Critical Analysis of Bladder Sparing with Trimodal Therapy in Muscle-invasive Bladder Cancer: A Systematic Review.

CONTEXT Aims of bladder preservation in muscle-invasive bladder cancer (MIBC) are to offer a quality-of-life advantage and avoid potential morbidity or mortality of radical cystectomy (RC) without compromising oncologic outcomes. Because of the lack of a completed randomised controlled trial, oncologic equivalence of bladder preservation modality treatments compared with RC remains unknown. OBJECTIVE This systematic review sought to assess the modern bladder-preservation treatment modalities, focusing on trimodal therapy (TMT) in MIBC. EVIDENCE ACQUISITION A systematic literature search in the PubMed and Cochrane databases was performed from 1980 to July 2013. EVIDENCE SYNTHESIS Optimal bladder-preservation treatment includes a safe transurethral resection of the bladder tumour as complete as possible followed by radiation therapy (RT) with concurrent radiosensitising chemotherapy. A standard radiation schedule includes external-beam RT to the bladder and limited pelvic lymph nodes to an initial dose of 40Gy, with a boost to the whole bladder to 54Gy and a further tumour boost to a total dose of 64-65Gy. Radiosensitising chemotherapy with phase 3 trial evidence in support exists for cisplatin and mitomycin C plus 5-fluorouracil. A cystoscopic assessment with systematic rebiopsy should be performed at TMT completion or early after TMT induction. Thus, nonresponders are identified early to promptly offer salvage RC. The 5-yr cancer-specific survival and overall survival rates range from 50% to 82% and from 36% to 74%, respectively, with salvage cystectomy rates of 25-30%. There are no definitive data to support the benefit of using of neoadjuvant or adjuvant chemotherapy. Critical to good outcomes is proper patient selection. The best cancers eligible for bladder preservation are those with low-volume T2 disease without hydronephrosis or extensive carcinoma in situ. CONCLUSIONS A growing body of accumulated data suggests that bladder preservation with TMT leads to acceptable outcomes and therefore may be considered a reasonable treatment option in well-selected patients. PATIENT SUMMARY Treatment based on a combination of resection, chemotherapy, and radiotherapy as bladder-sparing strategies may be considered as a reasonable treatment option in properly selected patients.

Patterns of alcohol and illicit substance use in the United States and Mexico. Substantive and methodologic issues in the cross-national analysis of alcohol and drug use data

This research examines prevalence of alcohol and illicit substance use in the United States and Mexico and associated socio-demographic characteristics. The sources of data for this study are public domain data from the U.S. National Household Survey of Drug Abuse, 1988 (n = 8814), and the Mexican National Survey of Addictions, 1988 (n = 12,579). In addition, this study discusses methodologic issues in cross-cultural and cross-national comparison of behavioral and epidemiologic data from population-based samples. The extent to which patterns of substance abuse vary among subgroups of the U.S. and Mexican populations is assessed, as well as the comparability and equivalence of measures of alcohol and drug use in these national samples.^ The prevalence of alcohol use was somewhat similar in the two countries for all three measures of use: lifetime, past year and past year heavy use, (85.0%, 68.1%, 39.6% and 72.6%, 47.7% and 45.8% for the U.S. and Mexico respectively). The use of illegal substances varied widely between countries, with U.S. respondents reporting significantly higher levels of use than their Mexican counterparts. For example, reported use of any illicit substance in lifetime and past year was 34.2%, 11.6 for the U.S., and 3.3% and 0.6% for Mexico. Despite these differences in prevalence, two demographic characteristics, gender and age, were important correlates of use in both countries. Men in both countries were more likely to report use of alcohol and illicit substances than women. Generally speaking, a greater proportion of respondents in both countries 18 years of age or older reported use of alcohol for all three measures than younger respondents; and a greater proportion of respondents between the ages of 18 and 34 years reported use of illicit substances during lifetime and past year than any other age group.^ Additional substantive research investigating population-based samples and at-risk subgroups is needed to understand the underlying mechanisms of these associations. Further development of cross-culturally meaningful survey methods is warranted to validate comparisons of substance use across countries and societies. ^

Time for actions in lucid dreams: effects of task modality, length, and complexity

