Psychophysiological responsivity on a laboratory stress task: methodological implications for a stress-muscle hyperactivity pain model

A stress-muscle hyperactivity-pain (SMP) model has been proposed to explain the etiology of certain musculoskeletal pain disorders. According to this model, subjects should show physiological arousal during periods of stress relative to periods of rest. In a test of this prediction, 31 subjects performed a reaction time task that has been used in previous laboratory studies. Multiple psychophysiological variables were monitored during initial and final 10-minute baselines, during performance on nine 2-minute reaction time tasks, and during 36-second rest intervals following each of the 2-minute tasks, Results showed small but statistically significant differences generally supporting the SMP model when masseter EMG was averaged over time periods of 12 seconds to 2 minutes, but not when masseter EMG was averaged over 10- to 18-minute blocks. These results demonstrated the importance of carefully selecting time intervals for analysis. Additional analyses that compared TMD with symptom-free subjects revealed small differences in EMG that supported the SMP model. Analyses of EMG over shorter time intervals also showed, however, that masseter EMG increased during the 36-second rest interval following performance on a 2-minute stress task; this result suggested that a modification of the SMP model may be necessary.     

Co-species housing in mice and rats: Effects on physiological and behavioral stress responsivity

Co-species housing of mice and rats is common practice at most breeding facilities and research laboratories, neglecting the possible effects on the animals. We investigated physiological as well as behavioral stress-reactivity in mice and rats which were either derived from a co-species or species-separated housing condition at the breeding facilities. The animals were kept under the housing condition they were used to or assigned to the opposite one. Co-species housing had a significant impact on acute stress reactivity in mice and rats but only if they were used to this housing condition throughout their lives. Moreover, the stress-effects appeared to be long lasting. Assigning animals, derived from a species-separated housing condition, to co-species housing led to chronic stress in mice and affected experimental behavior of rats.Our findings led to the conclusion that co-species housing in mice and rats should be avoided, supporting the recommendations by the U.S. National Institutes of Health (NIH) and the Dutch Ministry of Health, Welfare and Sport (VWS). In order to support the interpretation, facilitate the reproducibility and comparability and subsequently the generalizability of experimental results, breeding facilities should at least provide detailed information about their housing conditions.     

Eye-hand-coordination: A model for computing reaction times in a visually guided reach task

A model is described which provides a simple algorithm to compute the reaction times of saccadic eye movements and reach movements aimed at a single visual target. It is assumed, that the two movements are prepared inparallel and initiated independently unless the preparation of the saccade for some reason takes longer than the preparation of the reach movement. In the latter case the final command to execute the reach movement is synchronized with that to execute the eye movement and therefore the corresponding reaction times are highly correlated in a one-to-one relationship. Random variables are used to predict sets of data that are directly comparable with the experimental results. The algorithm includes the effects of daily practice (learning). The structure of the model and its computational results will be compared with the physiological data from monkey and man.     

Developing a laboratory animal model for perinatal endocrine disruption: the hamster chronicles

At the biomedical, regulatory, and public level, considerable concern surrounds the concept that inappropriate exposure to endocrine-disrupting chemicals, especially during the prenatal and/or neonatal period, may disrupt normal reproductive tract development and adult function. The intent of this review was to 1. Describe some unique advantages of the hamster for perinatal endocrine disruptor (ED) studies, 2. Summarize the morphological and molecular consequences of exposure to the established perinatal ED, diethylstilbestrol, in the female and male hamster, 3. Present some new, histomorphological insight into the process of neonatal diethylstilbestrol-induced disruption in the hamster uterus, and 4. Introduce recent efforts and future plans to evaluate the potency and mechanism of action of other putative EDs in the hamster experimental system. Taken together, the findings indicate that the hamster represents a unique and sensitive in vivo system to probe the phenomenon of endocrine disruption. The spectrum of candidate endpoints includes developmental toxicity, neoplasia, and more subtle endpoints of reproductive dysfunction.     

