Advances in the role of sacral nerve neuromodulation in lower urinary tract symptoms

Sacral neuromodulation has been developed to treat chronic lower urinary tract symptoms, resistant to classical conservative therapy. The suspected mechanisms of action include afferent stimulation of the central nervous system and modulation of activity at the level of the brain. Typical neuromodulation is indicated both in overactivity and in underactivity of the lower urinary tract. In the majority of patients, a unilateral electrode in a sacral foramen and connected to a pulse generator is sufficient to achieve significant clinical results also on long term. In recent years, other urological indications have been explored

The working alliance in a randomized controlled trial comparing online with face-to-face cognitive-behavioral therapy for depression

Background: Although numerous efficacy studies in recent years have found internet-based interventions for depression to be effective, there has been scant consideration of therapeutic process factors in the online setting. In face-to face therapy, the quality of the working alliance explains variance in treatment outcome. However, little is yet known about the impact of the working alliance in internet-based interventions, particularly as compared with face-to-face therapy. Methods: This study explored the working alliance between client and therapist in the middle and at the end of a cognitive-behavioral intervention for depression. The participants were randomized to an internet-based treatment group (n = 25) or face-to-face group (n = 28). Both groups received the same cognitive behavioral therapy over an 8-week timeframe. Participants completed the Beck Depression Inventory (BDI) post-treatment and the Working Alliance Inventory at mid- and post- treatment. Therapists completed the therapist version of the Working Alliance Inventory at post-treatment. Results: With the exception of therapists' ratings of the tasks subscale, which were significantly higher in the online group, the two groups' ratings of the working alliance did not differ significantly. Further, significant correlations were found between clients' ratings of the working alliance and therapy outcome at post-treatment in the online group and at both mid- and post-treatment in the face-to-face group. Correlation analysis revealed that the working alliance ratings did not significantly predict the BDI residual gain score in either group. Conclusions: Contrary to what might have been expected, the working alliance in the online group was comparable to that in the face-to-face group. However, the results showed no significant relations between the BDI residual gain score and the working alliance ratings in either group

Genetic Variants of Human Granzyme B Predict Transplant Outcomes after HLA Matched Unrelated Bone Marrow Transplantation for Myeloid Malignancies

Serine protease granzyme B plays important roles in infections, autoimmunity, transplant rejection, and antitumor immunity. A triple-mutated granzyme B variant that encodes three amino substitutions (Q48R, P88A, and Y245H) has been reported to have altered biological functions. In the polymorphism rs8192917 (2364A>G), the A and G alleles represent wild type QPY and RAH mutant variants, respectively. In this study, we analyzed the impact of granzyme B polymorphisms on transplant outcomes in recipients undergoing unrelated HLA-fully matched T-cell-replete bone marrow transplantation (BMT) through the Japan Donor Marrow Program. The granzyme B genotypes were retrospectively analyzed in a cohort of 613 pairs of recipients with hematological malignancies and their unrelated donors. In patients with myeloid malignancies consisting of acute myeloid leukemia and myelodysplastic syndrome, the donor G/G or A/G genotype was associated with improved overall survival (OS; adjusted hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.41–0.89; P = 0.01) as well as transplant related mortality (TRM; adjusted HR, 0.48; 95% CI, 0.27–0.86, P = 0.01). The recipient G/G or A/G genotype was associated with a better OS (adjusted HR, 0.68; 95% CI, 0.47–0.99; P = 0.05) and a trend toward a reduced TRM (adjusted HR, 0.61; 95% CI, 0.35–1.06; P = 0.08). Granzyme B polymorphism did not have any effect on the transplant outcomes in patients with lymphoid malignancies consisting of acute lymphoid leukemia and malignant lymphoma. These data suggest that there is an association between the granzyme B genotype and better clinical outcomes in patients with myeloid malignancies after unrelated BMT

