Inhibitor kinazy Brutona u chorych z nawrotowym lub opornym na leczenie chłoniakiem z komórek płaszcza – wyniki międzynarodowego,wieloośrodkowego,badania II fazy z ibrutynibem (PCI-32765) – EHA Encore

Bruton's tyrosine kinase (BTK) is a central mediator of B-cell receptor (BCR) signaling essential for normal B-cell development. Ibrutinib is an oral BTK inhibitor that induces apoptosis and inhibits migration and adhesion of malignant B-cells. Updated results of this international, multicenter, phase 2 study of single agent ibrutinib in relapsed or refractory MCL will be presented.Ibrutinib 560 mg PO QD was administered continuously until disease progression. Tumor response was assessed every 2 cycles (one cycle = 28 days). The study enrolled 115 patients (65 bortezomib-naïve, 50 bortezomib-exposed); 111 patients were treated; 110 were evaluable for response. Baseline characteristics included: median age 68 years, time since diagnosis 42 months, number of prior treatments 3; bulky disease (>10 cm) 13%, prior stem cell transplant 10%, high risk MIPI 49%.Median time on treatment was 9.2 months; 53% of patients remain on therapy. Median PFS was 13.9 months and DOR has not yet been reached. Responses increased with longer treatment: comparing to previous data described at ASH 2011, the CR rate increased from 16% to 39%, and the ORR increased from 69% to 75%.     

Impaired glucose tolerance in midlife and longitudinal changes in brain function during aging

We investigated whether individuals with impaired glucose tolerance (IGT) in midlife subsequently show regionally specific longitudinal changes in regional cerebral blood flow (rCBF) relative to those with normal glucose tolerance (NGT). Sixty-four cognitively normal participants in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging underwent serial ¹⁵O-water positron emission tomography scans (age at first scan, 69.6 ± 7.5 years) and oral glucose tolerance tests 12 years earlier (age at first oral glucose tolerance test, 57.2 ± 11.1 years). Using voxel-based analysis, we compared changes in rCBF over an 8-year period between 15 participants with IGT in midlife and 49 with NGT. Significant differences were observed in longitudinal change in rCBF between the IGT and NGT groups. The predominant pattern was greater rCBF decline in the IGT group in the frontal, parietal, and temporal cortices. Some brain regions in the frontal and temporal cortices also showed greater longitudinal increments in rCBF in the IGT group. Our findings suggest that IGT in midlife is associated with subsequent longitudinal changes in brain function during aging even in cognitively normal older individuals.     

Heightened Hippocampal β-Adrenergic Receptor Function Drives Synaptic Potentiation and Supports Learning and Memory in the TgF344-AD Rat Model during Prodromal Alzheimer's Disease

The central noradrenergic (NA) system is critical for the maintenance of attention, behavioral flexibility, spatial navigation, and learning and memory, those cognitive functions lost first in early Alzheimer''s disease (AD). In fact, the locus coeruleus (LC), the sole source of norepinephrine (NE) for >90% of the brain, is the first site of pathologic tau accumulation in human AD with axon loss throughout forebrain, including hippocampus. The dentate gyrus is heavily innervated by LC–NA axons, where released NE acts on β-adrenergic receptors (ARs) at excitatory synapses from entorhinal cortex to facilitate long-term synaptic plasticity and memory formation. These synapses experience dysfunction in early AD before cognitive impairment. In the TgF344-AD rat model of AD, degeneration of LC–NA axons in hippocampus recapitulates human AD, providing a preclinical model to investigate synaptic and behavioral consequences. Using immunohistochemistry, Western blot analysis, and brain slice electrophysiology in 6- to 9-month-old wild-type and TgF344-AD rats, we discovered that the loss of LC–NA axons coincides with the heightened β-AR function at medial perforant path–dentate granule cell synapses that is responsible for the increase in LTP magnitude at these synapses. Furthermore, novel object recognition is facilitated in TgF344-AD rats that requires β-ARs, and pharmacological blockade of β-ARs unmasks a deficit in extinction learning only in TgF344-AD rats, indicating a greater reliance on β-ARs in both behaviors. Thus, a compensatory increase in β-AR function during prodromal AD in TgF344-AD rats heightens synaptic plasticity and preserves some forms of learning and memory.SIGNIFICANCE STATEMENT The locus coeruleus (LC), a brain region located in the brainstem which is responsible for attention and arousal, is damaged first by Alzheimer''s disease (AD) pathology. The LC sends axons to hippocampus where released norepinephrine (NE) modulates synaptic function required for learning and memory. How degeneration of LC axons and loss of NE in hippocampus in early AD impacts synaptic function and learning and memory is not well understood despite the importance of LC in cognitive function. We used a transgenic AD rat model with LC axon degeneration mimicking human AD and found that heightened function of β-adrenergic receptors in the dentate gyrus increased synaptic plasticity and preserved learning and memory in early stages of the disease.     

