Phase-dependent responses in locomotor muscles of walking man

Bilateral reflex responses in locomotor muscles were studied in normal human subjects walking on a treadmill. Reflex responses were elicited in response to a momentary resistance applied to one leg. The responses were recorded electromyographically from superficial muscles of both lower limbs: the vastus lateralis, gluteus medius and tibialis anterior. A four-channel storage oscilloscope displayed a quartet record which consisted of phases of the walking cycle and patterns of EMG activity. Resistance and response data were collected for comparison. The appearance of reflex responses was found to be conditioned. The following two observations provide the phase-dependent characteristics of those responses: muscles of the ipsilateral limb elicited responses throughout the walking cycle regardless of whether the muscles were active or silent and muscles of the contralateral limb produced responses that depended on the point at which resistance occurred during the walking cycle. Discusion follows concerning inhibition of the response that may be responsible for this phase-dependent phenomenon.     

Spirituality: an overlooked predictor of placebo effects?

Empirical findings have identified spirituality as a potential health resource. Whereas older research has associated such effects with the social component of religion, newer conceptualizations propose that spiritual experiences and the intrapersonal effects that are facilitated by regular spiritual practice might be pivotal to understanding potential salutogenesis. Ongoing studies suggest that spiritual experiences and practices involve a variety of neural systems that may facilitate neural 'top-down' effects that are comparable if not identical to those engaged in placebo responses. As meaningfulness seems to be both a hallmark of spirituality and placebo reactions, it may be regarded as an overarching psychological concept that is important to engaging and facilitating psychophysiological mechanisms that are involved in health-related effects. Empirical evidence suggests that spirituality may under certain conditions be a predictor of placebo response and effects. Assessment of patients' spirituality and making use of various resources to accommodate patients' spiritual needs reflect our most current understanding of the physiological, psychological and socio-cultural aspects of spirituality, and may also increase the likelihood of eliciting self-healing processes. We advocate the position that a research agenda addressing responses and effects of both placebo and spirituality could therefore be (i) synergistic, (ii) valuable to each phenomenon on its own, and (iii) contributory to an extended placebo paradigm that is centred around the concept of meaningfulness.     

Placebos and painkillers: is mind as real as matter?

Considerable progress has been made in our understanding of the neurobiological mechanisms of the placebo effect, and most of our knowledge originates from the field of pain and analgesia. Today, the placebo effect represents a promising model that could allow us to shed new light on mind-body interactions. The mental events induced by placebo administration can activate mechanisms that are similar to those activated by drugs, which indicates a similarity between psychosocial and pharmacodynamic effects. These new neurobiological advances are already changing our conception of how clinical trials and medical practice must be viewed and conducted.     

Parasitism by Cuscuta pentagona sequentially induces JA and SA defence pathways in tomato

While plant responses to herbivores and pathogens are well characterized, responses to attack by other plants remain largely unexplored. We measured phytohormones and C₁₈ fatty acids in tomato attacked by the parasitic plant Cuscuta pentagona, and used transgenic and mutant plants to explore the roles of the defence‐related phytohormones salicylic acid (SA) and jasmonic acid (JA). Parasite attachment to 10‐day‐old tomato plants elicited few biochemical changes, but a second attachment 10 d later elicited a 60‐fold increase in JA, a 30‐fold increase in SA and a hypersensitive‐like response (HLR). Host age also influenced the response: neither Cuscuta seedlings nor established vines elicited a HLR in 10‐day‐old hosts, but both did in 20‐day‐old hosts. Parasites grew larger on hosts deficient in SA (NahG) or insensitive to JA [jasmonic acid‐insensitive1 (jai1) ], suggesting that both phytohormones mediate effective defences. Moreover, amounts of JA peaked 12 h before SA, indicating that defences may be coordinated via sequential induction of these hormones. Parasitism also induced increases in free linolenic and linoleic acids and abscisic acid. These findings provide the first documentation of plant hormonal signalling induced by a parasitic plant and show that tomato responses to C. pentagona display characteristics similar to both herbivore‐ and pathogen‐induced responses.     