The relationship between time in dreams and real time has intrigued scientists for centuries. The question if actions in dreams take the same time as in wakefulness can be tested by using lucid dreams where the dreamer is able to mark time intervals with prearranged eye movements that can be objectively identified in EOG recordings. Previous research showed an equivalence of time for counting in lucid dreams and in wakefulness (LaBerge, 1985; Erlacher and Schredl, 2004), but Erlacher and Schredl (2004) found that performing squats required about 40% more time in lucid dreams than in the waking state. To find out if the task modality, the task length, or the task complexity results in prolonged times in lucid dreams, an experiment with three different conditions was conducted. In the first condition, five proficient lucid dreamers spent one to three non-consecutive nights in the sleep laboratory. Participants counted to 10, 20, and 30 in wakefulness and in their lucid dreams. Lucidity and task intervals were time stamped with left-right-left-right eye movements. The same procedure was used for these condition where eight lucid dreamers had to walk 10, 20, or 30 steps. In the third condition, eight lucid dreamers performed a gymnastics routine, which in the waking state lasted the same time as walking 10 steps. Again, we found that performing a motor task in a lucid dream requires more time than in wakefulness. Longer durations in the dream state were present for all three tasks, but significant differences were found only for the tasks with motor activity (walking and gymnastics). However, no difference was found for relative times (no disproportional time effects) and a more complex motor task did not result in more prolonged times. Longer durations in lucid dreams might be related to the lack of muscular feedback or slower neural processing during REM sleep. Future studies should explore factors that might be associated with prolonged durations.

On the signature of positive braids and adjacency for torus knots

The objects of study in this thesis are knots. More precisely, positive braid knots, which include algebraic knots and torus knots. In the first part of this thesis, we compare two classical knot invariants - the genus g and the signature σ - for positive braid knots. Our main result on positive braid knots establishes a linear lower bound for the signature in terms of the genus. In the second part of the thesis, a positive braid approach is applied to the study of the local behavior of polynomial functions from the complex affine plane to the complex numbers. After endowing polynomial function germs with a suitable topology, the adjacency problem arises: for a fixed germ f, what classes of germs g can be found arbitrarily close to f? We introduce two purely topological notions of adjacency for knots and discuss connections to algebraic notions of adjacency and the adjacency problem.

Experimental, theoretical and numerical investigation of the nonlinear micromechanical properties of bone