Cladistic analysis of New World monkey sulcal patterns: Methodological implications for primate brain studies

Data on New World monkey sulcal patterns are summarized and subjected to the cladistic method of analysis. The problem of allometry is discussed and controlled. Seven derived cortical features are identified and used to construct three alternative cladograms for the bigger brained ceboid taxa. Using Saimiri as an example, it is shown that preconceived ideas of allometric and phylogenetic relationships influence the construction of cladograms. The relationship between brain size, number of sulci and number of derived cortical features is explored for ceboid monkeys. In addition to a greater number of sulci, bigger brained ceboids exhibit a greater number of obviously specialized cortical features than do smaller brained ceboids. It is concluded that cladistic analysis of neurological features must be conducted cautiously since primate brain studies show that parallel evolution should be carefully considered as an alternative to the hypothesis of descent from a common ancestor.     

A baboon model for endometriosis: implications for fertility

Endometriosis is one of the most common causes of chronic pelvic pain and infertility in women in the reproductive age group. Although the existence of this disease has been known for over 100 years our current knowledge of its pathogenesis and the pathophysiology of its related infertility remains unclear. Several reasons contribute to our lack of knowledge, the most critical being the difficulty in carrying out objective long-term studies in women. Thus, we and others have developed a model of this disease in the non-human primate, the baboon (Papio anubis). Intraperitoneal inoculation of autologous menstrual endometrium results in the development of endometriotic lesions with gross morphological characteristics similar to those seen in the human. Multiple factors have been implicated in endometriosis-associated infertility. We have described aberrant levels of factors involved in multiple pathways important in the establishment of pregnancy, in the endometrium of baboons induced with endometriosis. Specifically, we have observed dysregulation of proteins involved in invasion, angiogenesis, methylation, cell growth, immunomodulation, and steroid hormone action. These data suggest that, in an induced model of endometriosis in the baboon, an increased angiogenic capacity, decreased apoptotic potential, progesterone resistance, estrogen hyper-responsiveness, and an inability to respond appropriately to embryonic signals contribute to the reduced fecundity associated with this disease.     

Establishing an academic laboratory: mentoring as a business model

It is a tremendous honor for my group and me to receive the recognition of the 2014 Women in Cell Biology Junior Award. I would like to take the opportunity of this essay to describe my scientific journey, discuss my philosophy about running a group, and propose what I think is a generalizable model to efficiently establish an academic laboratory. This essay is about my view on the critical components that go into establishing a highly functional academic laboratory during the current tough, competitive times.     

Social dominance, task performance and nutrition: implications for reproduction in eusocial wasps

Dominance status is associated with individual differences in reproductive capacity in many animal societies, but the mechanisms that link social dominance to reproductive physiology are poorly understood. We propose a model for social dynamics that incorporates the nutritional costs and benefits of behavior: dominant individuals avoid energy-expensive behavior and build their nutritional reserves, thereby increasing their potential for reproduction. Greater reproductive capacity, once achieved, favors increased social dominance. To test the model, we measured relationships of females' nutrient storage and reproductive capacities with dominance status and task performance in the eusocial wasp Mischocyttarus mastigophorus. Ovary development was positively related with high levels of nutrient storage and with high rates of dominance behavior, but was not correlated with task performance. In contrast, high levels of nutrient storage were positively related with the performance of nutrient garnering and conserving tasks, but not with dominance behavior. These data support a model which places the nutritional costs of task performance as an intermediate causal link that connects dominance status with the accumulation of nutrient stores. Nutrient flow may be a general causal mechanism linking dominance status to reproductive capacity in animal societies.     

The effects of low-dose caffeine on perceived pain during a grip to exhaustion task

This double-blind, placebo-controlled, within-subject experiment examined the effects of low-dose caffeine on pain reported during an exhaustive grip task. The grip task consisted of holding a metal block attached to standard Olympic weight plates with the arm at the side until the participants could no longer maintain their grip. Apparently healthy recreationally trained college-aged adults (men, n = 5; women, n = 5) were given either a piece of Stay Alert? gum that delivered 85% of the effective dose of 100 mg of caffeine in 5 minutes or an identical placebo gum that contained no caffeine. Subsequently, pain perception and ratings of perceived exertion were recorded during an exhaustive grip task every 15 seconds and the overall time to exhaustion. No significant difference was found in time to exhaustion between treatments. A significant main effect of treatment for reported pain (p < 0.001, Φ = 0.377) was observed. Thus, in a population of recreationally trained college-aged adults, low-dose caffeine may attenuate the individual's perception of pain during a grip to exhaustion task.     

