Upfront lower dose lenalidomide is less toxic and does not compromise efficacy for vulnerable patients with relapsed refractory multiple myeloma: final analysis of the phase II RevLite study.

The combination of lenalidomide and dexamethasone is an established treatment for patients with multiple myeloma (MM). Increasingly, treatment attenuation is advocated for frail/elderly patients to minimize toxicity even though there have been no prospective studies to demonstrate whether lenalidomide dose attenuation impacts on response and survival outcome. This prospective multicentre phase II study assessed the efficacy and tolerability of lower dose lenalidomide (15 mg) and dexamethasone (20 mg) in 149 eligible patients with relapsed/refractory MM aged over 59 years and/or with renal impairment. The overall response rate was 71% (complete response 15%). Median (range) progression-free survival (PFS) and overall survival (OS) were 8·9 (6·9-11·5) and 30·5 (20·0-36·2) months, respectively. Upon formal statistical comparison of these endpoints to that of a matched cohort of patients from the pivotal phase III MM009/MM010 studies who received standard-dose lenalidomide (25 mg) and high-dose dexamethasone (40 mg) no difference was seen in PFS (P = 0·34) and OS (P = 0·21). Importantly, grade 3-4 toxicities were reduced with low-dose lenalidomide, mainly lower neutropenia (29% vs. 41%), infections (23% vs. 31%) and venous thromboembolism (3% vs. 13%). This study supports a strategy of lenalidomide dose reduction at the outset for at-risk patients, and prospectively confirms that such an approach reduces adverse events while not compromising patient response or survival outcomes.

A new gustometer for taste testing in rodents.

In recent years, to circumvent the interpretive limitations associated with intake tests commonly used to assess taste function in rodents, investigators have developed devices called gustometers to deliver small volumes of taste samples and measure immediate responses, thereby increasing confidence that the behavior of the animal is under orosensory control. Most of these gustometers can be used to measure unconditioned licking behavior to stimuli presented for short durations and/or can be used to train the animal to respond to various fluid stimuli differentially so as to obtain a reward and/or avoid punishment. Psychometric sensitivity and discrimination functions can thus be derived. Here, we describe a new gustometer design, successfully used in behavioral experiments, that was guided by our experience with an older version used for over 2 decades. The new computer-controlled gustometer features no dead space in stimulus delivery lines, effective cleaning of the licking substrate, and the ability to measure licking without passing electrical current through the animal. The parts and dimensions are detailed, and the benefits and limitations of certain design features are discussed. Schematics for key circuits are provided as supplemental information. Accordingly, it should be possible to fabricate this device in a fashion customized for one's needs.

Lymphoma for the acute physician: diagnostic challenges and initial treatment decisions.

Prompt diagnosis of lymphoma facilitates early treatment and improves outcomes for patients. For non-haemato-oncologists, it is important to have an understanding of how lymphoma can present and the initial work-up. This review is intended to provide clinicians with background to aid clinical decisional making at presentation and when managing treatment related complications. There will be particular emphasis on emergency presentations (tumour lysis syndrome, management of patients with a mediastinal mass, infections in lymphoma patients) and novel treatment options which have unique toxicities often requiring multi-specialty expertise.

Retinal nerve fiber layer thickness and cognitive ability in older people: the Lothian Birth Cohort 1936 study.

BACKGROUND: This study aims to examine the relationship between the retinal nerve fiber layer (RNFL) thickness as measured by optical coherence tomography (OCT) and lifetime cognitive change in healthy older people. METHODS: In a narrow-age sample population from the Lothian Birth Cohort 1936 who were all aged approximately 72 years when tested, participants underwent RNFL measurements using OCT. General linear modeling was used to calculate the effect of RNFL thickness on three domains; general cognitive ability (g-factor), general processing speed (g-speed) and general memory ability (g-memory) using age at time of assessment and gender as co-variates. RESULTS: Of 105 participants, 96 completed OCT scans that were of suitable quality for assessment were analyzed. Using age and gender as covariates, we found only one significant association, between the inferior area RNFL thickness and g-speed (p = 0.049, η2 = 0.045). Interestingly, when we included age 11 IQ as a covariate in addition to age and gender, there were several statistically significant associations (p = 0.029 to 0.048, η2 = 0.00 to 0.059) in a negative direction; decreasing scores on measures of g-factor and g-speed were associated with increasing RNFL thickness (r = -0.229 to -0.243, p < 0.05). No significant associations were found between RNFL thickness and g-memory ability. When we considered the number of years of education as a covariate, we found no significant associations between the RNFL thickness and cognitive scores. CONCLUSIONS: In a community dwelling cohort of healthy older people, increased RNFL thickness appeared to be associated with lower general processing speed and lower general cognitive ability when age 11 IQ scores were included as a covariate.