Aging societies suffer from an increasing incidence of bone fractures. Bone strength depends on the amount of mineral measured by clinical densitometry, but also on the micromechanical properties of the bone hierarchical organization. A good understanding has been reached for elastic properties on several length scales, but up to now there is a lack of reliable postyield data on the lower length scales. In order to be able to describe the behavior of bone at the microscale, an anisotropic elastic-viscoplastic damage model was developed using an eccentric generalized Hill criterion and nonlinear isotropic hardening. The model was implemented as a user subroutine in Abaqus and verified using single element tests. A FE simulation of microindentation in lamellar bone was finally performed show-ing that the new constitutive model can capture the main characteristics of the indentation response of bone. As the generalized Hill criterion is limited to elliptical and cylindrical yield surfaces and the correct shape for bone is not known, a new yield surface was developed that takes any convex quadratic shape. The main advantage is that in the case of material identification the shape of the yield surface does not have to be anticipated but a minimization results in the optimal shape among all convex quadrics. The generality of the formulation was demonstrated by showing its degeneration to classical yield surfaces. Also, existing yield criteria for bone at multiple length scales were converted to the quadric formulation. Then, a computational study to determine the influence of yield surface shape and damage on the in-dentation response of bone using spherical and conical tips was performed. The constitutive model was adapted to the quadric criterion and yield surface shape and critical damage were varied. They were shown to have a major impact on the indentation curves. Their influence on indentation modulus, hardness, their ratio as well as the elastic to total work ratio were found to be very well described by multilinear regressions for both tip shapes. For conical tips, indentation depth was not a significant fac-tor, while for spherical tips damage was insignificant. All inverse methods based on microindentation suffer from a lack of uniqueness of the found material properties in the case of nonlinear material behavior. Therefore, monotonic and cyclic micropillar com-pression tests in a scanning electron microscope allowing a straightforward interpretation comple-mented by microindentation and macroscopic uniaxial compression tests were performed on dry ovine bone to identify modulus, yield stress, plastic deformation, damage accumulation and failure mecha-nisms. While the elastic properties were highly consistent, the postyield deformation and failure mech-anisms differed between the two length scales. A majority of the micropillars showed a ductile behavior with strain hardening until failure by localization in a slip plane, while the macroscopic samples failed in a quasi-brittle fashion with microcracks coalescing into macroscopic failure surfaces. In agreement with a proposed rheological model, these experiments illustrate a transition from a ductile mechanical behavior of bone at the microscale to a quasi-brittle response driven by the growth of preexisting cracks along interfaces or in the vicinity of pores at the macroscale. Subsequently, a study was undertaken to quantify the topological variability of indentations in bone and examine its relationship with mechanical properties. Indentations were performed in dry human and ovine bone in axial and transverse directions and their topography measured by AFM. Statistical shape modeling of the residual imprint allowed to define a mean shape and describe the variability with 21 principal components related to imprint depth, surface curvature and roughness. The indentation profile of bone was highly consistent and free of any pile up. A few of the topological parameters, in particular depth, showed significant correlations to variations in mechanical properties, but the cor-relations were not very strong or consistent. We could thus verify that bone is rather homogeneous in its micromechanical properties and that indentation results are not strongly influenced by small de-viations from the ideal case. As the uniaxial properties measured by micropillar compression are in conflict with the current literature on bone indentation, another dissipative mechanism has to be present. The elastic-viscoplastic damage model was therefore extended to viscoelasticity. The viscoelastic properties were identified from macroscopic experiments, while the quasistatic postelastic properties were extracted from micropillar data. It was found that viscoelasticity governed by macroscale properties has very little influence on the indentation curve and results in a clear underestimation of the creep deformation. Adding viscoplasticity leads to increased creep, but hardness is still highly overestimated. It was possible to obtain a reasonable fit with experimental indentation curves for both Berkovich and spherical indenta-tion when abandoning the assumption of shear strength being governed by an isotropy condition. These results remain to be verified by independent tests probing the micromechanical strength prop-erties in tension and shear. In conclusion, in this thesis several tools were developed to describe the complex behavior of bone on the microscale and experiments were performed to identify its material properties. Micropillar com-pression highlighted a size effect in bone due to the presence of preexisting cracks and pores or inter-faces like cement lines. It was possible to get a reasonable fit between experimental indentation curves using different tips and simulations using the constitutive model and uniaxial properties measured by micropillar compression. Additional experimental work is necessary to identify the exact nature of the size effect and the mechanical role of interfaces in bone. Deciphering the micromechanical behavior of lamellar bone and its evolution with age, disease and treatment and its failure mechanisms on several length scales will help preventing fractures in the elderly in the future.

Endovascular treatment for acute ischemic stroke patients: implications and interpretation of IMS III, MR RESCUE, and SYNTHESIS EXPANSION trials: A report from the Working Group of International Congress of Interventional Neurology

OBJECTIVE The results of Interventional Management of Stroke (IMS) III, Magnetic Resonance and REcanalization of Stroke Clots Using Embolectomy (MR RESCUE), and SYNTHESIS EXPANSION trials are expected to affect the practice of endovascular treatment for acute ischemic stroke. The purpose of this report is to review the components of the designs and methods of these trials and to describe the influence of those components on the interpretation of trial results. METHODS A critical review of trial design and conduct of IMS III, MR RESCUE, and SYNTHESIS EXPANSION is performed with emphasis on patient selection, shortcomings in procedural aspects, and methodology of data ascertainment and analysis. The influence of each component is estimated based on published literature including multicenter clinical trials reporting on endovascular treatment for acute ischemic stroke and myocardial infarction. RESULTS We critically examined the time interval between symptom onset and treatment and rates of angiographic recanalization to differentiate between "endovascular treatment" and "parameter optimized endovascular treatment" as it relates to the IMS III, MR RESCUE, and SYNTHESIS EXPANSION trials. All the three trials failed to effectively test "parameter optimized endovascular treatment" due to the delay between symptom onset and treatment and less than optimal rates of recanalization. In all the three trials, the magnitude of benefit with endovascular treatment required to reject the null hypothesis was larger than could be expected based on previous studies. The IMS III and SYNTHESIS EXPANSION trials demonstrated that rates of symptomatic intracerebral hemorrhages subsequent to treatment are similar between IV thrombolytics and endovascular treatment in matched acute ischemic stroke patients. The trials also indirectly validated the superiority/equivalence of IV thrombolytics (compared with endovascular treatment) in patients with minor neurological deficits and those without large vessel occlusion on computed tomographic/magnetic resonance angiography. CONCLUSIONS The results do not support a large magnitude benefit of endovascular treatment in subjects randomized in all the three trials. The possibility that benefits of a smaller magnitude exist in certain patient populations cannot be excluded. Large magnitude benefits can be expected with implementation of "parameter optimized endovascular treatment" in patients with ischemic stroke who are candidates for IV thrombolytics.

