A new approach toward gait training in patients with Parkinson’s Disease

BackgroundTypically, people with Parkinson’s Disease (PD) progress to develop a gait pattern that is characterized by quick, short and shuffling steps. Gait cycle is altered and lacks definition and fluidity. Gait training combined with a variety of feedback modalities for PD are usually based on non-immediate and externally-based cues but none of these provide real-time feedback on gait quality and acquired gains tend to abate shortly after rehabilitation. Based on principals of motor learning, our team has developed the Heel2Toe sensor to provide real-time auditory feedback during gait training.Research questionIs a short-term training using the Heel2Toe sensor feasible and efficient to improve gait in people with PD? Our objectives are to identify the extent of the immediate response to the feedback within the same session and the carry-over response to training and; 2) to identify patients’ perceived effects, pleasures and challenges of using the Heel2Toe.MethodsSingle-arm, proof-of-concept study. Six people received five sessions of gait training over a 2–3-week period using the Heel2Toe augmented with mobility exercises as an adjunct to gait training. The main outcomes were technically assessed gait parameters collected over a 2-minute walk test, without and with feedback. Heel2Toe signals were analyzed to extract angular velocity(AV), percentage of good steps, average cadence, and AV coefficient of variation(CV).ResultsAn immediate response to the Heel2Toe use and a carry-over response to the short-term training with the sensor were observed: an increase in AV with a reduction in CV (better heel strike and gait regularity); an increase in %good steps; and a near-optimal and homogeneous cadence (∼100 steps/min), which is equivalent to a moderate-intensity walking.SignificanceGait training using the Heel2Toe sensor is feasible and potentially effective for improving gait quality in people with PD. A definitive trial is a logical next step.     

Valence-dependent brain potentials of processing augmented feedback in learning a complex arm movement sequence

ERPs in the EEG were scrutinized in learning a complex arm movement sequence with the aim to examine valence effects on processing augmented feedback during practice. Twenty-four healthy subjects practiced one session with 192 feedback trials according to an adaptive bandwidth feedback approach with a high informational level of feedback information (i.e., amplitude and direction of errors). The bandwidth for successful performance (increase of a score for a monetary competition) was manipulated to yield a success rate (positive feedback frequency) of approximately 50% adaptive to the current performance level. This allowed a variation of feedback valence unconfounded by success rate. In line with our hypotheses, the EEG data showed a valence-dependent feedback-related negativity (FRN) and a later fronto-central component at the FCz electrode as well as a P300 component at the Pz electrode. Moreover, the P300 and amplitudes in the FRN time window reduced in the second half of practice but were still dependent on feedback valence. Behavioral adjustments were larger after feedback with negative valence and were predicted by the late fronto-central component. The data support the assumption of feedback valence-dependent modulation of attentional cognitive involvement in motor control and learning.     

Genetic feedback for psychiatric conditions: Where are we now and where are we going

Genome‐wide association studies are rapidly advancing our understanding of the genetic architecture of complex disorders, including many psychiatric conditions such as major depression, schizophrenia, and substance use disorders. One common goal of genome‐wide association studies is to use findings for enhanced clinical prediction in the future, which can aid in identifying at‐risk individuals to enable more effective prevention screening and treatment strategies. In order to achieve this goal, we first need to gain a better understanding of the issues surrounding the return of complex genetic results. In this article, we summarize the current literature on: (a) genetic literacy in the general population, (b) the public's interest in receiving genetic test results for psychiatric conditions, (c) how individuals react to and interpret their genotypic information for specific psychiatric conditions, and (d) gaps in our knowledge that will be critical to address as we move toward returning genotypic information for psychiatric conditions in both research and clinical settings. By reviewing extant studies, we aim to increase awareness of the potential benefits and consequences of returning genotypic information for psychiatric conditions.     

Insulin and the glucose-glucagon feedback mechanism in the duck

Summary The relationship between insulin and the glucose-glucagon feedback mechanism was studied by testing the effectiveness of various routes, doses and timing of insulin administration prior to and during a glucose tolerance test in Peking ducks made transiently diabetic by subtotal pancreatectomy. Insulin injections or infusions given either before, or only during the glucose load, did not restore the A-cell response to glucose. Yet, if given both before and during the glucose test, in conditions which mimic the physiological basal insulin level and its variations (with, initially, intramuscular injections of 0.2 IU/kg and 8 g/kg glucagon, every six hours, and then an intravenous injection of 3.6 mU/kg plus an infusion of 0.9 mU/kg/ minute for one hour), the normal glucagon response to glucose was re-established. Insulin must therefore be present, both before and during glucose stimulation, for glucose to be effective as an A-cell suppressor.This work was supported by the CNRS (ERA 188) and the INSERM.     

