Effect of testosterone treatment on the trabecular bone score in older men with low serum testosterone.

The trabecular bone score (TBS) is an indirect measure of vertebral bone microarchitecture. Our objective was to examine the effect of testosterone treatment on TBS. One hundred and ninety-seven hypogonadal men were randomized to testosterone or placebo. After 12 months, there was no difference in the changes in TBS by randomized group. INTRODUCTION: In the Bone Trial of the Testosterone Trials, testosterone treatment increased trabecular volumetric bone mineral density (vBMD) and increased estimated bone strength as determined by finite element analysis. The trabecular bone score (TBS) is an indirect measure of vertebral bone microarchitecture. TBS predicts fracture independent of lumbar spine areal (a) BMD. The objective of this study was to examine the effect of testosterone treatment on TBS compared to its effects on vBMD and aBMD. METHODS: Two hundred and eleven men were enrolled in the Bone Trial of the Testosterone Trials. Of these, 197 men had 2 repeat TBS and vBMD measurements; 105 men were allocated to receive testosterone, and 92 men to placebo for 1 year. TBS, aBMD, and vBMD were assessed at baseline and month 12. RESULTS: There was no difference in the percent change in TBS by randomized group: 1.6% (95% confidence intervals (CI) 0.2-3.9) in the testosterone group and 1.4% (95% CI -0.2, 3.1) in the placebo group. In contrast, vBMD increased by 6% (95% CI 4.5-7.5) in the testosterone group compared to 0.4% (95% CI -1.65-0.88) in the placebo groups. CONCLUSIONS: TBS is not clinically useful in monitoring the 1-year effect of testosterone treatment on bone structure in older hypogonadal men.

Revisiting the Cholinergic Hypothesis in Alzheimer's Disease: Emerging Evidence from Translational and Clinical Research.

Scientific evidence collected over the past 4 decades suggests that a loss of cholinergic innervation in the cerebral cortex of patients with Alzheimer's disease is an early pathogenic event correlated with cognitive impairment. This evidence led to the formulation of the "Cholinergic Hypothesis of AD" and the development of cholinesterase inhibitor therapies. Although approved only as symptomatic therapies, recent studies suggest that long-term use of these drugs may also have disease-modifying benefits. A Cholinergic System Workgroup reassessed the role of the cholinergic system on AD pathogenesis in light of recent data, including neuroimaging data charting the progression of neurodegeneration in the cholinergic system and suggesting that cholinergic therapy may slow brain atrophy. Other pathways that contribute to cholinergic synaptic loss and their effect on cognitive impairment in AD were also reviewed. These studies indicate that the cholinergic system as one of several interacting systems failures that contribute to AD pathogenesis.

A Survey of Knowledge and Views Concerning Genetic and Amyloid PET Status Disclosure.

INTRODUCTION: This survey characterizes viewpoints of cognitively intact at-risk participants in an Alzheimer prevention registry if given the opportunity to learn their genetic and amyloid PET status. METHODS: 207 participants were offered a 25-item survey. They were asked if they wished to know their ApoE and amyloid PET status, and if so, reasons for wanting to know, or not, and the effects of such information on life plans. RESULTS: 164 (79.2%) of registrants completed the survey. Among those who were unaware of their ApoE or amyloid PET results, 80% desired to know this information. The most common reasons for wanting disclosure were to participate in research, to arrange personal affairs, to prepare family for illness, and to move life plans closer into the future. When asked if disclosure would help with making plans to end one's life when starting to lose their memory, 12.7% vs. 11.5% responded yes for ApoE and amyloid PET disclosures, respectively. Disclosure of these test results, if required for participation in a clinical trial, would make 15% of people less likely to participate. Likelihood of participation in prevention research and the desire to know test results were not related to scores on brief tests of knowledge about the tests. DISCUSSION: These results suggest that stakeholders in AD prevention research generally wish to know biological test information about their risk for developing AD to assist in making life plans.

Pedestal bifurcation and resonant field penetration at the threshold of edge-localized mode suppression in the DIII-D Tokamak.

Rapid bifurcations in the plasma response to slowly varying n=2 magnetic fields are observed as the plasma transitions into and out of edge-localized mode (ELM) suppression. The rapid transition to ELM suppression is characterized by an increase in the toroidal rotation and a reduction in the electron pressure gradient at the top of the pedestal that reduces the perpendicular electron flow there to near zero. These events occur simultaneously with an increase in the inner-wall magnetic response. These observations are consistent with strong resonant field penetration of n=2 fields at the onset of ELM suppression, based on extended MHD simulations using measured plasma profiles. Spontaneous transitions into (and out of) ELM suppression with a static applied n=2 field indicate competing mechanisms of screening and penetration of resonant fields near threshold conditions. Magnetic measurements reveal evidence for the unlocking and rotation of tearinglike structures as the plasma transitions out of ELM suppression.

