1,471 research outputs found
Reduction of freezing of gait in Parkinson's disease by repetitive robot-assisted treadmill training: a pilot study
<p>Abstract</p> <p>Background</p> <p>Parkinson's disease is a chronic, neurodegenerative disease characterized by gait abnormalities. Freezing of gait (FOG), an episodic inability to generate effective stepping, is reported as one of the most disabling and distressing parkinsonian symptoms. While there are no specific therapies to treat FOG, some external physical cues may alleviate these types of motor disruptions. The purpose of this study was to examine the potential effect of continuous physical cueing using robot-assisted sensorimotor gait training on reducing FOG episodes and improving gait.</p> <p>Methods</p> <p>Four individuals with Parkinson's disease and FOG symptoms received ten 30-minute sessions of robot-assisted gait training (Lokomat) to facilitate repetitive, rhythmic, and alternating bilateral lower extremity movements. Outcomes included the FOG-Questionnaire, a clinician-rated video FOG score, spatiotemporal measures of gait, and the Parkinson's Disease Questionnaire-39 quality of life measure.</p> <p>Results</p> <p>All participants showed a reduction in FOG both by self-report and clinician-rated scoring upon completion of training. Improvements were also observed in gait velocity, stride length, rhythmicity, and coordination.</p> <p>Conclusions</p> <p>This pilot study suggests that robot-assisted gait training may be a feasible and effective method of reducing FOG and improving gait. Videotaped scoring of FOG has the potential advantage of providing additional data to complement FOG self-report.</p
High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy
About one-third of patients with type 1 diabetes mellitus develop nephropathy, which often progresses to end-stage renal diseases. The present study demonstrates that below-normal Elmo1 expression in mice ameliorates the albuminuria and glomerular histological changes resulting from long-standing type 1 diabetes, whereas above-normal Elmo1 expression makes both worse. Increasing Elmo1 expression leads to aggravation of oxidative stress markers and enhances the expression of fibrogenic genes. Suppressing Elmo1 action in human patients could be a promising option for treating/preventing the progressive deterioration of renal function in diabetes
Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure
Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure
Warped Supersymmetric Grand Unification
We construct a realistic theory of grand unification in AdS_5 truncated by
branes, in which the unified gauge symmetry is broken by boundary conditions
and the electroweak scale is generated by the AdS warp factor. We show that the
theory preserves the successful gauge coupling unification of the 4D MSSM at
leading-logarithmic level. Kaluza-Klein (KK) towers, including those of XY
gauge and colored Higgs multiplets, appear at the TeV scale, while the extra
dimension provides natural mechanisms for doublet-triplet splitting and proton
decay suppression. In one possible scenario supersymmetry is strongly broken on
the TeV brane, in which case the lightest SU(3)_C x SU(2)_L x U(1)_Y gauginos
are approximately Dirac and the mass of the lightest XY gaugino is pushed well
below that of the lowest gauge boson KK mode, improving the prospects for its
production at the LHC. The bulk Lagrangian possesses a symmetry that we call
GUT parity. If GUT parity is exact, the lightest GUT particle, most likely an
XY gaugino, is stable. Once produced in a collider, the XY gaugino hadronizes
to form mesons, some of which will be charged and visible as highly ionizing
tracks. The lightest supersymmetric particle is the gravitino of mass \sim
10^{-3} eV, which is also stable if R parity is conserved.Comment: 41 pages, LaTeX, version to appear in Phys. Rev.
Flavour Physics in the Soft Wall Model
We extend the description of flavour that exists in the Randall-Sundrum (RS)
model to the soft wall (SW) model in which the IR brane is removed and the
Higgs is free to propagate in the bulk. It is demonstrated that, like the RS
model, one can generate the hierarchy of fermion masses by localising the
fermions at different locations throughout the space. However, there are two
significant differences. Firstly the possible fermion masses scale down, from
the electroweak scale, less steeply than in the RS model and secondly there now
exists a minimum fermion mass for fermions sitting towards the UV brane. With a
quadratic Higgs VEV, this minimum mass is about fifteen orders of magnitude
lower than the electroweak scale. We derive the gauge propagator and despite
the KK masses scaling as , it is demonstrated that the
coefficients of four fermion operators are not divergent at tree level. FCNC's
amongst kaons and leptons are considered and compared to calculations in the RS
model, with a brane localised Higgs and equivalent levels of tuning. It is
found that since the gauge fermion couplings are slightly more universal and
the SM fermions typically sit slightly further towards the UV brane, the
contributions to observables such as and , from the
exchange of KK gauge fields, are significantly reduced.Comment: 33 pages, 15 figures, 5 tables; v2: references added; v3:
modifications to figures 4,5 and 6. version to appear in JHE
Baryon Number in Warped GUTs : Model Building and (Dark Matter Related) Phenomenology
In the past year, a new non-supersymmetric framework for electroweak symmetry
breaking (with or without Higgs) involving SU(2)_L * SU(2)_R * U(1)_{B-L} in
higher dimensional warped geometry has been suggested. In this work, we embed
this gauge structure into a GUT such as SO(10) or Pati-Salam. We showed
recently (in hep-ph/0403143) that in a warped GUT, a stable Kaluza-Klein
fermion can arise as a consequence of imposing proton stability. Here, we
specify a complete realistic model where this particle is a weakly interacting