Involvement of pancreatic polypeptide (PP) in luminal feedback regulation in the conscious rat

The possibility of the involvement of pancreatic polypeptide (PP) release in luminal feedback regulation in the conscious rat was examined. Pancreatic secretion in the intestinal phase in the rat is regulated by negative feedback control so that a decrease in luminal protease activities produced by a diversion of bile-pancreatic juice (BPJ) from the intestine stimulates pancreatic secretion. Plasma concentration of rat PP and the effect of exogenous infusion of rat PP on pancreatic secretions during BPJ diversion were determined. Plasma PP concentration significantly increased with BPJ diversion and peaked at 90 min after BPJ diversion began, almost paralleling changes in protein output. Exogenous PP infusion (1, 2, and 10 g/kg/hr) inhibited pancreatic protein and fluid outputs but not the bicarbonate output during BPJ diversion. PP was shown to be physiologically released in the intestinal phase of pancreatic secretion; however, the physiological role of endogenous PP remains unknown.This study was supported in part by the Uehara Memorial Foundation and a grant in aid from the Japanese Ministry of Education.     

Emergence of homeostatic epithelial packing and stress dissipation through divisions oriented along the long cell axis

Cell division plays an important role in animal tissue morphogenesis, which depends, critically, on the orientation of divisions. In isolated adherent cells, the orientation of mitotic spindles is sensitive to interphase cell shape and the direction of extrinsic mechanical forces. In epithelia, the relative importance of these two factors is challenging to assess. To do this, we used suspended monolayers devoid of ECM, where divisions become oriented following a stretch, allowing the regulation and function of epithelial division orientation in stress relaxation to be characterized. Using this system, we found that divisions align better with the long, interphase cell axis than with the monolayer stress axis. Nevertheless, because the application of stretch induces a global realignment of interphase long axes along the direction of extension, this is sufficient to bias the orientation of divisions in the direction of stretch. Each division redistributes the mother cell mass along the axis of division. Thus, the global bias in division orientation enables cells to act collectively to redistribute mass along the axis of stretch, helping to return the monolayer to its resting state. Further, this behavior could be quantitatively reproduced using a model designed to assess the impact of autonomous changes in mitotic cell mechanics within a stretched monolayer. In summary, the propensity of cells to divide along their long axis preserves epithelial homeostasis by facilitating both stress relaxation and isotropic growth without the need for cells to read or transduce mechanical signals.The morphogenesis of animal tissues results from coordinated changes in the shape, size, and packing of their constituent cells (1–3). These include autonomous cell shape changes (4), the response of cells to extrinsic stresses, and the effects of passive tissue deformation (5). When coordinated across a tissue, these active cellular processes and passive responses enable epithelial sheets to undergo shape changes while retaining relatively normal cell packing (6) and help return tissues to their resting state following a perturbation (7). Although the molecular basis of this cooperation is not understood, several studies have suggested a role for mechanical feedback (8, 9). Cell division has been suggested to participate in this feedback (10) because the rate of animal cell proliferation responds to changes in extrinsic forces in several experimental settings (9). Further, division makes an important contribution to tissue morphogenesis in animals (11, 12), accounts for much of the topological disorder observed in epithelia (13), can drive tissue elongation (10), and can facilitate the return to homeostatic cell packing following a deformation (2). Importantly, for each of these functions, the impact of cell division depends critically on the orientation of divisions.At the cellular level, relatively simple rules appear to govern division orientation. These rules were first explored by Hertwig (14), who showed that cells from early embryos divide along their long axis, and were further refined using microfabricated chambers (15). However, by following division orientation in cells adhering to micropatterned substrates, more recent studies identified additional roles for both the geometrical arrangement of integrin-mediated cell–substrate adhesions (16) and extrinsic mechanical forces in orienting divisions (17). Consistent with this, adhesive and mechanical cues have been reported to guide division orientation in vivo (18) and in epithelial monolayers in developing embryos (12, 19). Nevertheless, the respective roles of cell shape and mechanical tension in guiding division orientation in epithelia remain poorly defined, as does the contribution of oriented division to mechanical feedback control.Previously, we established suspended epithelial monolayers lacking ECM as a minimal model system in which to study epithelial biology. Because cell divisions in these monolayers become oriented following a stretch, we were able to explore the regulation and function of division orientation. We found that divisions align better with the long, interphase cell axis than with the monolayer stress axis. This phenomenon, combined with the alignment of cellular long axes induced by stretch, results in a global bias in the orientation of divisions in the direction of extension. Each division redistributes cell mass along the axis of division. Thus, when oriented across a monolayer, divisions act collectively to redistribute mass along the axis of stretch, helping to return the monolayer to its resting state. In summary, this analysis shows that the propensity of cells to divide along their long axis preserves epithelial homeostasis by facilitating both stress relaxation and isotropic growth without the need for cells to read or transduce mechanical signals.     