Quantitative analysis of imprint shape and its relation to mechanical properties measured by microindentation in bone

Microindentation in bone is a micromechanical testing technique routinely used to extract material properties related to bone quality. As the analysis of microindentation data is based on assumptions about the contact between sample and surface, the aim of this study was to quantify the topological variability of indentations in bone and examine its relationship with mechanical properties. Indentations were performed in dry human and ovine bone in axial and transverse directions and their topology was measured by atomic force microscopy. Statistical shape modeling of the residual imprint allowed to define a mean shape and to describe the variability in terms of 21 principal components related to imprint depth, surface curvature and roughness. The indentation profile of bone was found to be highly consistent and free of any pile up while differing mostly by depth between species and direction. A few of the topological parameters, in particular depth, showed significant but rather weak and inconsistent correlations to variations in mechanical properties. The mechanical response of bone as well as the residual imprint shape was highly consistent within each category. We could thus verify that bone is rather homogeneous in its micromechanical properties and that indentation results are not strongly influenced by small deviations from an ideally flat surface.

Topology of the ambient boundary and the convergence of causal curves

We discuss the topological nature of the boundary spacetime, the conformal infinity of the ambient cosmological metric. Due to the existence of a homothetic group, the bounding spacetime must be equipped not with the usual Euclidean metric topology but with the Zeeman fine topology. This then places severe constraints to the convergence of a sequence of causal curves and the extraction of a limit curve, and also to our ability to formulate conditions for singularity formation.

Supersymmetric quantum mechanics on the lattice: III. Simulations and algorithms

In the fermion loop formulation the contributions to the partition function naturally separate into topological equivalence classes with a definite sign. This separation forms the basis for an efficient fermion simulation algorithm using a fluctuating open fermion string. It guarantees sufficient tunnelling between the topological sectors, and hence provides a solution to the fermion sign problem affecting systems with broken supersymmetry. Moreover, the algorithm shows no critical slowing down even in the massless limit and can hence handle the massless Goldstino mode emerging in the supersymmetry broken phase. In this paper – the third in a series of three – we present the details of the simulation algorithm and demonstrate its efficiency by means of a few examples.

Experimental and Theoretical Electron Density Analysis of Copper Pyrazine Nitrate Quasi-Low-Dimensional Quantum Magnets

The accurate electron density distribution and magnetic properties of two metal-organic polymeric magnets, the quasi-one-dimensional (1D) Cu(pyz)(NO3)2 and the quasi-two-dimensional (2D) [Cu(pyz)2(NO3)]NO3·H2O, have been investigated by high-resolution single-crystal X-ray diffraction and density functional theory calculations on the whole periodic systems and on selected fragments. Topological analyses, based on quantum theory of atoms in molecules, enabled the characterization of possible magnetic exchange pathways and the establishment of relationships between the electron (charge and spin) densities and the exchange-coupling constants. In both compounds, the experimentally observed antiferromagnetic coupling can be quantitatively explained by the Cu-Cu superexchange pathway mediated by the pyrazine bridging ligands, via a σ-type interaction. From topological analyses of experimental charge-density data, we show for the first time that the pyrazine tilt angle does not play a role in determining the strength of the magnetic interaction. Taken in combination with molecular orbital analysis and spin density calculations, we find a synergistic relationship between spin delocalization and spin polarization mechanisms and that both determine the bulk magnetic behavior of these Cu(II)-pyz coordination polymers.