right-handed neutrino, and present a detailed study of this new dark matter
candidate, providing relic density and detection predictions. We discuss
phenomenological aspects associated with the existence of other light (<~ TeV)
KK fermions (related to the neutrino), whose lightness is a direct consequence
of the top quark's heaviness. The AdS/CFT interpretation of this construction
is also presented. Most of our qualitative results do not depend on the nature
of the breaking of the electroweak symmetry provided that it happens near the
TeV brane.Comment: 61 pages, 12 figures; v2: minor changes; v3: Two additional diagrams
in Fig. 10; a numerical factor corrected in section 16.1 (baryogenesis
section), corresponding discussion slightly modified but qualitative results
unchange
Phase II, double blind, placebo controlled, multi-site study to evaluate the safety, feasibility and desirability of conducting a phase III study of anamorelin for anorexia in people with small cell lung cancer: a study protocol (LUANA trial)
AbstractAnorexia is experienced by most people with lung cancer during the course of their disease and treatment. Anorexia reduces response to chemotherapy and the ability of patients to cope with, and complete their treatment leading to greater morbidity, poorer prognosis and outcomes. Despite the significant importance of cancer-related anorexia, current therapies are limited, have marginal benefits and unwarranted side effects. In this multi-site, randomised, double blind, placebo controlled, phase II trial, participants will be randomly assigned (1:1) to receive once-daily oral dosing of 100mg of anamorelin HCl or matched placebo for 12 weeks. Participants can then opt into an extension phase to receive blinded intervention for another 12 weeks (weeks 13-24) at the same dose and frequency. Adults (≥18 years) with small cell lung cancer (SCLC); newly diagnosed with planned systemic therapy OR with first recurrence of disease following a documented disease-free interval ≥6 months, AND with anorexia (i.e., ≤ 37 points on the 12-item Functional Assessment of Anorexia Cachexia Treatment (FAACT A/CS) scale) will be invited to participate. Primary outcomes are safety, desirability and feasibility outcomes related to participant recruitment, adherence to interventions, and completion of study tools to inform the design of a robust Phase III effectiveness trial. Secondary outcomes are the effects of study interventions on body weight and composition, functional status, nutritional intake, biochemistry, fatigue, harms, survival and quality of life. Primary and secondary efficacy analysis will be conducted at 12 weeks. Additional exploratory efficacy and safety analyses will also be conducted at 24 weeks to collect data over longer treatment duration. The feasibility of economic evaluations in Phase III trial will be assessed, including the indicative costs and benefits of anamorelin for SCLC to the healthcare system and society, the choice of methods for data collection and the future evaluation design. The trial has been registered with the Australian New Zealand Clinical Trials Registry [ACTRN12622000129785] and approved by the South Western Sydney Local Health District Human Research Ethics Committee [2021/ETH11339]
SUSY Splits, But Then Returns
We study the phenomenon of accidental or "emergent" supersymmetry within
gauge theory and connect it to the scenarios of Split Supersymmetry and Higgs
compositeness. Combining these elements leads to a significant refinement and
extension of the proposal of Partial Supersymmetry, in which supersymmetry is
broken at very high energies but with a remnant surviving to the weak scale.
The Hierarchy Problem is then solved by a non-trivial partnership between
supersymmetry and compositeness, giving a promising approach for reconciling
Higgs naturalness with the wealth of precision experimental data. We discuss
aspects of this scenario from the AdS/CFT dual viewpoint of higher-dimensional
warped compactification. It is argued that string theory constructions with
high scale supersymmetry breaking which realize warped/composite solutions to
the Hierarchy Problem may well be accompanied by some or all of the features
described. The central phenomenological considerations and expectations are
discussed, with more detailed modelling within warped effective field theory
reserved for future work.Comment: 29 pages. Flavor and CP constraints on left-right symmetric structure
briefly discussed. References adde
Src Inhibition Blocks c-Myc Translation and Glucose Metabolism to Prevent the Development of Breast Cancer
Preventing breast cancer will require the development of targeted strategies that can effectively block disease progression. Tamoxifen and aromatase inhibitors are effective in addressing estrogen receptor–positive (ER+) breast cancer development, but estrogen receptor–negative (ER−) breast cancer remains an unmet challenge due to gaps in pathobiologic understanding. In this study, we used reverse-phase protein array to identify activation of Src kinase as an early signaling alteration in premalignant breast lesions of women who did not respond to tamoxifen, a widely used ER antagonist for hormonal therapy of breast cancer. Src kinase blockade with the small-molecule inhibitor saracatinib prevented the disorganized three-dimensional growth of ER− mammary epithelial cells in vitro and delayed the development of premalignant lesions and tumors in vivo in mouse models developing HER2+ and ER− mammary tumors, extending tumor-free and overall survival. Mechanistic investigations revealed that Src blockade reduced glucose metabolism as a result of an inhibition in ERK1/2–MNK1–eIF4E–mediated cap-dependent translation of c-Myc and transcription of the glucose transporter GLUT1, thereby limiting energy available for cell growth. Taken together, our results provide a sound rationale to target Src pathways in premalignant breast lesions to limit the development of breast cancers
- …