scholarly journals A Universal Law of Sensory Adaptation

2020 ◽  
Author(s):  
Willy Wong
Keyword(s):  
Steady State ◽  
Sensory Neurons ◽  
Geometric Mean ◽  
Peak Level ◽  
Constant Stimulus ◽  
Sensory Adaptation ◽  
Level Of Activity ◽  
Universal Relationship ◽  
Steady State Activity ◽  
Universal Law

AbstractSensory adaptation is the gradual decline in response as recorded from sensory neurons to a constant stimulus. Measuring adaptation involves counting the time-varying rate of action potentials generated by the sensory neuron. A typical adaptation curve will involve spontaneous activity prior to the introduction of the stimulus, a peak level of activity soon after the stimulus is presented, and a gradual fall to a new steady-state value. In this study, the steady-state activity is shown to be equal to the geometric mean of the spontaneous and peak activities. This remarkably simple equation holds across different sensory modalities and in different animal species. It is obeyed in both modern measurements of neural adaptation as well as the original recordings of Lord Adrian in his seminal work on the discovery of the all-or-nothing principle of nerves. It is likely a universal relationship governing the peripheral response of sensory neurons.

scholarly journals Consilience in the Peripheral Sensory Adaptation Response

2021 ◽  
Vol 15 ◽  
Author(s):  
Willy Wong
Keyword(s):  
Steady State ◽  
Animal Species ◽  
Geometric Mean ◽  
Fundamental Result ◽  
Sensory Adaptation ◽  
Extensive Review ◽  
Mathematical Relationship ◽  
Wide Range ◽  
Adaptation Response ◽  
Peripheral Sensory

Measurements of the peripheral sensory adaptation response were compared to a simple mathematical relationship involving the spontaneous, peak, and steady-state activities. This relationship is based on the geometric mean and is found to be obeyed to good approximation in peripheral sensory units showing a sustained response to prolonged stimulation. From an extensive review of past studies, the geometric mean relationship is shown to be independent of modality and is satisfied in a wide range of animal species. The consilience of evidence, from nearly 100 years of experiments beginning with the work of Edgar Adrian, suggests that this is a fundamental result of neurophysiology.

scholarly journals Steady-State Serum IgG Trough Levels Are Adequate for Pharmacokinetic Assessment in Patients with Immunodeficiencies Receiving Subcutaneous Immune Globulin

2021 ◽  
Author(s):  
Zhaoyang Li ◽  
Barbara McCoy ◽  
Werner Engl ◽  
Leman Yel
Keyword(s):  
Steady State ◽  
Trough Level ◽  
Geometric Mean ◽  
Time Profiles ◽  
Level Measurement ◽  
Serum Igg ◽  
Pharmacokinetic Assessment ◽  
Steady State Serum ◽  
Serum Igg Levels ◽  
Trough Levels

AbstractPatients with primary immunodeficiency diseases often require lifelong immunoglobulin (IG) therapy. Most clinical trials investigating IG therapies characterize serum immunoglobulin G (IgG) pharmacokinetic (PK) profiles by serially assessing serum IgG levels. This retrospective analysis evaluated whether steady-state serum IgG trough level measurement alone is adequate for PK assessment. Based on individual patient serum IgG trough levels from two pivotal trials (phase 2/3 European [NCT01412385] and North American [NCT01218438]) of weekly 20% subcutaneous IG (SCIG; Cuvitru, Ig20Gly), trough level-predicted IgG AUC (AUCτ,tp) were calculated and compared with the reported AUC calculated from serum IgG concentration-time profiles (AUCτ). In both studies, mean AUCτ,tp values for Ig20Gly were essentially equivalent to AUCτ with point estimates of geometric mean ratio (GMR) of AUCτ,tp/AUCτ near 1.0 and 90% CIs within 0.80–1.25. In contrast, for IVIG, 10%, mean AUCτ,tp values were lower than AUCτ by >20%, (GMR [90% CI]: 0.74 [0.70–0.78] and 0.77 [0.73–0.81] for the two studies, respectively). Mean AUCτ,tp values calculated for 4 other SCIG products (based on mean IgG trough levels reported in the literature/labels) were also essentially equivalent to the reported AUCτ (differences <10% for all except HyQvia, a facilitated SCIG product), while differences for IVIG products were >20%. In conclusion, steady-state serum IgG levels following weekly SCIG remain stable, allowing for reliable prediction of AUC over the dosing interval using trough IgG levels. These findings indicate that measuring steady-state serum IgG trough levels alone may be adequate for PK assessment of weekly SCIG.