Motivation and placebos: do different mechanisms occur in different contexts?

This paper challenges the common assumption that the mechanisms underlying short-term placebo paradigms (where there is no motivation for health improvement) and long-term placebo paradigms (where patients value improvement in their health) are the same. Three types of motivational theory are reviewed: (i) classical placebo motivation theory that the placebo response results from the desire for therapeutic improvement; (ii) goal activation model that expectancy-driven placebo responses are enhanced when the placebo response satisfies an activated goal; and (iii) motivational concordance model that the placebo response is the consequence of concordance between the placebo ritual and significant intrinsic motives. It is suggested that current data are consistent with the following theory: response expectancy, conditioning and goal activation are responsible for short-term placebo effects but long-term therapeutic change is achieved through the effects of goal satisfaction and affect on the inflammatory response system and hypothalamic-pituitary-adrenal axis. Empirical predictions of this new theory are outlined, including ways in which placebo effects can be combined with other psychologically mediated effects on short-term and long-term psychological and physiological state.     

Electrophysiological responses of female Helicoverpa armigera (Hübner) (Lepidoptera; Noctuidae) to synthetic host odours

Studies were conducted to investigate the electroantennographic (EAG) responses of adult female Helicoverpa armigera to a range of known and putative kairomone components. The studies show that at a given dose the EAG responses elicited by a series of straight-chain aliphatic primary alcohols were not dependent on volatility since butan-1-ol and pentan-1-ol elicited EAG responses that were significantly smaller than those elicited by hexan-1-ol. The amplitudes of responses to hexan-1-ol were found to be dose dependent with a dose of 10(-1) μmol at source in a non-volatile solvent eliciting the largest response. Similarly, changes in functionality in a range of C(6) straight-chain aliphatic compounds significantly changed the amplitude of response elicited, with aldehydes eliciting smaller responses than the related primary alcohols and saturated compounds eliciting higher responses than related unsaturated compounds. Of the range of nine host plant-produced terpenoids tested, ocimene and beta-phellandrene elicited the highest responses and of the six aromatic compounds tested phenylacetaldehyde and benzaldehyde elicited the largest responses, at the doses tested. The significance of these findings for analysis of floral odours by gas chromatography linked to electroantennography as a means of identifying kairomone components attractive to H. armigera are discussed.     

New insights into the placebo and nocebo responses

In modern medicine, the placebo response or placebo effect has often been regarded as a nuisance in basic research and particularly in clinical research. The latest scientific evidence has demonstrated, however, that the placebo effect and the nocebo effect, the negative effects of placebo, stem from highly active processes in the brain that are mediated by psychological mechanisms such as expectation and conditioning. These processes have been described in some detail for many diseases and treatments, and we now know that they can represent both strength and vulnerability in the course of a disease as well as in the response to a therapy. However, recent research and current knowledge raise several issues that we shall address in this review. We will discuss current neurobiological models like expectation-induced activation of the brain reward circuitry, Pavlovian conditioning, and anxiety mechanisms of the nocebo response. We will further explore the nature of the placebo responses in clinical trials and address major questions for future research such as the relationship between expectations and conditioning in placebo effects, the existence of a consistent brain network for all placebo effects, the role of gender in placebo effects, and the impact of getting drug-like effects without drugs.     

The placebo response: its putative role as a functional salutogenic mechanism of the central nervous system

The concept of placebo has evolved over time. Generally believed to be the basis of the premodern pharmacopoeia, the placebo has been adopted in practice as a harmless but unscientific approach towards alleviating symptoms. Currently, many medical scientists view placebos pejoratively as confounding elements in the analysis of randomized control trials.This article examines the changing attitudes towards placebos and the persistent controversies that surround their administration. The possible role of the placebo response as a functional salutogenic brain mechanism is considered, and elements of Edelman's neurobiological model of self and attractor theory are combined to explain how a unitary response by the central nervous system might yield diverse placebo effects. It is concluded that placebo responses are rooted in the complexity of mind/body interactions and that their underlying physiological mechanisms may be elucidated via methods that directly examine brain activity as the basis of subjective experience.     