APOE and BDNF polymorphisms moderate amyloid ß-related cognitive decline in preclinical Alzheimer's disease.

Accumulation of ß-amyloid (Aß) in the brain is associated with memory decline in healthy individuals as a prelude to Alzheimer's disease (AD). Genetic factors may moderate this decline. We examined the role of apolipoprotein E (ɛ4 carrier[ɛ4(+)], ɛ4 non-carrier[ɛ4(-)]) and brain-derived neurotrophic factor (BDNF(Val/Val), BDNF(Met)) in the extent to which they moderate Aß-related memory decline. Healthy adults (n=333, Mage=70 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent Aß neuroimaging. Neuropsychological assessments were conducted at baseline, 18-, 36- and 54-month follow-ups. Aß positron emission tomography neuroimaging was used to classify participants as Aß(-) or Aß(+). Relative to Aß(-)ɛ4(-), Aß(+)ɛ4(+) individuals showed significantly faster rates of cognitive decline over 54 months across all domains (d=0.40-1.22), while Aß(+)ɛ4(-) individuals showed significantly faster decline only on verbal episodic memory (EM). There were no differences in rates of cognitive change between Aß(-)ɛ4(-) and Aß(-)ɛ4(+) groups. Among Aß(+) individuals, ɛ4(+)/BDNF(Met) participants showed a significantly faster rate of decline on verbal and visual EM, and language over 54 months compared with ɛ4(-)/BDNF(Val/Val) participants (d=0.90-1.02). At least two genetic loci affect the rate of Aß-related cognitive decline. Aß(+)ɛ4(+)/BDNF(Met) individuals can expect to show clinically significant memory impairment after 3 years, whereas Aß(+)ɛ4(+)/BDNF(Val/Val) individuals can expect a similar degree of impairment after 10 years. Little decline over 54 months was observed in the Aß(-) and Aß(+) ɛ4(-) groups, irrespective of BDNF status. These data raise important prognostic issues in managing preclinical AD, and should be considered in designing secondary preventative clinical trials.

Access to a new plasma edge state with high density and pressures using the quiescent H mode.

A path to a new high performance regime has been discovered in tokamaks that could improve the attractiveness of a fusion reactor. Experiments on DIII-D using a quiescent H-mode edge have navigated a valley of improved edge peeling-ballooning stability that opens up with strong plasma shaping at high density, leading to a doubling of the edge pressure over the standard H mode with edge localized modes at these parameters. The thermal energy confinement time increases as a result of both the increased pedestal height and improvements in the core transport and reduced low-k turbulence. Calculations of the pedestal height and width as a function of density using constraints imposed by peeling-ballooning and kinetic-ballooning theory are in quantitative agreement with the measurements.

Karhunen-Loève treatment to remove noise and facilitate data analysis in sensing, spectroscopy and other applications.

Resolving weak spectral variations in the dynamic response of materials that are either dominated or excited by stochastic processes remains a challenge. Responses that are thermal in origin are particularly relevant examples due to the delocalized nature of heat. Despite its inherent properties in dealing with stochastic processes, the Karhunen-Loève expansion has not been fully exploited in measurement of systems that are driven solely by random forces or can exhibit large thermally driven random fluctuations. Here, we present experimental results and analysis of the archetypes (a) the resonant excitation and transient response of an atomic force microscope probe by the ambient random fluctuations and nanoscale photothermal sample response, and (b) the photothermally scattered photons in pump-probe spectroscopy. In each case, the dynamic process is represented as an infinite series with random coefficients to obtain pertinent frequency shifts and spectral peaks and demonstrate spectral enhancement for a set of compounds including the spectrally complex biomass. The considered cases find important applications in nanoscale material characterization, biosensing, and spectral identification of biological and chemical agents.

Observation of edge instability limiting the pedestal growth in tokamak plasmas.

With fusion device performance hinging on the edge pedestal pressure, it is imperative to experimentally understand the physical mechanism dictating the pedestal characteristics and to validate and improve pedestal predictive models. This Letter reports direct evidence of density and magnetic fluctuations showing the stiff onset of an edge instability leading to the saturation of the pedestal on the Alcator C-Mod tokamak. Edge stability analyses indicate that the pedestal is unstable to both ballooning mode and kinetic ballooning mode in agreement with observations.

Extended treatment of Cushing's disease with pasireotide: results from a 2-year, Phase II study.

