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Abstract Background Recent reviews on placebo effects in clinical trials suggest that objective changes following placebo treatments may not exist or, at least, have been considerably overestimated. However, the possibility that yet unidentified subsets of parameters are responsive to placebo treatments has not been taken into account. Therefore, the aim of the present study is to examine the effects of placebo treatments on objectively measured outcome parameters by specifically focusing on peripheral disease processes. Methods An initial dataset was collected from a MEDLINE search for placebo-controlled, randomized clinical trials. Trials with stable disease conditions were identified, and the effects of placebo treatments on peripheral outcome parameters were estimated by the changes from baseline in the placebo groups. An explorative data analysis was conducted in order to identify parameter classes with differential responsiveness to placebo treatments. A subgroup meta-analysis of a second dataset was performed to test whether the preliminary classification would also apply to placebo effects derived from the comparison of placebo groups with untreated control groups. Results The explorative analysis of outcome parameters and strength of placebo effects yielded a classification into responsive "physical" versus non-responsive "biochemical" parameters. In total, 50% of trials measuring physical parameters showed significant placebo effects, compared with 6% of trials measuring biochemical parameters. A subgroup meta-analysis substantiated the differential response (physical parameters: n = 14, Hedges' pooled effect size g = 0.34, 95% CI 0.22 to 0.46; biochemical parameters: n = 15, g = 0.03, 95% CI -0.04 to 0.10). The subanalysis of the second dataset supported the classification and revealed a significant improvement for physical parameters (n = 20, g = 0.22, 95% CI 0.07 to 0.36) and a deterioration for biochemical parameters (n = 6, g = -0.17, 95% CI -0.31 to -0.02). Conclusion The results suggest that placebo interventions can improve physical disease processes of peripheral organs more easily and effectively than biochemical processes. This differential response offers a good starting point for theoretical considerations on possible mediating mechanisms, and for future investigations in this field.

We report a case of moderately severe acute pancreatitis, hyperglycemia, acidosis, splenic, superior mesenteric, and portal vein thrombosis in relation to multisystem inflammatory syndrome in children (MIS-C). The patient responded well to intravenous immune globulin, corticosteroids, antibiotics, systemic anticoagulation, and drainage of peripancreatic fluid. The case highlights the polymorphic presentation of MIS-C and advises high level of suspicion for unusual, severe cases unresponsive to routine care., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). JPGN Reports Published by Wiley Periodicals LLC. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

This study aimed to determine whether there are regional influences on attitudes toward olfaction. A total of 1082 participants aged 21-50 years from 4 different regions (Mexican, Korean, Czech, and German) were asked to rate general attitudes toward olfaction in everyday life. To examine affective attitudes to odors (i.e., pleasantness), participants were also asked to list 3 odors as being the most pleasant or unpleasant, respectively. Next, the mentioned odor names were attributed to 1 of 4 main categories: "Food & Drink," "Social relationship," "Nature," and "Civilization" and the distribution of these categories was compared across regions. Mexicans were significantly different to the other regions in their general attitudes toward olfaction. In addition, in all regions, in comparison with men, women indicated a higher interest in the sense of smell. Moreover, a significant positive correlation was present between individuals' self-rating of olfactory sensitivity and general attitudes toward olfaction. Finally, there were significant cross-regional differences in affective attitudes toward specific categories of odors. In conclusion, our findings support and extend the notion that regions affect attitudes toward the olfactory world.

We studied the development of suckling behavior and weight gain in 11 litters (52 kittens) of free-ranging domestic cats until postnatal day 28 just before the start of weaning. In six of these litters, we also recorded milk intake and contests for access to nipples. Already within 12 hr of birth kittens showed a preference for posterior nipples, and by postnatal day 3 each had developed a preference for particular nipples. In fact, 86% of kittens used one particular nipple most often, and even when the mother changed the side she lay on to nurse. Contests for access to nipples occurred throughout the study period at an average rate of one to two contests per kitten per hour of nursing. Contrary to suggestions in the literature that kittens compete for more productive nipples, we found no relation between kittens' use of particular nipples and their weight gain, milk intake, or involvement in contests during suckling. We suggest that kittens' preference for posterior nipples as well as their establishment of an individual "teat order" might function to optimize the number of nipples remaining productive across lactation, and to reduce energetically costly scrambles and potentially injurious contests among littermates.