Load-induced changes in repolarization: evidence from experimental and clinical data

The high incidence of arrhythmias in patients with heart failure, hypertension, valvular heart disease, or mitral walve prolapse suggests a strong link between wall motion abnormalities and arrhythmias. A potential common mechanism underlying these observations may be that overload leads to electrophysiologic changes and facilitates arrhythmias. This article summarizes the interaction between changes in atrial and ventricular loading conditions and repolarization. Most experimental and clinical studies demonstrated 1) a reduction of action potential duration and refractoriness, 2) development of early afterdepolarizations, and 3) ectopic beats originating from these afterdepolarizations. Discrepancies between studies are related to different study designs, i.e., varying magnitude, velocity, and timing of increased load, the level of repolarization at which action potential duration is measured as well as different animal species. Direct effects of increased load on repolarization are most likely caused by activation of stretch-activated nonselective cation ion channels and changes in calcium handling. Current antiarrhythmic drug therapy is aimed at electrical disorders as the primary cause of arrhythmias. If mechanical disorders play a central role in the genesis of cardiac arrhythmias, future treatment should be directed at restoring a more normal mechanical function of the heart. Additional studies will further clarify the nature and clinical significance of load-related changes in repolarization and arrhythmogenesis. Received: 20 November 2000 / Returned for revision: 20 December 2000 / Revision received: 2 January 2001 / Accepted: 8 January 2001     

Motivating student learning using a formative assessment journey

Providing formative assessment opportunities has been recognised as a significant benefit to student learning. The outcome of any formative assessment should be one that ultimately helps improve student learning through familiarising students with the levels of learning required, informing them about gaps in their learning and providing feedback to guide the direction of learning. This article provides an example of how formative assessments can be developed into a formative assessment journey where a number of different assessments can be offered to students during the course of a module of teaching, thus utilising a spaced-education approach. As well as incorporating the specific drivers of formative assessment, we demonstrate how approaches deemed to be stimulating, interactive and entertaining with the aim of maximising enthusiasm and engagement can be incorporated. We provide an example of a mixed approach to evaluating elements of the assessment journey that focuses student reaction, appraisal of qualitative and quantitative feedback from student questionnaires, focus group analysis and teacher observations. Whilst it is not possible to determine a quantifiable effect of the assessment journey on student learning, usage data and student feedback shows that formative assessment can achieve high engagement and positive response to different assessments. Those assessments incorporating an active learning element and a quiz-based approach appear to be particularly popular. A spaced-education format encourages a building block approach to learning that is continuous in nature rather than focussed on an intense period of study prior to summative examinations.     

Glutathione and multidrug resistance protein transporter mediate a self-propelled disposal of bismuth in human cells