Dual role of respiratory syncytial virus glycoprotein fragment as a mucosal immunogen and chemotactic adjuvant

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract disease in infancy and early childhood. Despite its importance as a pathogen, there is no licensed vaccine to prevent RSV infection. The G glycoprotein of RSV, a major attachment protein, is a potentially important target for protective antiviral immune responses and has been shown to exhibit chemotactic activity through CX3C mimicry. Here, we show that sublingual or intranasal immunization of a purified G protein fragment of amino acids from 131 to 230, designated Gcf, induces strong serum IgG and mucosal IgA responses. Interestingly, these antibody responses could be elicited by Gcf even in the absence of any adjuvant, indicating a novel self-adjuvanting property of our vaccine candidate. Gcf exhibited potent chemotactic activity in in vitro cell migration assay and cysteine residues are necessary for chemotactic activity and self-adjuvanticity of Gcf in vivo. Mucosal immunization with Gcf also provides protection against RSV challenge without any significant lung eosinophilia or vaccine-induced weight loss. Together, our data demonstrate that mucosal administration of Gcf vaccine elicits beneficial protective immunity and represents a promising vaccine regimen preventing RSV infection.     

How to Study Placebo Responses in Motion Sickness with a Rotation Chair Paradigm in Healthy Participants

Placebo responses occur in every medical intervention when patients or participants expect to receive an effective treatment to relieve symptoms. However, underlying mechanisms of placebo responses are not fully understood. It has repeatedly been shown that placebo responses are associated with changes in neural activity but for many conditions it is unclear whether they also affect the target organ, such as the stomach in motion sickness. Therefore, we present a methodology for the multivariate assessment of placebo responses by subjective, behavioral and objective measures in motion sickness with a rotation chair paradigm. The physiological correlate of motion sickness is a shift in gastric myoelectrical activity towards tachygastria that can be recorded with electrogastrography. The presented study applied the so-called balanced placebo design (BPD) to investigate the effects of ginger compared to placebo and the effects of expectations by verbal information. However, the study revealed no significant main or interactional effects of ginger (as a drug) or information on outcome measures but showed interactions when sex of participants and experimenters are taken into considerations. We discuss limitations of the presented study and report modifications that were used in subsequent studies demonstrating placebo responses when rotation speed was lowered. In general, future placebo studies have to identify the appropriate target organ for the studied placebo responses and to apply the specific methods to assess the physiological correlates.     

De novo autoimmunity to cardiac myosin after heart transplantation and its contribution to the rejection process.

Allograft rejection is initiated by an immune response to donor MHC proteins. We recently reported that this response can result in breakdown of immune tolerance to a recipient self Ag. However, the contribution of this autoimmune response to graft rejection has yet to be determined. Here, we found that after mouse allogeneic heart transplantation, de novo CD4+ T cell and B cell autoimmune response to cardiac myosin (CM), a major contractile protein of cardiac muscle, is elicited in recipients. Importantly, CM is the autoantigen that causes autoimmune myocarditis, a heart autoimmune disease whose histopathological features resemble those observed in rejected cardiac transplants. Furthermore, T cell responses directed to CM peptide myhcalpha 334-352, a known myocarditogenic determinant, were detected in heart-transplanted mice. No responses to CM were observed in mice that had received an allogeneic skin graft or a syngeneic heart transplant, demonstrating that this response is tissue specific and that allogeneic response is necessary to break tolerance to CM. Next, we showed that sensitization of recipient mice with CM markedly accelerates the rejection of allogeneic heart. Therefore, posttransplant autoimmune response to CM is relevant to the rejection process. We conclude that transplantation-induced autoimmune response to CM represents a new mechanism that may play a significant role in cardiac transplant rejection.     