Quantitative measurements of enlarged perivascular spaces in the brain are associated with retinal microvascular parameters in older community-dwelling subjects.

BACKGROUND: Perivascular Spaces (PVS) become increasingly visible with advancing age on brain MRI, yet their relationship to morphological changes in the underlying microvessels remains poorly understood. Retinal and cerebral microvessels share morphological and physiological properties. We compared computationally-derived PVS morphologies with retinal vessel morphologies in older people. METHODS: We analysed data from community-dwelling individuals who underwent multimodal brain MRI and retinal fundus camera imaging at mean age 72.55 years (SD=0.71). We assessed centrum semiovale PVS computationally to determine PVS total volume and count, and mean per-subject individual PVS length, width and size. We analysed retinal images using the VAMPIRE software suite, obtaining the Central Retinal Artery and Vein Equivalents (CRVE and CRAE), Arteriole-to-Venule ratio (AVR), and fractal dimension (FD) of both eyes. We investigated associations using general linear models, adjusted for age, gender, and major vascular risk factors. RESULTS: In 381 subjects with all measures, increasing total PVS volume and count were associated with decreased CRAE in the left eye (volume ß=-0.170, count ß=-0.184, p<0.001). No associations of PVS with CRVE were found. The PVS total volume, individual width and size increased with decreasing FD of the arterioles (a) and venules (v) of the left eye (total volume: FDa ß=-0.137, FDv ß=-0.139, p<0.01; width: FDa ß=-0.144, FDv ß=-0.158, p<0.01; size: FDa ß=-0.157, FDv ß=-0.162, p<0.01). CONCLUSIONS: Increase in PVS number and size visible on MRI reflect arteriolar narrowing and lower retinal arteriole and venule branching complexity, both markers of impaired microvascular health. Computationally-derived PVS metrics may be an early indicator of failing vascular health and should be tested in longitudinal studies.

Is there a mismatch negativity during change blindness?

The mismatch negativity is an event-related potential that represents a preattentive change detection process. The aim of this study was to determine whether the mismatch negativity was present during 'change blindness', a striking phenomenon in which surprisingly large changes in a complex scene are not seen when they occur during a blink or an eye movement. In this study, large orientation changes elicited a candidate mismatch negativity between 180 and 320 ms that appeared to be independent of participants' performance (uncued 76% correct, miscued 59% correct with chance performance at 50%). This negativity, however, disappeared in the miscued 'change blind' condition. In conclusion, the mismatch negativity does not appear to be present during change blindness suggesting that in complex scenes even large changes may not trigger preattentive change detection processes.

Retinal vascular fractal dimension, childhood IQ, and cognitive ability in old age: the Lothian Birth Cohort Study 1936.

PURPOSE: Cerebral microvascular disease is associated with dementia. Differences in the topography of the retinal vascular network may be a marker for cerebrovascular disease. The association between cerebral microvascular state and non-pathological cognitive ageing is less clear, particularly because studies are rarely able to adjust for pre-morbid cognitive ability level. We measured retinal vascular fractal dimension (Df) as a potential marker of cerebral microvascular disease. We examined the extent to which it contributes to differences in non-pathological cognitive ability in old age, after adjusting for childhood mental ability. METHODS: Participants from the Lothian Birth Cohort 1936 Study (LBC1936) had cognitive ability assessments and retinal photographs taken of both eyes aged around 73 years (n = 648). IQ scores were available from childhood. Retinal vascular Df was calculated with monofractal and multifractal analysis, performed on custom-written software. Multiple regression models were applied to determine associations between retinal vascular Df and general cognitive ability (g), processing speed, and memory. RESULTS: Only three out of 24 comparisons (two eyes × four Df parameters × three cognitive measures) were found to be significant. This is little more than would be expected by chance. No single association was verified by an equivalent association in the contralateral eye. CONCLUSIONS: The results show little evidence that fractal measures of retinal vascular differences are associated with non-pathological cognitive ageing.