Quantitative Modeling of GRK-Mediated β2AR Regulation

We developed a unified model of the GRK-mediated β2 adrenergic receptor (β2AR) regulation that simultaneously accounts for six different biochemical measurements of the system obtained over a wide range of agonist concentrations. Using a single deterministic model we accounted for (1) GRK phosphorylation in response to various full and partial agonists; (2) dephosphorylation of the GRK site on the β2AR; (3) β2AR internalization; (4) recycling of the β2AR post isoproterenol treatment; (5) β2AR desensitization; and (6) β2AR resensitization. Simulations of our model show that plasma membrane dephosphorylation and recycling of the phosphorylated receptor are necessary to adequately account for the measured dephosphorylation kinetics. We further used the model to predict the consequences of (1) modifying rates such as GRK phosphorylation of the receptor, arrestin binding and dissociation from the receptor, and receptor dephosphorylation that should reflect effects of knockdowns and overexpressions of these components; and (2) varying concentration and frequency of agonist stimulation “seen” by the β2AR to better mimic hormonal, neurophysiological and pharmacological stimulations of the β2AR. Exploring the consequences of rapid pulsatile agonist stimulation, we found that although resensitization was rapid, the β2AR system retained the memory of the previous stimuli and desensitized faster and much more strongly in response to subsequent stimuli. The latent memory that we predict is due to slower membrane dephosphorylation, which allows for progressive accumulation of phosphorylated receptor on the surface. This primes the receptor for faster arrestin binding on subsequent agonist activation leading to a greater extent of desensitization. In summary, the model is unique in accounting for the behavior of the β2AR system across multiple types of biochemical measurements using a single set of experimentally constrained parameters. It also provides insight into how the signaling machinery can retain memory of prior stimulation long after near complete resensitization has been achieved

What Happened to Gray Whales during the Pleistocene? The Ecological Impact of Sea-Level Change on Benthic Feeding Areas in the North Pacific Ocean

Gray whales (Eschrichtius robustus) undertake long migrations, from Baja California to Alaska, to feed on seasonally productive benthos of the Bering and Chukchi seas. The invertebrates that form their primary prey are restricted to shallow water environments, but global sea-level changes during the Pleistocene eliminated or reduced this critical habitat multiple times. Because the fossil record of gray whales is coincident with the onset of Northern Hemisphere glaciation, gray whales survived these massive changes to their feeding habitat, but it is unclear how.We reconstructed gray whale carrying capacity fluctuations during the past 120,000 years by quantifying gray whale feeding habitat availability using bathymetric data for the North Pacific Ocean, constrained by their maximum diving depth. We calculated carrying capacity based on modern estimates of metabolic demand, prey availability, and feeding duration; we also constrained our estimates to reflect current population size and account for glaciated and non-glaciated areas in the North Pacific. Our results show that key feeding areas eliminated by sea-level lowstands were not replaced by commensurate areas. Our reconstructions show that such reductions affected carrying capacity, and harmonic means of these fluctuations do not differ dramatically from genetic estimates of carrying capacity.Assuming current carrying capacity estimates, Pleistocene glacial maxima may have created multiple, weak genetic bottlenecks, although the current temporal resolution of genetic datasets does not test for such signals. Our results do not, however, falsify molecular estimates of pre-whaling population size because those abundances would have been sufficient to survive the loss of major benthic feeding areas (i.e., the majority of the Bering Shelf) during glacial maxima. We propose that gray whales survived the disappearance of their primary feeding ground by employing generalist filter-feeding modes, similar to the resident gray whales found between northern Washington State and Vancouver Island

Neural Responses to Truth Telling and Risk Propensity under Asymmetric Information

This research was supported by the Laureate Institute for Brain Research and the William K. Warren Foundation. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.Trust is multi-dimensional because it can be characterized by subjective trust, trust antecedent, and behavioral trust. Previous research has investigated functional brain responses to subjective trust (e.g., a judgment of trustworthiness) or behavioral trust (e.g., decisions to trust) in perfect information, where all relevant information is available to all participants. In contrast, we conducted a novel examination of the patterns of functional brain activity to a trust antecedent, specifically truth telling, in asymmetric information, where one individual has more information than others, with the effect of varying risk propensity. We used functional magnetic resonance imaging (fMRI) and recruited 13 adults, who played the Communication Game, where they served as the “Sender” and chose either truth telling (true advice) or lie telling (false advice) regarding the best payment allocation for their partner. Our behavioral results revealed that subjects with recreational high risk tended to choose true advice. Moreover, fMRI results yielded that the choices of true advice were associated with increased cortical activation in the anterior rostral medial and frontopolar prefrontal cortices, middle frontal cortex, temporoparietal junction, and precuneus. Furthermore, when we specifically evaluated a role of the bilateral amygdala as the region of interest (ROI), decreased amygdala response was associated with high risk propensity, regardless of truth telling or lying. In conclusion, our results have implications for how differential functions of the cortical areas may contribute to the neural processing of truth telling.Yeshttp://www.plosone.org/static/editorial#pee