Glutathione and multidrug resistance protein (MRP) play an important role on the metabolism of a variety of drugs. Bismuth drugs have been used to treat gastrointestinal disorder and Helicobacter pylori infection for decades without exerting acute toxicity. They were found to interact with a wide variety of biomolecules, but the major metabolic pathway remains unknown. For the first time (to our knowledge), we systematically and quantitatively studied the metabolism of bismuth in human cells. Our data demonstrated that over 90% of bismuth was passively absorbed, conjugated to glutathione, and transported into vesicles by MRP transporter. Mathematical modeling of the system reveals an interesting phenomenon. Passively absorbed bismuth consumes intracellular glutathione, which therefore activates de novo biosynthesis of glutathione. Reciprocally, sequestration by glutathione facilitates the passive uptake of bismuth and thus completes a self-sustaining positive feedback circle. This mechanism robustly removes bismuth from both intra- and extracellular space, protecting critical systems of human body from acute toxicity. It elucidates the selectivity of bismuth drugs between human and pathogens that lack of glutathione, such as Helicobacter pylori, opening new horizons for further drug development.Bismuth (Bi) compounds have been used in clinical medicine for over a century in various infectious diseases (1–4). Together with antibiotics, bismuth drugs such as bismuth subsalicylate (Pepto-Bismol) and colloidal bismuth subcitrate (CBS; De-Nol) are used to treat Helicobacter pylori infection and gastrointestinal disorder (5–7). Interestingly, bismuth drugs rarely exert acute toxicity in human but instead mitigate other drugs’ toxicity (8). This drug selectivity between human and certain pathogens has been well observed yet poorly understood. Because bismuth is a heavy metal, its disposal in human cells becomes the key of this conundrum.Low uptake of bismuth by human gastrointestinal tract (GIT) was often considered as the reason of bismuth’s low toxicity (1). However, it contradicted the fact that no severe toxicity appeared, even when bismuth was repeatedly injected intramuscularly to treat syphilis (9). Furthermore, even at very extreme doses or physical conditions, bismuth only causes reversible nephropathy or encephalopathy (10, 11). And last, over 90% of absorbed bismuth was found metabolized into bismuth–sulfur particles (12). These particles were exclusively located in subcellular vesicles of a variety of organs (e.g., kidney, liver, brain, and testicle), which is indicative of a universal disposal mechanism at cellular level (12–14).Based on the hard–soft acid-base concept, Bi³⁺ is a borderline metal ion. It exhibits high affinity toward many biological thiols (15–17). Glutathione (GSH) and metallothionein are the two key thiols of bismuth pharmacology in mammalian cells (15, 18). Bismuth was found to induce metallothionein expression in renal proximal tubules; however, only a small portion of bismuth was actually bound to it (8, 19). Bismuth also affected glutathione metabolism in different types of cells. It caused an exponential decay on ¹H NMR signal of glutathione in human red blood cells and a hepatobiliary coexcretion of bismuth and glutathione in rodents (18, 20). However, the origin of sulfur in bismuth–sulfur particles in mammalian cells remains unknown. It is interesting to note that neither glutathione nor metallothionein exists in H. pylori; cysteine is the major thiol (21). Cysteine-rich proteins with high binding affinity to bismuth have also been identified (22). Unlike in mammalian cells, bismuth caused severe cell vacuolation, degradation, and death in H. pylori (12, 23, 24).Previously, we have studied the formation of Bi³⁺–glutathione complex [Bi(GS)₃] both in vitro and in vivo (18). We found that the complex is thermodynamically stable yet kinetically labile, with the exchange rate of Bi³⁺ between glutathione molecules of ∼1,500 s⁻¹ at pH 7.4. Because Bi³⁺ exhibits higher affinity with metallothionein than with glutathione, metallothionein seems to be a better choice for Bi³⁺ ions. However, glutathione has its advantages. Its conjugates can be swiftly transported through multiple transporters, which mainly belong to the multidrug resistance protein/cystic fibrosis transmembrane conductance regulator (MRP/CFTR) family in human cells (e.g., MRP1) (25, 26). And with 63% sequence similarity to human MRP1, Ycf1p was found to transport multiple metal–glutathione conjugates (As³⁺, Cd²⁺, Hg²⁺) into yeast vacuoles (27, 28). MRP1 was also found on subcellular vesicles, conferring drug resistance to doxorubicin (29).In this report, we demonstrate that most bismuth was passively absorbed, sequestrated by glutathione and MRP transporter in human cells. We propose a quantitative mathematical model based directly on these biochemical facts, i.e., sequestration-aided passive transport (SAPT) model. We present explicit mathematical solution for the model as a function of parameters, which can explain the mechanism behind the pattern of bismuth uptake. It describes a self-propelled system of bismuth disposal and reveals detailed information about cell permeability of bismuth and glutathione level when the time and dose of bismuth treatment were varied.     

Plasma CCK levels in patients with pancreatic insufficiency

After stimulation with a Lundh test meal, plasma concentrations of cholecystokinin (CCK) and pancreatic polypeptide (PP) and output of pancreatic enzymes were measured in 33 patients with exocrine pancreatic insufficiency and 26 healthy subjects. Patients with impairment of pancreatic function were subdivided into those with moderate and severe insufficiency. Plasma CCK and PP were measured by radioimmunoassay. Fasting plasma CCK in patients with pancreatic insufficiency (5.8±1.1 pmol/liter) did not differ significantly from controls (4.2±0.6 pmol/liter). After endogenous stimulation with a Lundh meal, plasma CCK increased in both groups without significant differences over 2 hr. Basal and stimulated plasma levels of pancreatic polypeptide (PP) were markedly decreased only in patients with severe pancreatic insufficiency. Our results demonstrate that basal and meal-stimulated CCK levels in patients with pancreatic insufficiency do not differ from controls. Furthermore the extent of functional impairment of the exocrine pancreas did not influence basal and postprandial CCK release.