In a previous 15-day, Phase II study of patients with de novo or persistent/recurrent Cushing's disease (core study), treatment with pasireotide 600 µg sc bid reduced urinary free cortisol (UFC) levels in 76% of patients and normalized UFC in 17%. The objective of this study was to evaluate the efficacy and safety of extended treatment with pasireotide. This was a planned, open-ended, single-arm, multicenter extension study (primary endpoint: 6 months). Patients aged ≥18 years with Cushing's disease who completed the core study could enter the extension if they achieved UFC normalization at core study end and/or obtained significant clinical benefit. Of the 38 patients who completed the core study, 19 entered the extension and 18 were included in the efficacy analyses (three responders, 11 reducers, four non-reducers in the core study). At data cut-off, median treatment duration in the extension was 9.7 months (range: 2 months to 4.8 years). At extension month 6, 56% of the 18 patients had lower UFC than at core baseline and 22% had normalized UFC. Of the four patients who remained on study drug at month 24, one had normalized UFC. Reductions in serum cortisol, plasma adrenocorticotropic hormone, body weight and diastolic blood pressure were observed. The most common adverse events were mild-to-moderate gastrointestinal disorders and hyperglycemia. Pasireotide offers a tumor-directed medical therapy that may be effective for the extended treatment of some patients with Cushing's disease.

Vertebral deformities and fractures are associated with MRI and pQCT measures obtained at the distal tibia and radius of postmenopausal women.

SUMMARY: We investigated the association of postmenopausal vertebral deformities and fractures with bone parameters derived from distal extremities using MRI and pQCT. Distal extremity measures showed variable degrees of association with vertebral deformities and fractures, highlighting the systemic nature of postmenopausal bone loss. INTRODUCTION: Prevalent vertebral deformities and fractures are known to predict incident further fractures. However, the association of distal extremity measures and vertebral deformities in postmenopausal women has not been fully established. METHODS: This study involved 98 postmenopausal women (age range 60-88 years, mean 70 years) with DXA BMD T-scores at either the hip or spine in the range of -1.5 to -3.5. Wedge, biconcavity, and crush deformities were computed on the basis of spine MRI. Vertebral fractures were assessed using Eastell's criterion. Distal tibia and radius stiffness was computed using MRI-based finite element analysis. BMD at the distal extremities were obtained using pQCT. RESULTS: Several distal extremity MRI and pQCT measures showed negative association with vertebral deformity on the basis of single parameter correlation (r up to 0.67) and two-parameter regression (r up to 0.76) models involving MRI stiffness and pQCT BMD. Subjects who had at least one prevalent vertebral fracture showed decreased MRI stiffness (up to 17.9 %) and pQCT density (up to 34.2 %) at the distal extremities compared to the non-fracture group. DXA lumbar spine BMD T-score was not associated with vertebral deformities. CONCLUSIONS: The association between vertebral deformities and distal extremity measures supports the notion of postmenopausal osteoporosis as a systemic phenomenon.

Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial.

The Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer's disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer's disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described.

Infection deflection: hosts control parasite location with behaviour to improve tolerance.

Anti-parasite behaviour can reduce parasitic infections, but little is known about how such behaviours affect infection location within the host's body and whether parasite distribution ultimately affects tolerance of infection. To assess these questions, we exposed both anaesthetized (no behaviour) and non-anaesthetized Hyla femoralis tadpoles to plagiorchiid cercariae (larval trematodes), and quantified resistance, tolerance (relationship between mass change and infection intensity) and encystment location. Non-anaesthetized tadpoles had significantly more infections in their tail region than anaesthetized tadpoles, which had the majority of their infections in the head. This pattern indicates that parasites preferred to infect the head, but that hosts shunted infections to the tail when possible. Furthermore, there was a significant effect of encystment location on tolerance, with head-infected tadpoles having poorer tolerance to infection than tail-infected tadpoles. Variance partitioning suggests that, among infected tadpoles, behaviour contributed more to tolerance than resistance. These results suggest that, in addition to using behaviour to resist parasites, H. femoralis tadpoles also use behaviour to enhance infection tolerance by deflecting infections posteriorly, away from their vital sensory organs. These findings highlight the need to assess how widespread and important behaviour is to the tolerance of infections.

Is the haematopoietic effect of testosterone mediated by erythropoietin? The results of a clinical trial in older men.