Temperature sensing by plants: a review and hypothesis

Abstract. The different effects which fast versus slow cooling have on such fundamental plant processes as ion transport, protoplasmic streaming, phloem translocation, growth, cell motility, water absorption and membrane potential are reviewed. When plant cells are rapidly cooled to non-injurious temperatures, many of the physiological ramifications of rapid-cooling stimulation are only transiently observed. It is proposed that these transient rapid-cooling-induced responses, sometimes elicited by temperature drops of only a few degrees centigrade, are manifestations of temperature sensing. The hypothesis is advanced that graded potentials, produced in response to rapidly falling temperature, are associated with graded increases in cytosolic free calcium. These transient increases in cytosolic free calcium give rise to many of the physiological effects elicited by rapid cooling. Other effects, however, such as those associated with alterations in membrane composition, gene expression and post-translational modifications of proteins, may persist longer. The questions of the possible physiological advantage of temperature sensing, and its implications for the study of chilling injury, are discussed.     

The placebo response in clinical trials: more questions than answers

Meta-analyses and re-analyses of trial data have not been able to answer some of the essential questions that would allow prediction of placebo responses in clinical trials. We will confront these questions with current empirical evidence. The most important question asks whether the placebo response rates in the drug arm and in the placebo arm are equal. This 'additive model' is a general assumption in almost all placebo-controlled drug trials but has rarely been tested. Secondly, we would like to address whether the placebo response is a function of the likelihood of receiving drug/placebo. Evidence suggests that the number of study arms in a trial may determine the size of the placebo and the drug response. Thirdly, we ask what the size of the placebo response is in 'comparator' studies with a direct comparison of a (novel) drug against another drug. Meta-analytic and experimental evidence suggests that comparator studies may produce higher placebo response rates when compared with placebo-controlled trials. Finally, we address the placebo response rate outside the laboratory and outside of trials in clinical routine. This question poses a serious challenge whether the drug response in trials can be taken as evidence of drug effects in clinical routine.     

Are All Placebo Effects Equal? Placebo Pills,Sham Acupuncture,Cue Conditioning and Their Association

Placebo treatments and healing rituals have been used to treat pain throughout history. The present within-subject crossover study examines the variability in individual responses to placebo treatment with verbal suggestion and visual cue conditioning by investigating whether responses to different types of placebo treatment, as well as conditioning responses, correlate with one another. Secondarily, this study also examines whether responses to sham acupuncture correlate with responses to genuine acupuncture. Healthy subjects were recruited to participate in two sequential experiments. Experiment one is a five-session crossover study. In each session, subjects received one of four treatments: placebo pills (described as Tylenol), sham acupuncture, genuine acupuncture, or no treatment rest control condition. Before and after each treatment, paired with a verbal suggestion of positive effect, each subject''s pain threshold, pain tolerance, and pain ratings to calibrated heat pain were measured. At least 14 days after completing experiment one, all subjects were invited to participate in experiment two, during which their analgesic responses to conditioned visual cues were tested. Forty-eight healthy subjects completed experiment one, and 45 completed experiment two. The results showed significantly different effects of genuine acupuncture, placebo pill and rest control on pain threshold. There was no significant association between placebo pills, sham acupuncture and cue conditioning effects, indicating that individuals may respond to unique healing rituals in different ways. This outcome suggests that placebo response may be a complex behavioral phenomenon that has properties that comprise a state, rather than a trait characteristic. This could explain the difficulty of detecting a signature for “placebo responders.” However, a significant association was found between the genuine and sham acupuncture treatments, implying that the non-specific effects of acupuncture may contribute to the analgesic effect observed in genuine acupuncture analgesia.     