Atrial fibrillation pacing decreases intravascular shear stress in a New Zealand white rabbit model: implications in endothelial function

Atrial fibrillation (AF) is characterized by multiple rapid and irregular atrial depolarization, leading to rapid ventricular responses exceeding 100 beats per minute (bpm). We hypothesized that rapid and irregular pacing reduced intravascular shear stress (ISS) with implication to modulating endothelial responses. To simulate AF, we paced the left atrial appendage of New Zealand White rabbits (n = 4) at rapid and irregular intervals. Surface electrical cardiograms were recorded for atrial and ventricular rhythm, and intravascular convective heat transfer was measured by microthermal sensors, from which ISS was inferred. Rapid and irregular pacing decreased arterial systolic and diastolic pressures (baseline, 99/75 mmHg; rapid regular pacing, 92/73; rapid irregular pacing, 90/68; p < 0.001, n = 4), temporal gradients ( ${\partial\tau/\partial t}$ from 1,275 ± 80 to 1,056 ± 180 dyne/cm² s), and reduced ISS (from baseline at 32.0 ± 2.4 to 22.7 ± 3.5 dyne/cm²). Computational fluid dynamics code demonstrated that experimentally inferred ISS provided a close approximation to the computed wall shear stress at a given catheter to vessel diameter ratio, shear stress range, and catheter position. In an in vitro flow system in which time-averaged shear stress was maintained at ${{\tau_{\rm avg}} = 23 \pm 4\, {\rm dyn}\, {\rm cm}^{-2} {\rm s}^{-1}}$ , we further demonstrated that rapid pulse rates at 150 bpm down-regulated endothelial nitric oxide, promoted superoxide (O ₂ ^.? ) production, and increased monocyte binding to endothelial cells. These findings suggest that rapid pacing reduces ISS and ${\partial\tau/\partial t}$ , and rapid pulse rates modulate endothelial responses.     

Comparative bone anatomy of commonly used laboratory animals: implications for drug discovery

To accommodate functional demands, the composition and organization of the skeleton differ among species. Microcomputed tomography has improved our ability markedly to assess structural parameters of cortical and cancellous bone. The current study describes differences in cortical and cancellous bone structure, bone mineral density, and morphology (geometry) at the proximal femur, proximal femoral diaphysis, lumbar vertebrae, and mandible in mice, rats, rabbits, dogs, and nonhuman primates. This work enhances our understanding of bone gross and microanatomy across lab animal species and likely will enable scientists to select the most appropriate species and relevant bone sites for research involving skeleton. We evaluated the gross and microanatomy of the femora head and neck, lumbar spine, and mandible and parameters of cancellous bone, including trabecular number, thickness, plate separation, and connectivity among species. The skeletal characteristics of rabbits, including a very short femoral neck and small amounts of cancellous bone at the femoral neck, vertebral body, and mandible, seem to make this species the least desirable for preclinical research of human bone physiology; in comparison, nonhuman primates seem the most applicable for extrapolation of data to humans. However, rodent (particularly rat) models are extremely useful for conducting basic research involving the skeleton and represent reliable and affordable alternatives to dogs and nonhuman primates. Radiology and microcomputed tomography allow for reliable evaluation of bone morphology, microarchitecture, and bone mineral density in preclinical and clinical environments.     

Transport mechanisms in oral transmucosal drug delivery: implications for pain management

The mechanism for the oral transmucosal delivery of fentanyl citrate (OTFC) was investigated in this work. A developed mathematical model included the following transport characteristics: dissolution of the fentanyl citrate lozenge, diffusion through the saliva and oral mucosal membrane and equilibrium between adjacent layers. An orthogonal-collocation-based solution procedure was adopted to discretize the governing equations and boundary conditions. The Mathematica® built-in function, NDSolve, was applied to integrate the equations with respect to time. Simulations were conducted with a 200 μg-dosage. A novel fabrication method, aimed at maintaining a high flux for a prolonged period of time, was proposed based on the calculated delivery rate and cumulative amount of medicament absorbed into the systemic circulation. The model allows drug manufacturers to decide when to replace the unit based on estimated drug concentrations in the saliva and the mucosal membrane. Both the model and solution strategies were validated using serum fentanyl citrate concentration collected from adult subjects. The predicted profiles, based on parameters obtained from the literature, agree well with the experimental data.     