scholarly journals Pearl Index study with levonorgestrel-releasing intravaginal rings: using pharmacokinetic results to investigate treatment compliance as a potential contributor for contraceptive failure

2020 ◽  
Vol 35 (11) ◽  
pp. 2515-2523
Author(s):  
R Nave ◽  
J Höchel ◽  
U Mellinger ◽  
A Kohnke ◽  
J Elliesen ◽  
...  
Keyword(s):  
Steady State ◽  
Geometric Mean ◽  
Treatment Compliance ◽  
Steady State Concentration ◽  
Contraceptive Efficacy ◽  
Unintended Pregnancies ◽  
The Us ◽  
The Usa ◽  
Pearl Index ◽  
State Concentration

Abstract STUDY QUESTION What is the reason for insufficient contraceptive efficacy of levonorgestrel (LNG) delivered by intravaginal ring (IVR) releasing comparable amounts of LNG as approved progestogen-only pills (POPs)? SUMMARY ANSWER The pharmacokinetic (PK) evaluation in a subpopulation indicated that the steady-state concentration of plasma LNG was markedly lower in the participants in the USA compared to those in Japan suggesting non-compliance in the US participants which may explain a clearly higher Pearl Index (PI) in USA (8.2, unadjusted PI) compared to Japan (1.4, unadjusted PI). WHAT IS KNOWN ALREADY Contraceptive efficacy of LNG in POPs has been demonstrated following different routes of administration (e.g. orally, implants, intrauterine systems), and the PK is well-characterized including a target exposure needed for contraception. Exposure above this target concentration was reached in Phase 1 studies using IVR delivering 40 µg LNG per day. STUDY DESIGN, SIZE, DURATION The primary objective of this multicenter, open-label, single-arm study conducted in the USA and in Japan was to assess the contraceptive efficacy of an LNG-containing IVR during a planned treatment period of 1 year in healthy women 18–35 years of age. The study was planned to be conducted in 1600 participants (1300 in the USA, 300 in Japan). The study was prematurely terminated after approximately one-third of the planned exposure was reached due to a high number of pregnancies (28) in the US study population. PARTICIPANTS/MATERIALS, SETTING, METHODS In total, 1471 participants were treated (1166 participants in the USA and 305 participants in Japan). The PI as a measure of contraceptive efficacy was calculated from the frequency of unintended pregnancies during treatment. LNG exposure in the systemic circulation was assessed during treatment in 136 participants (PK subgroups: 106 in the USA and 30 in Japan). MAIN RESULTS AND THE ROLE OF CHANCE The PK evaluation in the PK subgroups indicated that the steady-state concentration of plasma LNG after 6 months was markedly lower in the participants in the USA (geometric mean 91.2 ng/l) compared to those in Japan (263.8 ng/l). This PK finding cannot be explained by the regional differences in body weight observed between the PK subgroups, thus suggesting non-compliance in the US participants. In 15.7% of the samples collected in the USA and 3.5% samples in Japan, the LNG concentration at steady state was below the lower limit of quantification (10 ng/l), which is not expected with the required continuous use of the IVR documented in most of the eDiaries. LIMITATIONS, REASONS FOR CAUTION The planned duration of treatment was 12 months, but due to the premature termination of the study none of the participants completed the 12-month treatment. All data collected until the study termination were considered, but it is to be noted that the amount of missing data limits the conclusions that can be drawn from the data. WIDER IMPLICATIONS OF THE FINDINGS The results of this study triggered the termination of the project, because the objective to show sufficient contraceptive efficacy of the LNG IVR was not met. The choice of a user-dependent contraceptive method with an LNG dose that is not inhibiting ovulation is not advisable for women who may have compliance issues. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by Bayer AG and all authors are employees of Bayer AG. TRIAL REGISTRATION NUMBER NCT02403401

scholarly journals Temporal Evolution of “Automatic Gain-Scaling”