Tone-dependent responses to acetylcholine in the feline pulmonary vascular bed

The effects of an increase in base-line tone on pulmonary vascular responses to acetylcholine were investigated in the pulmonary vascular bed of the intact-chest cat. Under conditions of controlled blood flow and constant left atrial pressure, intralobar injections of acetylcholine under low-tone base-line conditions increased lobar arterial pressure in a dose-related manner. When tone was increased moderately by alveolar hypoxia, acetylcholine elicited dose-dependent decreases in lobar arterial pressure, and at the highest dose studied, acetylcholine produced a biphasic response. When tone was raised to a high steady level with the prostaglandin analogue, U46619, acetylcholine elicited marked dose-related decreases in lobar arterial pressure. Atropine blocked both vasoconstrictor responses at low tone and vasodilator responses at high tone, whereas meclofenamate and BW 755C had no effect on responses to acetylcholine at low or high tone. The vasoconstrictor response at low tone was blocked by pirenzepine (20 and 50 micrograms/kg iv) but not gallamine (10 mg/kg iv). The vasodilator response at high tone was not blocked by pirenzepine (50 micrograms/kg iv) or gallamine or pancuronium (10 mg/kg iv). The present data support the concept that pulmonary vascular responses to acetylcholine are tone dependent and suggest that the vasoconstrictor response under low-tone conditions is mediated by a high-affinity muscarinic (M1)-type receptor. These data also suggest that vasodilator responses under high-tone conditions are mediated by muscarinic receptors that are neither M1 nor M2 low-affinity muscarinic-type receptor and that responses to acetylcholine are not dependent on the release of cyclooxygenase or lipoxygenase products.     

Effects of exogenous ganglioside and cholesterol application on excitability of Aplysia neurons

The effects of pressure-ejected gangliosides GM1 and GMix ("Cronassial") and cholesterol dissolved in sea water on the electrophysiological characteristics of Aplysia neurons were studied using voltage-clamp recording techniques. Two types of electrophysiological effects were found. In about 5% of neurons brief pulses (0.1-0.2 sec) of GM1 or GMix elicited fast and large currents associated with an increase in membrane conductance and clear reversal potentials. These currents were similar to those elicited by common neuro-transmitters. Thus it appears that gangliosides may activate a membrane-bound receptor on at least some neurons. Most (about 85%) of the 121 neurons studied showed responses to longer pulses (1.0-2.5 sec) of gangliosides. These responses were much smaller, usually had a relatively slow component, and could be mimicked by application of cholesterol. The currents elicited were either inward or outward and were often biphasic, with an small initial outward component followed by a larger slow inward current. The responses often became larger upon repeated application at short intervals, and long periods of wash were required for recovery. This type of response appears to reflect changes in the electrical properties of the cell induced by incorporation of small amounts of gangliosides or cholesterol into the membrane.     

Respiratory pumping in Aplysia fasciata as part of an integrated defensive response to increases and decreases in seawater concentration

Much of the neural circuitry controlling respiratory pumping in Aplysia has been well characterized, but the function of this movement is incompletely understood. To gain insight into possible functions of respiratory pumping, responses were examined for a 40 min exposure to two stimuli that modulate the movement: 1) increase and 2) decrease in seawater concentration. Thresholds were present for both stimuli to affect respiratory pumping. Above threshold, there were graded increases in the number of pumps elicited. There were decrements in respiratory pump frequency as a function of time exposed to the stimulus. Increased respiratory pumping did not contribute to volume regulation in response to exposure to altered seawaters, but was associated with increased defensive responses, such as escape locomotion (swimming) and inking. In addition, head shock, a well-established noxious stimulus, elicited temporal patterns of respiratory pumping similar to those elicited by altered seawaters. The data indicate that in our experimental conditions, respiratory pumping is elicited as part of an integrated defensive response to noxious seawaters.