Browsing by Author "Rusyniak, Daniel E."

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    Acute Methylenedioxypyrovalerone Toxicity
    (Springer-Verlag, 2015-06) Froberg, Blake A.; Levine, Michael; Beuhler, Michael C.; Judge, Bryan S.; Moore, Philip W.; Engebretsen, Kristin M.; Mckeown, Nathanael J.; Rosenbaum, Christopher D.; Young, Amy C.; Rusyniak, Daniel E.; ACMT Toxicology Investigators Consortium (ToxIC); Department of Pediatrics, IU School of Medicine
    The objective of this study was to characterize the acute clinical effects, laboratory findings, complications, and disposition of patients presenting to the hospital after abusing synthetic cathinone. We conducted a retrospective multicenter case series of patients with synthetic cathinone abuse by searching for the terms bath salts, MDPV, methylenedioxypyrovalerone, mephedrone, methcathinone, methylone, methedrone, and cathinone within the "agent" field of a national clinical toxicology database (ToxIC). The medical records of these patients were obtained and abstracted by investigators at each study site. Patients with confirmatory testing that identified a synthetic cathinone in either blood or urine were included in the series. Patients who had either an undetectable synthetic cathinone test or no confirmatory testing were excluded. A data abstraction sheet was used to obtain information on each patient. We entered data into an Excel spreadsheet and calculated descriptive statistics. We identified 23 patients with confirmed synthetic cathinone exposure--all were positive for methylenedioxyprovalerone (MDPV). Eighty-three percent were male and 74 % had recreational intent. The most common reported clinical effects were tachycardia (74 %), agitation (65 %), and sympathomimetic syndrome (65 %). Acidosis was the most common laboratory abnormality (43 %). Seventy-eight percent of patients were treated with benzodiazepines and 30 % were intubated. Ninety-six percent of patients were hospitalized and 87 % were admitted to the ICU. The majority (61 %) of patients was discharged home but 30 % required inpatient psychiatric care. There was one death in our series. The majority of patients presenting to the hospital after abusing MDPV have severe sympathomimetic findings requiring hospitalization. A number of these patients require inpatient psychiatric care after their acute presentation.
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    Automatic analysis of treadmill running to estimate times to fatigue and exhaustion in rodents
    (PeerJ, 2018-07-06) Zaretsky, Dmitry V.; Kline, Hannah; Zaretskaia, Maria V.; Rusyniak, Daniel E.; Emergency Medicine, School of Medicine
    Introduction: The determination of fatigue and exhaustion in experimental animals is complicated by the subjective nature of the measurement. Typically, it requires an observer to watch exercising animals, e.g. rats running on the treadmill, and to identify the time of the event. In this study, we hypothesized that automatic analysis of the time-averaged position of a rat on a treadmill could be an objective way for estimating times to fatigue and exhaustion. To test this hypothesis, we compared these times measured by a human observer to the results of an automated video tracking system. Methods: Rats, previously familiarized to running on the treadmill, ran at a fixed speed with zero incline, until exhaustion. The experiments were performed at either room temperature (24 °C) or in a hot environment (32 °C). Each experiment was video recorded. A trained observer estimated the times to fatigue and exhaustion. Then, video tracking software was used to determine the position of the animals on the treadmill belt. The times to fatigue and exhaustion were determined, based on the position on the treadmill using predefined criteria. Results: Manual scores and the average position on the treadmill had significant correlation. Both the observer and the automated video tracking determined that exercise in a hot environment, compared with the exercise at room temperature, results in shorter times to exhaustion and fatigue. Also, estimates of times made by the observer and the automated video tracking were not statistically different from each other. Discussion: A similarity between the estimates of times to fatigue and exhaustion made by the observer and the automated technique suggests that video tracking of rodents running on a treadmill can be used to determine both parameters in experimental studies. Video tracking technique allows for a more objective measure and would allow for an increased performance in experimentation. The Supplemental information to this manuscript contains an Excel file, which includes the code in Virtual Basic with freeware license, to process and visualize running data and automatically estimate the times to fatigue and exhaustion. Instructions for the software are also included.
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    Availability of mobile phones for discharge follow-up of pediatric Emergency Department patients in western Kenya
    (PeerJ, 2015-03) House, Darlene R.; Cheptinga, Philip; Rusyniak, Daniel E.; Department of Emergency Medicine, IU School of Medicine
    Objective. Mobile phones have been successfully used for Emergency Department (ED) patient follow-up in developed countries. Mobile phones are widely available in developing countries and may offer a similar potential for follow-up and continued care of ED patients in low and middle-income countries. The goal of this study was to determine the percentage of families with mobile phones presenting to a pediatric ED in western Kenya and rate of response to a follow-up phone call after discharge. Methods. A prospective, cross-sectional observational study of children presenting to the emergency department of a government referral hospital in Eldoret, Kenya was performed. Documentation of mobile phone access, including phone number, was recorded. If families had access, consent was obtained and families were contacted 7 days after discharge for follow-up. Results. Of 788 families, 704 (89.3%) had mobile phone access. Of those families discharged from the ED, successful follow-up was made in 83.6% of cases. Conclusions. Mobile phones are an available technology for follow-up of patients discharged from a pediatric emergency department in resource-limited western Kenya.
