Improving diagnosis of tumor-induced osteomalacia with gallium-68 DOTATATE PET/CT

Context: Tumor-induced osteomalacia (TIO) is a rarely diagnosed disorder presenting with bone pain, fractures, muscle weakness, and moderate-to-severe hypophosphatemia resulting from fibroblast growth factor 23-mediated renal phosphate wasting. Tumors secreting fibroblast growth factor 23 are often small and difficult to find with conventional imaging. Objective: We studied the utility of 68Ga-DOTA-octreotate (DOTATATE) somatostatin receptor positron emission tomography (PET)/computed tomography (CT) imaging in the diagnosis of TIO. Design and Setting: A multicenter case series was conducted at tertiary referral hospitals. Patients and Methods: Six patients with TIO diagnosed between 2003 and 2012 in Australia were referred for DOTATATE PET imaging. We reviewed the clinical history, biochemistry, imaging characteristics, histopathology, and clinical outcome of each patient. Results: Each case demonstrated delayed diagnosis despite severe symptoms. DOTATATE PET/CT imaging demonstrated high uptake and localized the tumor with confidence in each case. After surgical excision, there was resolution of clinical symptoms and serum phosphate, except in one patient who demonstrated residual disease on PET/CT. All tumors demonstrated high somatostatin receptor subtype 2 cell surface receptor expression using immunohistochemistry. Conclusions: In patients with TIO, DOTATATE PET/CT can successfully localize phosphaturic mesenchymal tumors and may be a practical first step in functional imaging for this disorder. Serum phosphate should be measured routinely in patients with unexplained muscle weakness, bone pain, or stress fractures to allow earlier diagnosis of TIO. - See more at: http://press.endocrine.org/doi/abs/10.1210/jc.2012-3642#sthash.eXD0CopL.dpuf

Molecular genetics of X-linked cone-rod dystrophy and Åland Island eye disease

Inherited retinal diseases are the most common cause of vision loss among the working population in Western countries. It is estimated that ~1 of the people worldwide suffer from vision loss due to inherited retinal diseases. The severity of these diseases varies from partial vision loss to total blindness, and at the moment no effective cure exists. To date, nearly 200 mapped loci, including 140 cloned genes for inherited retinal diseases have been identified. By a rough estimation 50% of the retinal dystrophy genes still await discovery. In this thesis we aimed to study the genetic background of two inherited retinal diseases, X-linked cone-rod dystrophy and Åland Island eye disease. X-linked cone-rod dystrophy (CORDX) is characterized by progressive loss of visual function in school age or early adulthood. Affected males show reduced visual acuity, photophobia, myopia, color vision defects, central scotomas, and variable changes in fundus. The disease is genetically heterogeneous and two disease loci, CORDX1 and CORDX2, were known prior to the present thesis work. CORDX1, located on Xp21.1-11.4, is caused by mutations in the RPGR gene. CORDX2 is located on Xq27-28 but the causative gene is still unknown. Åland Island eye disease (AIED), originally described in a family living in Åland Islands, is a congenital retinal disease characterized by decreased visual acuity, fundus hypopigmentation, nystagmus, astigmatism, red color vision defect, myopia, and defective night vision. AIED shares similarities with another retinal disease, congenital stationary night blindness (CSNB2). Mutations in the L-type calcium channel α1F-subunit gene, CACNA1F, are known to cause CSNB2, as well as AIED-like disease. The disease locus of the original AIED family maps to the same genetic interval as the CACNA1F gene, but efforts to reveal CACNA1F mutations in patients of the original AIED family have been unsuccessful. The specific aims of this study were to map the disease gene in a large Finnish family with X-linked cone-rod dystrophy and to identify the disease-causing genes in the patients of the Finnish cone-rod dystrophy family and the original AIED family. With the help of linkage and haplotype analyses, we could localize the disease gene of the Finnish cone-rod dystrophy family to the Xp11.4-Xq13.1 region, and thus establish a new genetic X-linked cone-rod dystrophy locus, CORDX3. Mutation analyses of candidate genes revealed three novel CACNA1F gene mutations: IVS28-1 GCGTC>TGG in CORDX3 patients, a 425 bp deletion, comprising exon 30 and flanking intronic regions in AIED patients, and IVS16+2T>C in an additional Finnish patient with a CSNB2-like phenotype. All three novel mutations altered splice sites of the CACNA1F gene, and resulted in defective pre-mRNA splicing suggesting altered or absent channel function as a disease mechanism. The analyses of CACNA1F mRNA also revealed novel alternative wt splice variants, which may enhance channel diversity or regulate the overall expression level of the channel. The results of our studies may be utilized in genetic counseling of the families, and they provide a basis for studies on the pathogenesis of these diseases. In the future, the knowledge of the genetic defects may be used in the identification of specific therapies for the patients.