Protease signaling to G protein-coupled receptors: implications for inflammation and pain

Proteases, like thrombin, trypsin, cathepsins, or tryptase, can signal to cells by cleaving in a specific manner, a family of G protein-coupled receptors, the protease-activated receptors (PARs). Proteases cleave the extracellular N-terminal domain of PARs to reveal tethered ligand domains that bind to and activate the receptors. Recent evidence has supported the involvement of PARs in inflammation and pain. Activation of PAR(1), PAR(2), and PAR(4) either by proteinases or by selective agonists causes inflammation inducing most of the cardinal signs of inflammation: swelling, redness, and pain. Recent studies suggest a crucial role for the different PARs in innate immune response. The role of PARs in the activation of pain pathways appears to be dual. Subinflammatory doses of PAR(2) agonists induce hyperalgesia and allodynia, and PAR(2) activation has been implicated in the generation of inflammatory hyperalgesia. In contrast, subinflammatory doses of PAR(1) or PAR(4) increase nociceptive threshold, inhibiting inflammatory hyperalgesia, thereby acting as analgesic mediators. PARs have to be considered as an additional subclass of G protein-coupled receptors that are active participants to inflammation and pain responses and that could constitute potential novel therapeutic targets.     

Exploring the predictive performance of several temperature measurements on Neotropical dung beetle assemblages: Methodological implications

Basic characteristics of species assemblages are frequently related to temperature variables recorded at a coarse‐grained scale. In this study, 15 min instant‐measurements of environmental and soil temperatures were recorded during 1 year in six Atlantic Forest sites of southern Brazil, ranging from 250 to 1,630 m a.s.l. These measurements were used to examine the comparative explanatory capacity of several temperature variables in predicting species richness and total or specific variations of dung beetle abundance. The results suggest that temperature measurements obtained during the survey period have the highest explanatory capacity. Furthermore, average temperature values seem to have a relatively higher explanatory capacity than absolute minimum or maximum values reflecting extreme conditions. In general, there is no rule in selecting a temperature variable when the objective involves explaining the variation in species abundances. Both soil and air variables can have similar explanatory capacities. The present results should be considered when designing future ecological studies in Neotropical conditions.     

Oxidative stress biomarkers responses to physical overtraining: implications for diagnosis

Overtraining syndrome is characterized by declining performance and transient inflammation following periods of severe training with major health implications for the athletes. Currently, there is no single diagnostic marker for overtraining. The present investigation examined the responses of oxidative stress biomarkers to a resistance training protocol of progressively increased and decreased volume/intensity. Twelve males (21.3+/-2.3 years) participated in a 12-week resistance training consisting of five 3-week periods (T1, 2 tones/week; T2, 8 tones/week; T3, 14 tones/week; T4, 2 tones/week), followed by a 3-week period of complete rest. Blood/urine samples were collected at baseline and 96 h following the last training session of each period. Performance (strength, power, jumping ability) increased after T2 and declined thereafter, indicating an overtraining response. Overtraining (T3) induced sustained leukocytosis, an increase of urinary isoprostanes (7-fold), TBARS (56%), protein carbonyls (73%), catalase (96%), glutathione peroxidase, and oxidized glutathione (GSSG) (25%) and a decline of reduced glutathione (GSH) (31%), GSH/GSSG (56%), and total antioxidant capacity. Isoprostanes and GSH/GSSG were highly (r=0.764-0.911) correlated with performance drop and training volume increase. In conclusion, overtraining induces a marked response of oxidative stress biomarkers which, in some cases, was proportional to training load, suggesting that they may serve as a tool for overtraining diagnosis.