Ovarian steroid hormones modulate circadian rhythms of neuroendocrine dopaminergic neuronal activity.

Dopamine (DA) is the primary inhibitor of prolactin (PRL) secretion. Three populations of neuroendocrine dopaminergic neurons (NDNs) designated tuberoinfundibular (TIDA), tuberohypophyseal (THDA) and periventricular hypophyseal DAergic (PHDA) neurons regulate PRL secretion. Given that ovarian steroids modulate both DA release and PRL secretion independently, we characterized the role of steroid hormones in coupling rhythmic NDN activity and PRL secretion. OVX rats under a standard 12:12 L:D cycle (L:D), constant dark (DD), or a 6-h phase-delayed L:D cycle (pdL:D) were treated with Estradiol-17beta (E) or E and Progesterone (E+P). NDN activity, defined by DA:DOPAC ratio in nerve terminals, was determined by HPLC-EC. E or E+P stimulated PRL surges in L:D that persisted under DD. In TIDA neurons, E or E+P treatment reduced the amount of DA released under L:D and DD and advanced the rhythm of DA turnover. E and E+P treatment reduced THDA and PHDA neuron activity under L:D, but did not affect these rhythms under DD. Circadian rhythms of PRL, corticosterone and DA turnover in NDN terminals from steroid treated rats entrained to a pdL:D cycle within 7 days. Therefore, ovarian steroids differentially adjust the timing and magnitude of NDN activity to facilitate coupling of DA release and PRL secretion.

Event-related potentials (ERPs) to schematic faces in adults and children.

Event-related potentials (ERPs) were recorded from 4-year-old 8-10-year-old children and adults to a schematic face, inverted face and jumbled face. The subjects were instructed to fixate the stimuli and no other response was required. The schematic face and inverted face were shown with a frequency of 20% each and the remaining presentations (60%) were of the jumbled face. P1 and N170 peak latency were measurable in the children and adults. These peaks were at longer latencies in the children. P3 was measurable in the adults and 8-10-year-old children but not the 4-year-olds. The adults had larger and longer latency P1 and smaller amplitude N170 to the inverted face than the other faces. In contrast, the P1 was unaffected by inversion in the children and the N170 was not smaller to the inverted or jumbled face. It is concluded that this result reflects developmental differences in the processing of configuration, with the children relying on an under-specified configuration of the face.

Unipro UGENE NGS pipelines and components for variant calling, RNA-seq and ChIP-seq data analyses.

The advent of Next Generation Sequencing (NGS) technologies has opened new possibilities for researchers. However, the more biology becomes a data-intensive field, the more biologists have to learn how to process and analyze NGS data with complex computational tools. Even with the availability of common pipeline specifications, it is often a time-consuming and cumbersome task for a bench scientist to install and configure the pipeline tools. We believe that a unified, desktop and biologist-friendly front end to NGS data analysis tools will substantially improve productivity in this field. Here we present NGS pipelines "Variant Calling with SAMtools", "Tuxedo Pipeline for RNA-seq Data Analysis" and "Cistrome Pipeline for ChIP-seq Data Analysis" integrated into the Unipro UGENE desktop toolkit. We describe the available UGENE infrastructure that helps researchers run these pipelines on different datasets, store and investigate the results and re-run the pipelines with the same parameters. These pipeline tools are included in the UGENE NGS package. Individual blocks of these pipelines are also available for expert users to create their own advanced workflows.

Personality, health, and brain integrity: the Lothian birth cohort study 1936.