Derivation of Change from Sequences of Snapshots

Current research in the domain of geographic information science considers possibilities of including another dimension, time, which is generally missing to this point. Users interested in changes have few functions available to compare datasets of spatial configurations at different points in time. Such a comparison of spatial configurations requires large amounts of manual labor. An automatic derivation of changes would decrease amounts of manual labor. The thesis introduces a set of methods that allows for an automatic derivation of changes. These methods analyze identity and topological states of objects in snapshots and derive types of change for the specific configuration of data. The set of change types that can be computed by the methods presented includes continuous changes such as growing, shrinking, and moving of objects. For these continuous changes identity remains unchanged, while topological relations might be altered over time. Also discrete changes such as merging and splitting where both identity and topology are affected can be derived. Evaluation of the methods using a prototype application with simple examples suggests that the methods compute uniquely and correctly the type of change that applied in spatial scenarios captured in two snapshots.

Role of phosphatidylethanolamine in the function and assembly of phenylalanine-specific permease of Escherichia coli

Transmembrane segments of polytopic membrane proteins once inserted are generally considered stably oriented due to the large free energy barrier for topological reorientation of adjacent extra-membrane domains. However, proper topology and function of the polytopic membrane protein lactose permease (LacY) of Escherichia coli is dependent on the membrane phospholipid composition revealing topological dynamics of transmembrane domains (Bogdanov, M., Heacock, P. N., and Dowhan, W. (2002) EMBO J. 21, 2107–2116). The high affinity phenylalanine permease PheP shares many topological similarities with LacY. In this study, mutant E. coli cells lacking phosphatidylethanolamine (PE) as a membrane component were used to evaluate the role of PE in the function and assembly of PheP. Active transport of phenylalanine by cells lacking PE was severely inhibited (both Vmax and Km were altered), whereas the PheP protein level in membranes was unaffected. Cysteine residues were introduced into predicted periplasmic or cytoplasmic segments of cysteine-less PheP, and the topology of the protein was explored using a membrane-impermeable thiol-specific biotinylated probe. Based on the biotinylation patterns of PheP in whole cells, the N-terminus and adjoining transmembrane hairpin of PheP adopted an inverted topological orientation in PE-lacking cells. Introduction of PE following the assembly of PheP triggered a reorientation of the N-terminus and adjacent hairpin to their native orientation associated with regain of wild type transport function. These results coupled with the results for LacY support a specific role for membrane lipid composition in determining topological organization and function of membrane proteins. Several other secondary symporters are compromised for activity in PE-lacking cells suggesting that lipid-assisted topogenesis is a general property of such transporters. The reversible orientation of these secondary transport proteins in response to a change of phospholipid composition might be a result of inherent conformational flexibility necessary for transport function or during protein assembly. ^

Intrinsic characteristics of the proton pump in the luminal membrane of a tight urinary epithelium. The relation between transport rate and delta mu H.

A number of tight urinary epithelia, as exemplified by the turtle bladder, acidify the luminal solution by active transport of H+ across the luminal cell membrane. The rate of active H+ transport (JH) decreases as the electrochemical potential difference for H+ [delta mu H = mu H(lumen) - mu H(serosa)] across the epithelium is increased. The luminal cell membrane has a low permeability for H+ equivalents and a high electrical resistance compared with the basolateral cell membrane. Changes in JH thus reflect changes in active H+ transport across the luminal membrane. To examine the control of JH by delta mu H in the turtle bladder, transepithelial electrical potential differences (delta psi) were imposed at constant acid-base conditions or the luminal pH was varied at delta psi = 0 and constant serosal PCO2 and pH. When the luminal compartment was acidified from pH 7 to 4 or was made electrically positive, JH decreased as a linear function of delta mu H as previously described. When the luminal compartment was made alkaline from pH 7 to 9 or was made electrically negative, JH reached a maximal value, which was the same whether the delta mu H was imposed as a delta pH or a delta psi. The nonlinear JH vs. delta mu H relation does not result from changes in the number of pumps in the luminal membrane or from changes in the intracellular pH, but is a characteristic of the H+ pumps themselves. We propose a general scheme, which, because of its structural features, can account for the nonlinearity of the JH vs. delta mu H relations and, more specifically, for the kinetic equivalence of the effects of the chemical and electrical components of delta mu H. According to this model, the pump complex consists of two components: a catalytic unit at the cytoplasmic side of the luminal membrane, which mediates the ATP-driven H+ translocation, and a transmembrane channel, which mediates the transfer of H+ from the catalytic unit to the luminal solution. These two components may be linked through a buffer compartment for H+ (an antechamber).