Asymptotic analysis for the coupled wavenumbers in an infinite fluid-filled flexible cylindrical shell: The beam mode

Using asymptotics, the coupled wavenumbers in an infinite fluid-filled flexible cylindrical shell vibrating in the beam mode (viz. circumferential wave order n = 1) are studied. Initially, the uncoupled wavenumbers of the acoustic fluid and the cylindrical shell structure are discussed. Simple closed form expressions for the structural wavenumbers (longitudinal, torsional and bending) are derived using asymptotic methods for low- and high-frequencies. It is found that at low frequencies the cylinder in the beam mode behaves like a Timoshenko beam. Next, the coupled dispersion equation of the system is rewritten in the form of the uncoupled dispersion equation of the structure and the acoustic fluid, with an added fluid-loading term involving a parameter mu due to the coupling. An asymptotic expansion involving mu is substituted in this equation. Analytical expressions are derived for the coupled wavenumbers (as modifications to the uncoupled wavenumbers) separately for low- and high-frequency ranges and further, within each frequency range, for large and small values of mu. Only the flexural wavenumber, the first rigid duct acoustic cut-on wavenumber and the first pressure-release acoustic cut-on wavenumber are considered. The general trend found is that for small mu, the coupled wavenumbers are close to the in vacuo structural wavenumber and the wavenumbers of the rigid-acoustic duct. With increasing mu, the perturbations increase, until the coupled wavenumbers are better identified as perturbations to the pressure-release wavenumbers. The systematic derivation for the separate cases of small and large mu gives more insight into the physics and helps to continuously track the wavenumber solutions as the fluid-loading parameter is varied from small to large values. Also, it is found that at any frequency where two wavenumbers intersect in the uncoupled analysis, there is no more an intersection in the coupled case, but a gap is created at that frequency. This method of asymptotics is simple to implement using a symbolic computation package (like Maple). (C) 2008 Elsevier Ltd. All rights reserved.

Auger-emitter radiochemotherapy in squamous cell cancers : in vitro and in vivo experiments with In-111-BLMC