To our knowledge there has been no study of the effect of everyday air pollution on olfactory function. It was therefore the aim of this study to compare the olfactory performance of long-term residents of Mexico City, an environment with high air pollution, with the olfactory performance of residents of the Mexican state of Tlaxcala, a region geographically similar to Mexico City but with low air pollution. Healthy volunteers [82 Mexico City subjects (MEX), 86 Tlaxcala subjects (TLX)] 20-63 years of age and balanced for age and gender between the two localities were tested for the perception of the odors of everyday beverages presented in squeeze bottles. When tested with ascending concentrations of stimuli in a three-way oddball paradigm, residents of Tlaxcala detected the odors of instant coffee and of an orange drink at significantly lower concentrations than residents of Mexico City. They also performed significantly better in discriminating between the two similar-smelling Mexican beverages horchata and atole in an oddball test. Significant differences between the two populations in overall olfactory performance were apparent in three of the four age classes (20- to 29-, 30- to 39-, and 40- to 49-year-old subjects) but not in the 50-63 years age class. About 10% of MEX subjects compared to about 2% of TLX subjects were judged to have poor olfactory function; all were from the older age classes (mean age: 48.6 years). Thus, air pollution in Mexico City appears to have a substantial impact on olfactory function even in young and middle-aged residents.

Rabbits (Oryctolagus cuniculus), like many small mammals, have a marked postpartum estrus, and during the breeding season, are often both pregnant and lactating. We examined reproductive performance and allocation of resources by rabbit mothers with overlapping litters under presumably optimal conditions of unrestricted food, standardized litter size, and young reproductive age. Even under these conditions, females raising overlapping litters incurred higher costs in terms of greatly increased food intake and pup mortality than females raising nonoverlapping litters. Despite such costs, females with overlapping litters raised a larger total number of young to weaning than females without the load of simultaneous lactation and pregnancy. By more than doubling food intake during lactation, females maintained a stable baseline body weight throughout the study, suggesting that this, in a species with low fat reserves, might have priority over the short-term raising of a maximum number of young. Contrary to the expectation that females with overlapping litters would allocate more resources to their senior young, no appreciable difference in number, growth, or survival between pups of senior and junior litters was found either at birth or weaning. While this might reflect a strategy in this opportunistic breeder of distributing reproductive chances similarly between senior and junior litters, it is now necessary to investigate females' breeding strategy when resources are limited., (Copyright 2004 Elsevier Inc.)

Transient expression of axon collaterals plays an important role in enabling neurons to find appropriate targets during development. In the olfactory bulb, the numbers of both sensory neurons and their targets, the glomeruli, increase markedly during the postnatal period. In the present study, the morphology of developing olfactory axons in the olfactory bulb of 1-21-day-old rabbits was analyzed using stereological methods and the rapid Golgi technique. The findings demonstrated a change in axon morphology from the olfactory nerve layer to the glomeruli suggestive of a sequence in axon development. In the olfactory nerve layer, axons typically had knob-like growth cones and a few collateral branches. Close to glomeruli, axons increased in thickness, formed rather complex and irregular growth cones, and typically gave off many collaterals. Within glomeruli, the axons formed terminal branches and boutons. Extraglomerular branches were apparently removed once axons had entered a glomerulus, insofar as these branches often displayed morphological signs of degeneration. In contrast, collateral branches ending in the same glomerulus remained, indicating that formation of collaterals may assist olfactory axons in locating glomerular targets., (Copyright 2000 Wiley-Liss, Inc.)

Despite the importance of chemosensation in the regulation of ingestive behavior, we still know surprisingly little about the development of the olfactory, trigeminal and gustatory systems. All three, however, are functional to some degree prenatally, and by birth infants are able to respond to a wide range of odors and can clearly distinguish between the tastes of sweet, sour and bitter. Based on findings from our work in the rabbit, we report that learning of odors associated with the mother's diet can occur very early in development, even prenatally, that it can have a long-term influence on later food choice, and may even lead to enhanced, stimulus-specific sensitivity of the basic sensory apparatus. Whether comparable phenomena exist in human infants is not known, although our recent findings that nationalities differ in judgements of the pleasantness of food odors depending on whether these are recognized as representing familiar, culture-typical foods, suggests that it might. A cross-cultural study is currently in progress examining the influence of culture-specific childhood eating experiences on adult preferences for food-associated odors.

To investigate the influence of experience on odor perception the responses of 40 Japanese and 44 age-matched German women to everyday odorants were compared. Subjects were presented with six 'Japanese,' six 'European' and six 'international' odorants and asked to rate them on intensity, familiarity, pleasantness and edibility, and to describe associations elicited by them, and if possible to name them. Significant differences were found between the two populations on all measures, with a close association of pleasantness ratings and edibility judgments suggesting the particular influence of eating habits on odor perception. Positive correlations between familiarity and pleasantness, strength of hedonic judgment and intensity, and familiarity and intensity were also found in both groups and for most individuals. The generality of these findings was supported by the results obtained from testing 40 Mexican women with the same odorants.