The stimulatory effects of testosterone on erythropoiesis are very well known, but the mechanisms underlying the erythropoietic action of testosterone are still poorly understood, although erythropoietin has long been considered a potential mediator. A total of 108 healthy men >65 years old with serum testosterone concentration <475 ng/dL were recruited by direct mailings to alumni of the University of Pennsylvania and Temple University, and randomized to receive a 60-cm(2) testosterone or placebo patch for 36 months. Ninety-six subjects completed the trial. We used information and stored serum specimens from this trial to test the hypothesis that increasing testosterone increases haemoglobin by stimulating erythropoietin production. We used information of 67 men, 43 in the testosterone group and 24 in the placebo group who had banked specimens available for assays of testosterone, haemoglobin and erythropoietin at baseline and after 36 months. The original randomized clinical study was primarily designed to verify the effects of testosterone on bone mineral density. The primary outcome of this report was to investigate whether or not transdermal testosterone increases haemoglobin by increasing erythropoietin levels. The mean age ± SD of the 67 subjects at baseline was 71.8 ± 4.9 years. Testosterone replacement therapy for 36 months, as compared with placebo, induced a significant increase in haemoglobin (0.86 ± 0.31 g/dL, p = 0.01), but no change in erythropoietin levels (-0.24 ± 2.16 mIU/mL, p = 0.91). Included time-varying measure of erythropoietin did not significantly account for the effect of testosterone on haemoglobin (Treatment-by-time: ß = 0.93, SE = 0.33, p = 0.01). No serious adverse effect was observed. Transdermal testosterone treatment of older men for 36 months significantly increased haemoglobin, but not erythropoietin levels. The haematopoietic effect of testosterone does not appear to be mediated by stimulation of erythropoietin production.

Characterizing the transition from paediatric to adult care among emerging adults with Type 1 diabetes.

AIMS: The goals of the study were to describe the transition of youth with Type 1 diabetes from paediatric to adult healthcare services, examine the link of this transition with self care and glycaemic control, and distinguish youth who received medical treatment from different physicians in terms of demographic and parent relationship variables. METHODS: Youth with Type 1 diabetes (n = 118) were enrolled in a prospective study that examined the transition from the paediatric to adult healthcare systems and were evaluated during their senior year of high school (time 1) and 1 year later (time 2). Data on self care, glycaemic control and parent relationship were collected. RESULTS: The majority of youth saw a paediatric endocrinologist at both assessments (n = 64); others saw an adult care physician at both assessments (n = 26) or transitioned from a paediatric endocrinologist to an adult care physician (n = 19). Nine youth saw no physician between time 1 and time 2. There were group differences in demographic and parent relationship variables and self-care behaviour and glycaemic control related to the transition of care. Youth who remained in the paediatric healthcare system had the best self care and did not experience declines in glycaemic control over time. CONCLUSIONS: Early transition from the paediatric healthcare system to the adult healthcare system is associated with psychosocial variables and worse glycaemic control. Future research should identify factors that determine optimal timing and strategies to avoid deterioration of care and control during this transition.

Reduction of edge-localized mode intensity using high-repetition-rate pellet injection in tokamak H-mode plasmas.

High repetition rate injection of deuterium pellets from the low-field side (LFS) of the DIII-D tokamak is shown to trigger high-frequency edge-localized modes (ELMs) at up to 12× the low natural ELM frequency in H-mode deuterium plasmas designed to match the ITER baseline configuration in shape, normalized beta, and input power just above the H-mode threshold. The pellet size, velocity, and injection location were chosen to limit penetration to the outer 10% of the plasma. The resulting perturbations to the plasma density and energy confinement time are thus minimal (<10%). The triggered ELMs occur at much lower normalized pedestal pressure than the natural ELMs, suggesting that the pellet injection excites a localized high-n instability. Triggered ELMs produce up to 12× lower energy and particle fluxes to the divertor, and result in a strong decrease in plasma core impurity density. These results show for the first time that shallow, LFS pellet injection can dramatically accelerate the ELM cycle and reduce ELM energy fluxes on plasma facing components, and is a viable technique for real-time control of ELMs in ITER.

ECE-imaging of the H-mode pedestal (invited).

A synthetic diagnostic has been developed that reproduces the highly structured electron cyclotron emission (ECE) spectrum radiated from the edge region of H-mode discharges. The modeled dependence on local perturbations of the equilibrium plasma pressure allows for interpretation of ECE data for diagnosis of local quantities. Forward modeling of the diagnostic response in this region allows for improved mapping of the observed fluctuations to flux surfaces within the plasma, allowing for the poloidal mode number of coherent structures to be resolved. In addition, other spectral features that are dependent on both T(e) and n(e) contain information about pedestal structure and the electron energy distribution of localized phenomena, such as edge filaments arising during edge-localized mode (ELM) activity.

Initial results of the high resolution edge Thomson scattering upgrade at DIII-D.