Head and neck squamous cell cancer (HNSCC) is the sixth most common cancer worldwide. Despite advances in combined modality therapy (surgery, radiotherapy, chemotherapy) the 5-year survival rate in stage III and IV disease remains at 40% - 60%. Short-range Auger-electron emitters, such as In-111 and In-114m, tagged with a drug, molecule, peptide, protein or nanoparticles brought in close proximity to nuclear DNA represent a fascinating alternative for treating cancer. In this thesis, we studied the usefulness of Indium-111-bleomycin complex (In-111-BLMC) in the diagnostics and potential therapy of HNSCC using in vitro HNSCC cell lines, in vivo nude mice, and in vivo HNSCC patients. In in vitro experiments with HNSCC cell lines, the sensitivity to external beam radiation, BLM, In-111-BLMC, and In-111-Cl3 was studied using the 96-well plate clonogenic assay. The influence of BLM and In-111-BLMC on the cell cycle was measured with flow cytometry. In in vivo nude mice xenograft studies, the activity ratios of In-111-BLMC were obtained in gamma camera images. The effect of In-111-BLMC in HNSCC xenografts was studied. In in vivo patient studies, we determined the tumor uptake of In-111-BLMC with gamma camera and the radioactivity from tumor samples using In-111-BLMC with specific activity of 75, 175, or 375 MBq/mg BLM. The S values, i.e. absorbed dose in a target organ per cumulated activity in a source organ, were simulated for In-111 and In-114m. In vitro studies showed the variation of sensitivity for external beam radiation, BLM, and In-111-BLMC between HNSCC cell lines. IC50 values for BLM were 1.6-, 1.8-, and 2.1-fold higher than In-111-BLMC (40 MBq/mg BLM) in three HNSCC cell lines. Specific In-111 activity of 40 MBq/mgBLM was more effective in killing cells than specific In-111 activity of 195MBq/mgBLM (p=0.0023). In-111-Cl3 alone had no killing effect. The percentage of cells in the G2/M phase increased after exposure to BLM and especially to In-111-BLMC in the three cell lines studied, indicating a G2/M block. The tumor-seeking behavior was shown in the in vivo imaging study of xenografted mice. BLM and In-111-BLMC were more effective than NaCl in reducing xenografted tumor size in HNSCC. The uptake ratios received from gamma images in the in vivo patient study varied from 1.2 to 2.8 in malignant tumors. However, the uptake of In-111-BLMC was unaffected by increasing the injected activity. A positive correlation existed between In-111-BLMC uptake, Ki-67/MIB activity, and number of mitoses. Regarding the S values, In-114m delivered a 4-fold absorbed radiation dose into the tumor compared with In-111, and thus, In-114m-BLMC might be more effective than In-111-BLMC at the DNA level. Auger-electron emitters, such as In-111 and In-114m, might have potential in the treatment of HNSCC. Further studies are needed to develop a radiopharmaceutical agent with appropriate physical properties of the radionuclide and a suitable carrier to bring it to the targeted tissue.

Measurement of shock stand-off distance on a 120 degrees blunt cone model at hypersonic Mach number in Argon

The flow around a 120 degrees blunt cone model with a base radius of 60mm has been visualised at Mach 14.8 and 9.1 using argon as the test gas, at the newly established high speed schlieren facility in the IISc hypersonic shock tunnel HST2. The experimental shock stand off distance around the blunt cone is compared with that obtained using a commercial CFD package. The computed values of shock stand off distance of the blunt cone is found to agree reasonably well with the experimental data.

Consistent quaternion interpolation for objective finite element approximation of geometrically exact beam

We explore an isoparametric interpolation of total quaternion for geometrically consistent, strain-objective and path-independent finite element solutions of the geometrically exact beam. This interpolation is a variant of the broader class known as slerp. The equivalence between the proposed interpolation and that of relative rotation is shown without any recourse to local bijection between quaternions and rotations. We show that, for a two-noded beam element, the use of relative rotation is not mandatory for attaining consistency cum objectivity and an appropriate interpolation of total rotation variables is sufficient. The interpolation of total quaternion, which is computationally more efficient than the one based on local rotations, converts nodal rotation vectors to quaternions and interpolates them in a manner consistent with the character of the rotation manifold. This interpolation, unlike the additive interpolation of total rotation, corresponds to a geodesic on the rotation manifold. For beam elements with more than two nodes, however, a consistent extension of the proposed quaternion interpolation is difficult. Alternatively, a quaternion-based procedure involving interpolation of relative rotations is proposed for such higher order elements. We also briefly discuss a strategy for the removal of possible singularity in the interpolation of quaternions, proposed in [I. Romero, The interpolation of rotations and its application to finite element models of geometrically exact rods, Comput. Mech. 34 (2004) 121–133]. The strain-objectivity and path-independence of solutions are justified theoretically and then demonstrated through numerical experiments. This study, being focused only on the interpolation of rotations, uses a standard finite element discretization, as adopted by Simo and Vu-Quoc [J.C. Simo, L. Vu-Quoc, A three-dimensional finite rod model part II: computational aspects, Comput. Methods Appl. Mech. Engrg. 58 (1986) 79–116]. The rotation update is achieved via quaternion multiplication followed by the extraction of the rotation vector. Nodal rotations are stored in terms of rotation vectors and no secondary storages are required.