Internet-Based Behavioral Activation Program for Depression and Problem Gambling: Lessons Learned from Stakeholder Interviews

International Journal of Mental Health and Addiction - Behavioral activation (BA) is a well-established treatment for depression, often used as an adjuvant for gambling disorder. Internet-based BA...     

Influence of muscle strength to weight ratio on functional task performance

Existing models of muscle deconditioning such as bed rest are expensive and time-consuming. We propose a new model utilizing a weighted suit to manipulate muscle strength, power, or endurance relative to body weight. The aims of the study were to determine as to which muscle measures best predict functional task performance and to determine muscle performance thresholds below which task performance is impaired. Twenty subjects performed seven occupational astronaut tasks (supine and upright seat egress and walk, rise from fall, hatch opening, ladder climb, object carry, and construction board activity), while wearing a suit weighted with 0–120 % of body weight. Models of the relationship between muscle function/body weight and task completion time were developed using fractional polynomial regression and verified with pre- and post-flight astronaut performance data. Spline regression was used to identify muscle function thresholds for each task. Upright seat egress and walk was the most difficult task according to the spline regression analysis thresholds. Thresholds normalized to body weight were 17.8 N/kg for leg press isometric force, 17.6 W/kg for leg press power, 78.8 J/kg for leg press work, 5.9 N/kg isometric knee extension and 1.9 Nm/kg isokinetic knee extension torque. Leg press maximal isometric force/body weight was the most reliable measure for modeling performance of ambulatory tasks. Laboratory-based manipulation of relative strength has promise as an analog for spaceflight-induced loss of muscle function. Muscle performance values normalized to body weight can be used to predict occupational task performance and to establish relevant strength thresholds.     

How can we calculate the "E" in "CEA"?

Because full funding for HIV/AIDS prevention interventions is unlikely to occur in the near future, it is essential that the resources available are spent in the most effective way possible. This paper presents a matrix of effectiveness coefficients for HIV/AIDS-related prevention interventions that can be used as an integral part of the coordinated strategic planning process currently underway by the World Bank and UNAIDS, as the interventions in the matrix are harmonized with the interventions in that process. Coefficients for four types of sexual behavior change (condom use, partner reduction, sexually transmitted infection treatment-seeking behavior, age at first sex) across three different risk groups (high, medium, low) are presented, along with their interquartile ranges. Results indicate that: (1) impacts seem greater when an intervention includes interpersonal contact, rather than targeting a more general audience; (2) although significant impacts are observed in the columns measuring changing condom use, other impacts are lower, and sometimes are actually (measured) zero; and (3) additional studies have evaluations of the number of sexual partners and have found a greater impact than previous studies. Although progress has been made in increasing the number of evaluation studies that can be utilized in this impact matrix, particularly in the area of youth interventions, there are still empty cells in which no studies report impacts. Finally, it is important to note that issues such as quality differences and synergies between programmes could have an effect on the impacts calculated for a particular strategic plan.