Validation of models of pedestal structure is an important part of predicting pedestal height and performance in future tokamaks. The Thomson scattering diagnostic at DIII-D has been upgraded in support of validating these models. Spatial and temporal resolution, as well as signal to noise ratio, have all been specifically enhanced in the pedestal region. This region is now diagnosed by 20 view-chords with a spacing of 6 mm and a scattering length of just under 5 mm sampled at a nominal rate of 250 Hz. When mapped to the outboard midplane, this corresponds to ~3 mm spacing. These measurements are being used to test critical gradient models, in which pedestal gradients increase in time until a threshold is reached. This paper will describe the specifications of the upgrade and present initial results of the system.

Pulmonary abnormalities in dogs with renal azotemia.

BACKGROUND: Clinical signs associated with respiratory tract disease are regularly encountered in people with kidney failure, and have been anecdotally reported in dogs. OBJECTIVES: To compare clinical signs indicative of pulmonary disease, clinicopathologic findings, radiographic abnormalities, and histologic findings in dogs with acute kidney injury (AKI) or International Renal Interest Society Stage 3 or 4 chronic kidney disease (CKD) to nonazotemic dogs. To determine associations between abnormalities indicative of pulmonary disease and outcome in azotemic dogs. ANIMALS: One hundred sixty-seven pet dogs (54 AKI dogs, 50 CKD dogs, 63 nonazotemic control dogs diagnosed with intracranial disease). METHODS: Retrospective cohort study comparing signalment, clinical signs, clinicopathologic variables, prevalence, and severity of pulmonary radiographic patterns, histopathologic findings, and survival times in AKI, CKD, and control dogs. RESULTS: Clinical signs of pulmonary disease were significantly more common in AKI dogs. Prevalence of an alveolar lung pattern was greater in AKI and CKD dogs. Alveolar mineralization was the most common pulmonary histologic lesion in AKI dogs (6 of 8 dogs), with concurrent alveolar concretions or mineralization of pulmonary vessels or bronchioles noted in 1 dog each; mineralization of lung tissues was not noted in control dogs. Neither clinical signs nor presence of an alveolar pattern were associated with likelihood of survival to discharge or median number of days from discharge until death. CONCLUSIONS AND CLINICAL IMPORTANCE: Abnormalities indicative of pulmonary disease are more common in azotemic dogs than in control dogs; however, prognosis is not associated with presence of clinical or radiographic pulmonary dysfunction.

High-frequency coherent edge fluctuations in a high-pedestal-pressure quiescent H-mode plasma.

A set of high frequency coherent (HFC) modes (f=80-250 kHz) is observed with beam emission spectroscopy measurements of density fluctuations in the pedestal of a strongly shaped quiescent H-mode plasma on DIII-D, with characteristics predicted for kinetic ballooning modes (KBM): propagation in the ion-diamagnetic drift direction; a frequency near 0.2-0.3 times the ion-diamagnetic frequency; inferred toroidal mode numbers of n∼10-25; poloidal wave numbers of k(θ)∼0.17-0.4 cm(-1); and high measured decorrelation rates (τ(c)(-1)∼ω(s)∼0.5×10(6) s(-1)). Their appearance correlates with saturation of the pedestal pressure.

EHT0202 in Alzheimer's disease: a 3-month, randomized, placebo-controlled, double-blind study.

BACKGROUND: EHT0202 (etazolate hydrochloride) is a new compound exhibiting both potential disease-modifying and symptomatic treatment properties in Alzheimer's Disease increasing alpha-secretase activity and sAPP alpha secretion, as well as acting as a GABA-A receptor modulator and as a PDE-4 inhibitor. METHODS: This pilot, randomized, double-blind, placebo-controlled, parallel group, multicentre, Phase IIA study was conducted in 159 randomized patients suffering from mild to moderate Alzheimer's Disease. EHT0202 (40 or 80 mg bid) or placebo was administered as adjunctive therapy to one acetylcholinesterase inhibitor over a 3-month period. This study was designed to assess the clinical safety and tolerability of EHT0202 as a primary objective, with secondary endpoints (cognitive function, daily living activities, behaviour, caregiver burden and global functioning) included to explore clinical efficacy of EHT0202 versus placebo. RESULTS: EHT0202 was shown to be safe and generally well tolerated. Dose-dependent numbers of early withdrawal and central nervous system related adverse events were observed. As expected, since the study was not powered and not designed to show drug efficacy, and except for ratings on the ADCS-ADL scale, no significant differences were seen between treatment groups. CONCLUSIONS: These first encouraging safety results do support further development of EHT0202 in order to assess its clinical efficacy and to confirm its tolerability in a larger cohort of Alzheimer patients and for a longer period.