Dynamics and control of buckling type devices using SMA wire integrated beam

An analysis and design study using Shape Memory Alloy (SMA) wire integrated beam and its buckling shape control are reported. The dynamical system performance is analyzed with a mathematical set-up involving nonlocal and rate sensitive kinetics of phase transformation in the SMA wire. A standard phenomenological constitutive model reported by Brinson (1993) is modified by considering certain consistency conditions in the material property tensors and by eliminating spurious singularity. Considering the inhomogeneity effects, a finite element model of the SMA wire is developed. Simulations are carried out to study the buckling shape control of a beam integrated with SMA wire.

Finnish Dosimetric Practice for Epithermal Neutron Beam Dosimetry in Boron Neutron Capture Therapy

Boron neutron capture therapy (BNCT) is a form of chemically targeted radiotherapy that utilises the high neutron capture cross-section of boron-10 isotope to achieve a preferential dose increase in the tumour. The BNCT dosimetry poses a special challenge as the radiation dose absorbed by the irradiated tissues consists of several dose different components. Dosimetry is important as the effect of the radiation on the tissue is correlated with the radiation dose. Consistent and reliable radiation dose delivery and dosimetry are thus basic requirements for radiotherapy. The international recommendations for are not directly applicable to BNCT dosimetry. The existing dosimetry guidance for BNCT provides recommendations but also calls for investigating for complementary methods for comparison and improved accuracy. In this thesis the quality assurance and stability measurements of the neutron beam monitors used in dose delivery are presented. The beam monitors were found not to be affected by the presence of a phantom in the beam and that the effect of the reactor core power distribution was less than 1%. The weekly stability test with activation detectors has been generally reproducible within the recommended tolerance value of 2%. An established toolkit for epithermal neutron beams for determination of the dose components is presented and applied in an international dosimetric intercomparison. The measured quantities (neutron flux, fast neutron and photon dose) by the groups in the intercomparison were generally in agreement within the stated uncertainties. However, the uncertainties were large, ranging from 3-30% (1 standard deviation), emphasising the importance of dosimetric intercomparisons if clinical data is to be compared between different centers. Measurements with the Exradin type 2M ionisation chamber have been repeated in the epithermal neutron beam in the same measurement configuration over the course of 10 years. The presented results exclude severe sensitivity changes to thermal neutrons that have been reported for this type of chamber. Microdosimetry and polymer gel dosimetry as complementary methods for epithermal neutron beam dosimetry are studied. For microdosimetry the comparison of results with ionisation chambers and computer simulation showed that the photon dose measured with microdosimetry was lower than with the two other methods. The disagreement was within the uncertainties. For neutron dose the simulation and microdosimetry results agreed within 10% while the ionisation chamber technique gave 10-30% lower neutron dose rates than the two other methods. The response of the BANG-3 gel was found to be linear for both photon and epithermal neutron beam irradiation. The dose distribution normalised to dose maximum measured by MAGIC polymer gel was found to agree well with the simulated result near the dose maximum while the spatial difference between measured and simulated 30% isodose line was more than 1 cm. In both the BANG-3 and MAGIC gel studies, the interpretation of the results was complicated by the presence of high-LET radiation.

Accuracy of absorbed dose in external photon beam radiotherapy : what level is sufficient and how to approach it?