2009 ◽  
Vol 102 (2) ◽  
pp. 992-1003 ◽  
Author(s):  
J. Andrew Pruszynski ◽  
Isaac Kurtzer ◽  
Timothy P. Lillicrap ◽  
Stephen H. Scott
Keyword(s):  
Steady State ◽  
Muscle Activity ◽  
Temporal Evolution ◽  
Rapid Decrease ◽  
Short Latency ◽  
State Activity ◽  
Long Latency ◽  
Short Latency Response ◽  
Latency Response ◽  
Steady State Activity

The earliest neural response to a mechanical perturbation, the short-latency stretch response (R1: 20–45 ms), is known to exhibit “automatic gain-scaling” whereby its magnitude is proportional to preperturbation muscle activity. Because gain-scaling likely reflects an intrinsic property of the motoneuron pool (via the size-recruitment principle), counteracting this property poses a fundamental challenge for the nervous system, which must ultimately counter the absolute change in load regardless of the initial muscle activity (i.e., show no gain-scaling). Here we explore the temporal evolution of gain-scaling in a simple behavioral task where subjects stabilize their arm against different background loads and randomly occurring torque perturbations. We quantified gain-scaling in four elbow muscles (brachioradialis, biceps long, triceps lateral, triceps long) over the entire sequence of muscle activity following perturbation onset—the short-latency response, long-latency response (R2: 50–75 ms; R3: 75–105 ms), early voluntary corrections (120–180 ms), and steady-state activity (750–1250 ms). In agreement with previous observations, we found that the short-latency response demonstrated substantial gain-scaling with a threefold increase in background load resulting in an approximately twofold increase in muscle activity for the same perturbation. Following the short-latency response, we found a rapid decrease in gain-scaling starting in the long-latency epoch (∼75-ms postperturbation) such that no significant gain-scaling was observed for the early voluntary corrections or steady-state activity. The rapid decrease in gain-scaling supports our recent suggestion that long-latency responses and voluntary control are inherently linked as part of an evolving sensorimotor control process through similar neural circuitry.

scholarly journals Basal CHK1 activity safeguards its stability to maintain intrinsic S-phase checkpoint functions

2019 ◽  
Vol 218 (9) ◽  
pp. 2865-2875 ◽  
Author(s):  
Jone Michelena ◽  
Marco Gatti ◽  
Federico Teloni ◽  
Ralph Imhof ◽  
Matthias Altmeyer
Keyword(s):  
Cell Proliferation ◽  
Steady State ◽  
Cell Survival ◽  
Replication Fork ◽  
S Phase ◽  
Genome Integrity ◽  
Replication Machinery ◽  
Replication Fork Progression ◽  
Steady State Activity ◽  
S Phase Checkpoint

The DNA replication machinery frequently encounters impediments that slow replication fork progression and threaten timely and error-free replication. The CHK1 protein kinase is essential to deal with replication stress (RS) and ensure genome integrity and cell survival, yet how basal levels and activity of CHK1 are maintained under physiological, unstressed conditions is not well understood. Here, we reveal that CHK1 stability is controlled by its steady-state activity during unchallenged cell proliferation. This autoactivatory mechanism, which depends on ATR and its coactivator ETAA1 and is tightly associated with CHK1 autophosphorylation at S296, counters CHK1 ubiquitylation and proteasomal degradation, thereby preventing attenuation of S-phase checkpoint functions and a compromised capacity to respond to RS. Based on these findings, we propose that steady-state CHK1 activity safeguards its stability to maintain intrinsic checkpoint functions and ensure genome integrity and cell survival.

Phase 2 Trial of Alisertib (MLN8237), An Investigational, Potent Inhibitor of Aurora A Kinase (AAK), in Patients (pts) with Aggressive B- and T-Cell Non-Hodgkin Lymphoma (NHL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 95-95 ◽  
Author(s):  
Jonathan Friedberg ◽  
Daruka Mahadevan ◽  
JungAh Jung ◽  
Daniel O. Persky ◽  
Izidore S Lossos ◽  
...  
Keyword(s):  
Steady State ◽  
T Cell ◽  
Adverse Events ◽  
Protein Expression ◽  
Gene Amplification ◽  
Trough Concentration ◽  
Geometric Mean ◽  
Single Agent ◽  
Aurora A Kinase ◽  
Aurora A