The high dimensionality and unpredictability of the chemical world makes it difficult for the olfactory system to anticipate relevant stimuli and construct neural filters accordingly. A developmental solution to this problem would be to alter the sensory surface according to environmental conditions so as to enhance sensitivity to molecules of particular relevance. Evidence for this has been obtained in the rabbit. By feeding pregnant does aromatic juniper berries, it could be shown that newborn, weanling and even adult animals demonstrate a preference for juniper odor without subsequent postnatal experience, and that this is associated with enhanced peripheral sensitivity for juniper odor as measured by electro-olfactogram (EOG). This is consistent with the report that in young salmon olfactory imprinting is associated with enhanced, odor-specific sensitivity of receptor cells as measured by patch clamp. The mechanisms underlying such changes are unknown, including the extent to which they are a particular feature of developing systems.

After being nursed just once for 4-5 min by an artificially scented doe, newborn rabbits show the full pattern of nipple-search behavior when placed on a fur scented with the same odor as their mother. It was the aim of the present study to test whether such rapid learning is dependent on age. In Experiment 1 in which normally raised pups were nursed by a scented doe either on Days 1, 3 or 5, conditionability was found to decline markedly by postnatal Day 5. In Experiment 2 conditionability was maintained in pups deprived of suckling experience by bottle feeding from Days 1-4, but not in hand-raised pups allowed to search on a doe for 4 min daily without milk intake. Possible mechanisms underlying the decline in conditionability to suckling odors, as well as the potential functional significance of this early learning for immediate postnatal and later life are discussed.

As part of a study of the development of olfactory function in the rabbit, a morphometric analysis of the olfactory epithelium in newborn and 30-day-old animals was carried out. Surface area, thickness and cell densities of the olfactory epithelium were compared in hematoxylin-eosin stained serial sections through the nasal cavities of 4 newborn and 3 weanling rabbits. While the basic structure of the olfactory cavity changed little with age, a large quantitative development in the epithelium was observed. The pattern of growth appeared uniform and resulted in a 3-fold increase in total surface area from about 1 cm2 per side in the newborn to about 3 cm2 in the weanling, and an increase in thickness from approximately 65 microns to about 90 microns. The increase in thickness was due mainly to a disproportionate, 5-fold increase in the number of olfactory neurons. This resulted in a total of about 32 million cells per side by day 30, and represented an increase in the ratio of neurons to basal cells of 7:1 to 10:1, and neurons to supporting cells of 2:1 to 4:1. While such an increase in the number of primary neurons presumably improves the animal's perceptual abilities, it nevertheless raises the question as to how perceptual constancy can be maintained during a period of such rapid neural change.

Newborn rabbits are completely dependent on a pheromone on the mother's belly for the release of nipple-search behaviour and suckling. Using the stereotyped behavioural response of the pups as a bioassay it could be shown that: 1. In non-breeding does pheromone emission is stimulated by experimental long day and suppressed by experimental short day conditions within 1 to 2 weeks of reversing the light regime. 2. Under constant long day conditions pheromone emission, readiness to mate, conception rate and litter size remain high with no evidence of endogenous seasonal rhythmicity. 3. Experimental changes in daylength of just 1 or 2 h in either direction are sufficient to induce marked alterations in the level of pheromone emission, number of successful matings and average litter size within 2 to 3 weeks. Pheromone emission would thus seem to provide a sensitive test of photoperiodic responsiveness in non-breeding female rabbits, and a convenient, non-invasive indicator of their reproductive state.

To investigate environmental influences on the development of the olfactory epithelium, semi-thin sections were taken from the nasal septum of newborn and 30-day-old rabbits; the epithelial thickness and the number of olfactory knobs, supporting cells, dark basal cells, and receptor cells were compared. During normal development, a marked increase in epithelial thickness was found, largely because of an increase in the number of receptor cells. Whereas unilateral nare occlusion on day 1 resulted in 10% fewer receptor cells and 25% fewer knobs on the deprived side by day 30, nare occlusion either up to or after day 5 had little effect, and even temporary reopening from days 6-7 was sufficient to stimulate receptor-cell development on the occluded side. Although in these latter cases, a slight deprivation effect of 6% was still found in the number of receptor-cell nuclei, there was no longer a significant difference in the number of knobs between the open and closed sides. Thus, whereas exposure to the environment during the first days of life appears to be sufficient to stimulate sustained growth, the deprived epithelium may retain the capacity to respond to such cues beyond this time. However, as nare occlusion also had an effect on the respiratory epithelium and nasal lymphatic tissue, the nature of the cues stimulating receptor-cell development, whether olfactory or non-olfactory, is not yet clear.