Radiation therapy (RT) plays currently significant role in curative treatments of several cancers. External beam RT is carried out mostly by using megavoltage beams of linear accelerators. Tumor eradication and normal tissue complications correlate to dose absorbed in tissues. Normally this dependence is steep and it is crucial that actual dose within patient accurately correspond to the planned dose. All factors in a RT procedure contain uncertainties requiring strict quality assurance. From hospital physicist´s point of a view, technical quality control (QC), dose calculations and methods for verification of correct treatment location are the most important subjects. Most important factor in technical QC is the verification that radiation production of an accelerator, called output, is within narrow acceptable limits. The output measurements are carried out according to a locally chosen dosimetric QC program defining measurement time interval and action levels. Dose calculation algorithms need to be configured for the accelerators by using measured beam data. The uncertainty of such data sets limits for best achievable calculation accuracy. All these dosimetric measurements require good experience, are workful, take up resources needed for treatments and are prone to several random and systematic sources of errors. Appropriate verification of treatment location is more important in intensity modulated radiation therapy (IMRT) than in conventional RT. This is due to steep dose gradients produced within or close to healthy tissues locating only a few millimetres from the targeted volume. The thesis was concentrated in investigation of the quality of dosimetric measurements, the efficacy of dosimetric QC programs, the verification of measured beam data and the effect of positional errors on the dose received by the major salivary glands in head and neck IMRT. A method was developed for the estimation of the effect of the use of different dosimetric QC programs on the overall uncertainty of dose. Data were provided to facilitate the choice of a sufficient QC program. The method takes into account local output stability and reproducibility of the dosimetric QC measurements. A method based on the model fitting of the results of the QC measurements was proposed for the estimation of both of these factors. The reduction of random measurement errors and optimization of QC procedure were also investigated. A method and suggestions were presented for these purposes. The accuracy of beam data was evaluated in Finnish RT centres. Sufficient accuracy level was estimated for the beam data. A method based on the use of reference beam data was developed for the QC of beam data. Dosimetric and geometric accuracy requirements were evaluated for head and neck IMRT when function of the major salivary glands is intended to be spared. These criteria are based on the dose response obtained for the glands. Random measurement errors could be reduced enabling lowering of action levels and prolongation of measurement time interval from 1 month to even 6 months simultaneously maintaining dose accuracy. The combined effect of the proposed methods, suggestions and criteria was found to facilitate the avoidance of maximal dose errors of up to even about 8 %. In addition, their use may make the strictest recommended overall dose accuracy level of 3 % (1SD) achievable.

Terahertz wave characteristics of a single-walled carbon nanotube containing a fluid flow using the nonlocal Timoshenko beam model

This paper presents the effect of nonlocal scaling parameter on the terahertz wave propagation in fluid filled single walled carbon nanotubes (SWCNTs). The SWCNT is modeled as a Timoshenko beam,including rotary inertia and transverse shear deformation by considering the nonlocal scale effects. A uniform fluid velocity of 1000 m/s is assumed. The analysis shows that, for a fluid filled SWCNT, the wavenumbers of flexural and shear waves will increase and the corresponding wave speeds will decrease as compared to an empty SWCNT. The nonlocal scale parameter introduces certain band gap region in both flexural and shear wave mode where no wave propagation occurs. This is manifested in the wavenumber plots as the region where the wavenumber tends to infinite (or wave speed tends to zero). The frequency at which this phenomenon occurs is called the ``escape frequency''. The effect of fluid density on the terahertz wave propagation in SWCNT is also studied and the analysis shows that as the fluid becomes denser, the wave speeds will decrease. The escape frequency decreases with increase in nonlocal scaling parameter, for both wave modes. We also show that the effect of fluid density and velocity are negligible on the escape frequencies of flexural and shear wave modes. (C) 2010 Elsevier B.V. All rights reserved.

Strength design of composite beam using gradient and particle swarm optimization

This work addresses the optimum design of a composite box-beam structure subject to strength constraints. Such box-beams are used as the main load carrying members of helicopter rotor blades. A computationally efficient analytical model for box-beam is used. Optimal ply orientation angles are sought which maximize the failure margins with respect to the applied loading. The Tsai-Wu-Hahn failure criterion is used to calculate the reserve factor for each wall and ply and the minimum reserve factor is maximized. Ply angles are used as design variables and various cases of initial starting design and loadings are investigated. Both gradient-based and particle swarm optimization (PSO) methods are used. It is found that the optimization approach leads to the design of a box-beam with greatly improved reserve factors which can be useful for helicopter rotor structures. While the PSO yields globally best designs, the gradient-based method can also be used with appropriate starting designs to obtain useful designs efficiently. (C) 2006 Elsevier Ltd. All rights reserved.