OBJECTIVE: To explore associations between the 5-factor model (FFM; neuroticism, extraversion, openness/intellect, agreeableness, and conscientiousness), personality traits, and measures of whole-brain integrity in a large sample of older people, and to test whether these associations are mediated by health-related behaviors. METHOD: Participants from the Lothian Birth Cohort 1936 completed the International Personality Item Pool measure, a 5-factor public-domain personality measure (http://ipip.ori.org), and underwent a structural magnetic resonance brain scan at the mean age of 73 years, yielding 3 measures of whole brain integrity: average white matter fractional anisotropy (FA), brain-tissue loss, and white matter hyperintensities (N = 529 to 565). Correlational and mediation analyses were used to test the potential mediating effects of health-related behaviors on the associations between personality and integrity. RESULTS: Lower conscientiousness was consistently associated with brain-tissue loss (ß = -0.11, p < 0.01), lower FA (ß = 0.16, p < 0.001) and white matter hyperintensities (ß = -0.10, p < 0.05). Smoking, alcohol consumption, diet, physical activity, body mass index and a composite health-behavior variable displayed significant associations with measures of brain integrity (range of r = 0.10 to 0.25). The direct effects of conscientiousness on brain integrity were mediated to some degree by health behaviors, with the proportions of explained direct effects ranging from 0.1% to 13.7%. CONCLUSION: Conscientiousness was associated with all 3 measures of brain integrity, which we tentatively interpret as the effects of personality on brain aging. Small proportions of the direct effects were mediated by individual health behaviors. RESULTS provide initial indications that lifetime stable personality traits may influence brain health in later life through health-promoting behaviors.

Incidental findings on brain MR imaging in older community-dwelling subjects are common but serious medical consequences are rare: a cohort study.

OBJECTIVES: Incidental findings in neuroimaging occur in 3% of volunteers. Most data come from young subjects. Data on their occurrence in older subjects and their medical, lifestyle and financial consequences are lacking. We determined the prevalence and medical consequences of incidental findings found in community-dwelling older subjects on brain magnetic resonance imaging. DESIGN: Prospective cohort observational study. SETTING: Single centre study with input from secondary care. PARTICIPANTS: Lothian Birth Cohort 1936, a study of cognitive ageing. MAIN OUTCOME MEASURES: Incidental findings identified by two consultant neuroradiologists on structural brain magnetic resonance imaging at age 73 years; resulting medical referrals and interventions. PRIMARY AND SECONDARY OUTCOME MEASURES: PREVALENCE OF INCIDENTAL FINDINGS BY INDIVIDUAL CATEGORIES: neoplasms, cysts, vascular lesions, developmental, ear, nose or throat anomalies, by intra- and extracranial location; visual rating of white matter hyperintensities and brain atrophy. RESULTS: There were 281 incidental findings in 223 (32%) of 700 subjects, including 14 intra- or extracranial neoplasms (2%), 15 intracranial vascular anomalies (2%), and 137 infarcts or haemorrhages (20%). Additionally, 153 had moderate/severe deep white matter hyperintensities (22%) and 176 had cerebral atrophy at, or above, the upper limit of normal (25%) compared with a normative population template. The incidental findings were unrelated to white matter hyperintensities or atrophy; about a third of subjects had both incidental findings and moderate or severe WMH and a quarter had incidental findings and atrophy. The incidental findings resulted in one urgent and nine non-urgent referrals for further medical assessment, but ultimately in no new treatments. CONCLUSIONS: In community-dwelling older subjects, incidental findings, including white matter hyperintensities and atrophy, were common. However, many findings were not of medical importance and, in this age group, most did not result in further assessment and none in change of treatment.

Brain white matter tract integrity and cognitive abilities in community-dwelling older people: the Lothian Birth Cohort, 1936.

OBJECTIVE: The present study investigates associations between brain white matter tract integrity and cognitive abilities in community-dwelling older people (N = 655). We explored two potential confounds of white matter tract-cognition associations in later life: (a) whether the associations between tracts and specific cognitive abilities are accounted for by general cognitive ability (g); and (b) how the presence of atrophy and white matter lesions affect these associations. METHOD: Tract integrity was determined using quantitative diffusion magnetic resonance imaging tractography (tract-averaged fractional anisotropy [FA]). Using confirmatory factor analysis, we compared first-order and bifactor models to investigate whether specific tract-ability associations were accounted for by g. RESULTS: Significant associations were found between g and FA in bilateral anterior thalamic radiations (r range: .16-.18, p < .01), uncinate (r range: .19-.26, p < .001), arcuate fasciculi (r range: .11-.12, p < .05), and the splenium of corpus callosum (r = .14, p < .01). After controlling for g within the bifactor model, some significant specific cognitive domain associations remained. Results also suggest that the primary effects of controlling for whole brain integrity were on g associations, not specific abilities. CONCLUSION: Results suggest that g accounts for most of, but not all, the tract-cognition associations in the current data. When controlling for age-related overall brain structural changes, only minor attenuations of the tract-cognition associations were found, and these were primarily with g. In totality, the results highlight the importance of controlling for g when investigating associations between specific cognitive abilities and neuropsychology variables.

