3489826  PMID: 23013319
11.  Surface Engineering of Core/Shell Iron/Iron Oxide Nanoparticles from Microemulsions for Hyperthermia 
This paper describes the synthesis and surface engineering of core/shell-type iron/iron oxide nanoparticles for magnetic hyperthermia cancer therapy. Iron/iron oxide nanoparticles were synthesized from microemulsions of NaBH4 and FeCl3, followed by surface modification in which a thin hydrophobic hexamethyldisilazane layer - used to protect the iron core - replaced the CTAB coating on the particles. Phosphatidylcholine was then assembled on the nanoparticle surface. The resulting nanocomposite particles have a biocompatible surface and show good stability in both air and aqueous solution. Compared to iron oxide nanoparticles, the nanocomposites show much better heating in an alternating magnetic field. They are good candidates for both hyperthermia and magnetic resonance imaging applications.
PMCID: PMC3151654  PMID: 21833157
12.  The Association of C-Reactive Protein and CRP Genotype with Coronary Heart Disease: Findings from Five Studies with 4,610 Cases amongst 18,637 Participants 
PLoS ONE  2008;3(8):e3011.
It is unclear whether C-reactive protein (CRP) is causally related to coronary heart disease (CHD). Genetic variants that are known to be associated with CRP levels can be used to provide causal inference of the effect of CRP on CHD. Our objective was to examine the association between CRP genetic variant +1444C>T (rs1130864) and CHD risk in the largest study to date of this association.
Methods and Results
We estimated the association of CRP genetic variant +1444C>T (rs1130864) with CRP levels and with CHD in five studies and then pooled these analyses (N = 18,637 participants amongst whom there were 4,610 cases). CRP was associated with potential confounding factors (socioeconomic position, physical activity, smoking and body mass) whereas genotype (rs1130864) was not associated with these confounders. The pooled odds ratio of CHD per doubling of circulating CRP level after adjustment for age and sex was 1.13 (95%CI: 1.06, 1.21), and after further adjustment for confounding factors it was 1.07 (95%CI: 1.02, 1.13). Genotype (rs1130864) was associated with circulating CRP; the pooled ratio of geometric means of CRP level among individuals with the TT genotype compared to those with the CT/CC genotype was 1.21 (95%CI: 1.15, 1.28) and the pooled ratio of geometric means of CRP level per additional T allele was 1.14 (95%CI: 1.11, 1.18), with no strong evidence in either analyses of between study heterogeneity (I2 = 0%, p>0.9 for both analyses). There was no association of genotype (rs1130864) with CHD: pooled odds ratio 1.01 (95%CI: 0.88, 1.16) comparing individuals with TT genotype to those with CT/CC genotype and 0.96 (95%CI: 0.90, 1.03) per additional T allele (I2<7.5%, p>0.6 for both meta-analyses). An instrumental variables analysis (in which the proportion of CRP levels explained by rs1130864 was related to CHD) suggested that circulating CRP was not associated with CHD: the odds ratio for a doubling of CRP level was 1.04 (95%CI: 0.61, 1.80).
We found no association of a genetic variant, which is known to be related to CRP levels, (rs1130864) and having CHD. These findings do not support a causal association between circulating CRP and CHD risk, but very large, extended, genetic association studies would be required to rule this out.
PMCID: PMC2507759  PMID: 18714384

Results 1-12 (12)