Abstract Abstract 95 Background: Aurora kinases are a family of oncogenic serine-threonine kinases that regulate multiple phases of the mitotic signaling cascade. Inhibition of aurora A kinase (AAK) leads to mitotic errors, followed by aneuploidy, apoptosis, and senescence. Investigational drug alisertib is an ATP-competitive, orally available inhibitor of AAK, that has been evaluated for safety and efficacy in Phase I hematological malignancies. We conducted the first phase II multicenter trial of alisertib in adult patients with aggressive B- and T- cell NHL. Methods: Eligible patients had normal organ function, ANC ≥1250/mm3, platelets ≥ 75,000/mm3 and no prior allogeneic transplant. Patients were treated with alisertib at a dose of 50mg twice daily for 7 days on 21 day cycles until either documented progression or unacceptable treatment-related toxicity. Using fluorescent in situ hybridization (FISH), gene amplification was assessed in archived tumors by a dual assay measuring AAK copy number on chromosome 20q13 as well as the ratio to a control probe located on chromosome 20q11. Immunohistochemistry (IHC) was performed on archived paraffin embedded diagnostic tissue using a dual assay measuring the protein levels of total AAK and that of phospho histone H3. PK sampling was performed with inclusion of steady-state trough plasma PK samples on the morning of Cycle 1 Day 8. Results: 48 pts were enrolled, including 41 response-evaluable. Histologies included DLBCL (n=21, 44%), mantle cell (MCL; n=13, 27%), peripheral T- cell (n=8, 17%), transformed follicular (n=5, 10%) and Burkitt (n=1, 2%). Median age was 68 y (range 32–85). Pts received median 3 prior regimens (range 1–11); 11 pts received prior ASCT. Most common Grade 3/4 adverse events were neutropenia (63%), thrombocytopenia (31%), stomatitis (15%), febrile neutropenia (13%) and fatigue (6%). Four deaths on study were attributed to progressive NHL (2), treatment-related sepsis (1), and unknown cause (1). 11 pts discontinued and 24 reduced dose due to adverse events (AEs). Evaluation of steady state trough concentration of alisertib (N=25) revealed that PK variability was consistent with that observed in other trials with alisertib, and there was a trend toward higher levels in patients who required AE-related dose reductions compared to those who did not (geometric mean 2375 nM [n=10, CV: 54%] vs. 1504 nM [n=15, CV: 35%]). FISH analysis for AAK gene amplification did not reveal differences between histologies (N=31). When total AAK protein was evaluated by immunohistochemistry (N=32), marked variability in both proportion of expression as well as intensity was observed both between and within histologies; there was no correlation of AAK protein expression and clinical response. The overall response rate (ORR) was 32% (95% CI 0.181–0.481); response by histology: DLBCL 20%; MCL 23% and T- cell NHL 57%. Conclusion: Current data suggests that alisertib is generally well-tolerated, with responses observed in heavily pretreated patients with aggressive NHL, including patients after ASCT. Emerging data supports single agent activity in several histologies, with proportionally more responses observed in relapsed/refractory T-cell NHL. Some patients have now been treated for up to two years with this agent, and the generally manageable toxicity profile suggests an opportunity to combine this drug with other agents. IHC of aggressive lymphoma histologies suggests heterogeneity in AAK protein expression and intensity. The geometric mean of alisertib steady-state trough concentration was 1.8 μM (CV= 47%, N = 25), which was above the 1 μM steady-state plasma concentrations associated with saturating levels of pharmacodynamics and antitumor activity in preclinical xenograft models. The observed trend for association between trough concentration of alisertib and AEs supports the dose modification scheme implemented in this trial. Based upon these results, planned future trials include a single-agent study in T-cell NHL, and a combination study exploring alisertib with rituximab and vincristine in aggressive B-cell NHL. Disclosures: Friedberg: Genentech: Consultancy; astellas:; Lilly:; Abbott/Trubion:; Seattle Genetics: Honoraria; Cephalon: Consultancy. Off Label Use: novel agents for relapsed DLBCL. Jung:Millennium: Employment. Danaee:Millennium Pharmaceuticals Inc.: Employment. Zhou:millennium: Employment. Leonard:millennium: Employment.

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