Pelamis: experience from concept to connection.

The development of the Pelamis wave energy converter from its conceptual origins to its commercial deployment is reviewed. The early emphasis on designing for survivability and favourable power absorption characteristics focused attention towards a self-referenced articulated line-absorber in an attenuator orientation. A novel joint and control system allow the machine to be actively tuned to provide a resonant response power amplification in small and moderate seas. In severe seas, the machine is left in its default or natural condition, which is benign and non-resonant. Hydraulic rams at the joints provide the primary power take-off with medium-term storage in high-pressure accumulators yielding smooth electricity generation. Land-based modular construction requiring minimal weather windows for rapid offshore installation is an essential engineering feature necessary for viable commercialization. The second-generation Pelamis designs built for E.ON and ScottishPower Renewables are presented, and the scope for further cost reduction and performance enhancements are explained.

The association between retinal vessel morphology and retinal nerve fiber layer thickness in an elderly population.

BACKGROUND AND OBJECTIVE: To investigate the relationship between retinal vessel morphology (branching coefficient, bifurcation angle, and fractal analysis) and retinal nerve fiber layer (RNFL) thickness in an elderly population. PATIENTS AND METHODS: One hundred and one participants from the Lothian Birth Cohort 1936 (population of people all born in 1936) were studied. RNFL thickness measurements (using optical coherence tomography [OCT]) and digital retinal photographs were collected. The retinal images were analyzed using custom-designed software called the Vascular Assessment and Measurement Platform for Images of the Retina. RESULTS: Greater deviation from the optimal arteriolar branching coefficient was associated with greater RNFL thickness (r = 0.249, P = .028). There was no significant association between RNFL thickness and the other retinal vessel morphology parameters. CONCLUSION: RNFL thickness increased significantly with suboptimality of arteriole branching coefficient. These findings cannot be explained by our current understanding of OCT. OCT-based biomarker metrics require further study to better define retinal neurovascular imaging and anatomy.

PROTHROMBINEX(®)-VF (PTX-VF) usage for reversal of coagulopathy: prospective evaluation of thrombogenic risk.

INTRODUCTION: Prothrombin complex concentrates (PCCs) are used for the urgent reversal of oral vitamin K antagonists in patients with life-threatening bleeding or prior to urgent procedures/surgery. PCCs offer rapid and complete reversal without the disadvantages of volume overload and adverse reactions seen with fresh frozen plasma (FFP). There is concern about the risk of thrombosis associated with the use PCCs; data on this is limited at present. OBJECTIVES: To determine the incidence of objectively confirmed arterial or venous thromboembolism within 30 days following the administration of PROTHROMBINEX®-VF (PTX-VF) to acutely reverse a prolonged INR. MATERIALS/METHODS: A prospective observational study was conducted at two teaching hospitals in Auckland, NZ. All patients who received PTX-VF for the acute reversal of prolonged INR were eligible. Baseline patient demographics and reasons for PTX-VF administration were recorded. Patients were reviewed at days 7 and 30, to confirm/exclude thromboembolism or adverse events. RESULTS: 173 patients were enrolled from August 2008 to March 2009. The most frequent indication for reversal was acute bleeding. At 30 days 4.6% (8/173) patients had a definite/probable thrombotic event, and 16.7% had died either due to the presenting bleed (intracranial haemorrhage) or a complication of their presenting complaint (e.g. sepsis, renal failure). CONCLUSIONS: Acute reversal of anticoagulant therapy with PTX-VF is associated with a significant rate of thromboembolism (4.6%) within 30 days. These events can be explained by ongoing cessation of anticoagulant therapy in patients with ongoing risk factors for arterial or venous thrombosis, rather than directly attributable to PTX-VF therapy.