Fast Algorithms Using Minimal Data Structures for Common Topological Relationships in Large, Irregularly-spaced Topographic Data Sets

Digital terrain models (DTM) typically contain large numbers of postings, from hundreds of thousands to billions. Many algorithms that run on DTMs require topological knowledge of the postings, such as finding nearest neighbors, finding the posting closest to a chosen location, etc. If the postings are arranged irregu- larly, topological information is costly to compute and to store. This paper offers a practical approach to organizing and searching irregularly-space data sets by presenting a collection of efficient algorithms (O(N),O(lgN)) that compute important topological relationships with only a simple supporting data structure. These relationships include finding the postings within a window, locating the posting nearest a point of interest, finding the neighborhood of postings nearest a point of interest, and ordering the neighborhood counter-clockwise. These algorithms depend only on two sorted arrays of two-element tuples, holding a planimetric coordinate and an integer identification number indicating which posting the coordinate belongs to. There is one array for each planimetric coordinate (eastings and northings). These two arrays cost minimal overhead to create and store but permit the data to remain arranged irregularly.

The in vivo and in vitro formation of sticky DNA and the GAA.TTC trinucleotide repeat associated with Friedreich's ataxia

Friedreich's ataxia is caused by the expansion of the GAA•TTC trinucleotide repeat sequence located in intron 1 of the frataxin gene. The long GAA•TTC repeats are known to form several non-B DNA structures including hairpins, triplexes, parallel DNA and sticky DNA. Therefore it is believed that alternative DNA structures play a role in the loss of mRNA transcript and functional frataxin protein in FRDA patients. We wanted to further elucidate the characteristics for formation and stability of sticky DNA by evaluating the structure in a plasmid based system in vitro and in vivo in Escherichia coli. The negative supercoil density of plasmids harboring different lengths of GAA•TTC repeats, as well as either one or two repeat tracts were studied in E. coli to determine if plasmids containing two long tracts (≥60 repeats) in a direct repeat orientation would have a different topological effect in vivo compared to plasmids that harbored only one GAA•TTC tract or two tracts of < 60 repeats. The experiments revealed that, in fact, sticky DNA forming plasmids had a lower average negative supercoil density (-σ) compared to all other control plasmids used that had the potential to form other non-B DNA structures such as triplexes or Z-DNA. Also, the requirements for in vitro dissociation and reconstitution of the DNA•DNA associated region of sticky DNA were evaluated. Results conclude that the two repeat tracts associate in the presence of negative supercoiling and MgCl 2 or MnCl2 in a time and concentration-dependent manner. Interaction of the repeat sequences was not observed in the absence of negative supercoiling and/or MgCl2 or in the presence of other monovalent or divalent cations, indicating that supercoiling and quite specific cations are needed for the association of sticky DNA. These are the first experiments studying a more specific role of supercoiling and cation influence on this DNA conformation. To support our model of the topological effects of sticky DNA in plasmids, changes in sticky DNA band migration was measured with reference to the linear DNA after treatment with increasing concentrations of ethidium bromide (EtBr). The presence of independent negative supercoil domains was confirmed by this method and found to be segregated by the DNA-DNA associated region. Sequence-specific polyamide molecules were used to test the effect of binding of the ligands to the GAA•TTC repeats on the inhibition of sticky DNA. The destabilization of the sticky DNA conformation in vitro through this binding of the polyamides demonstrated the first conceptual therapeutic approach for the treatment of FRDA at the DNA molecular level. ^ Thus, examining the properties of sticky DNA formed by these long repeat tracts is important in the elucidation of the possible role of sticky DNA in Friedreich's ataxia. ^