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    Brief Toxicology Observation: What Kind of Burger Did This Patient Eat?
    (Springer, 2015-09) Rood, Loren K.; Rusyniak, Daniel E.; Department of Emergency Medicine, IU School of Medicine
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    Circadian variability of body temperature responses to methamphetamine
    (American Physiological Society, 2018-01) Behrouzvaziri, Abolhassan; Zaretskaia, Maria V.; Rusyniak, Daniel E.; Zaretsky, Dmitry V.; Molkov, Yaroslav I.; Mathematical Sciences, School of Science
    Vital parameters of living organisms exhibit circadian rhythmicity. Although rats are nocturnal animals, most of the studies involving rats are performed during the day. The objective of this study was to examine the circadian variability of the body temperature responses to methamphetamine. Body temperature was recorded in male Sprague-Dawley rats that received intraperitoneal injections of methamphetamine (Meth, 1 or 5 mg/kg) or saline at 10 AM or at 10 PM. The baseline body temperature at night was 0.8°C higher than during the day. Both during the day and at night, 1 mg/kg of Meth induced monophasic hyperthermia. However, the maximal temperature increase at night was 50% smaller than during the daytime. Injection of 5 mg/kg of Meth during the daytime caused a delayed hyperthermic response. In contrast, the same dose at night produced responses with a tendency toward a decrease of body temperature. Using mathematical modeling, we previously showed that the complex dose dependence of the daytime temperature responses to Meth results from an interplay between inhibitory and excitatory drives. In this study, using our model, we explain the suppression of the hyperthermia in response to Meth at night. First, we found that the baseline activity of the excitatory drive is greater at night. It appears partially saturated and thus is additionally activated by Meth to a lesser extent. Therefore, the excitatory component causes less hyperthermia or becomes overpowered by the inhibitory drive in response to the higher dose. Second, at night the injection of Meth results in reduction of the equilibrium body temperature, leading to gradual cooling counteracting hyperthermia.
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    Disinhibiting neurons in the dorsomedial hypothalamus delays the onset of exertional fatigue and exhaustion in rats exercising in a warm environment
    (Elsevier, 2018-06) Zaretsky, Dmitry V.; Kline, Hannah; Zaretskaia, Maria V.; Brown, Mary Beth; Durant, Pamela J.; Alves, Nathan J.; Rusyniak, Daniel E.; Emergency Medicine, School of Medicine
    Stimulants cause hyperthermia, in part, by increasing heat generation through exercise. Stimulants also delay the onset of fatigue and exhaustion allowing animals to exercise longer. If used in a warm environment, this combination (increased exercise and decreased fatigue) can cause heat stroke. The dorsomedial hypothalamus (DMH) is involved in mediating locomotion from stimulants. Furthermore, inhibiting the DMH decreases locomotion and prevents hyperthermia in rats given stimulants in a warm environment. Whether the DMH is involved in mediating exercise-induced fatigue and exhaustion is not known. We hypothesized that disinhibiting neurons in the dorsomedial hypothalamus (DMH) would delay the onset of fatigue and exhaustion in animals exercising in a warm environment. To test this hypothesis, we used automated video tracking software to measure fatigue and exhaustion. In rats, using wearable mini-pumps, we demonstrated that disinhibiting the DMH, via bicuculline perfusion (5 µM), increased the duration of exercise in a warm environment as compared to control animals (25 ± 3 min vs 15 ± 2 min). Bicuculline-perfused animals also had higher temperatures at exhaustion (41.4 ± 0.2 °C vs 40.0 ± 0.4 °C). Disinhibiting neurons in the DMH also increased the time to fatigue. Our data show that the same region of the hypothalamus that is involved in mediating locomotion to stimulants, is also involved in controlling exhaustion and fatigue. These findings have implications for understanding the cause and treatment of stimulant-induced-hyperthermia.
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    Disinhibiting neurons in the dorsomedial hypothalamus delays the onset of exertional fatigue and exhaustion in rats exercising in a warm environment
    (Elsevier, 2018-06-15) Zaretsky, Dmitry V.; Kline, Hannah; Zaretskaia, Maria V.; Brown, Mary Beth; Durant, Pamela J.; Alves, Nathan J.; Rusyniak, Daniel E.; Emergency Medicine, School of Medicine
    Stimulants cause hyperthermia, in part, by increasing heat generation through exercise. Stimulants also delay the onset of fatigue and exhaustion allowing animals to exercise longer. If used in a warm environment, this combination (increased exercise and decreased fatigue) can cause heat stroke. The dorsomedial hypothalamus (DMH) is involved in mediating locomotion from stimulants. Furthermore, inhibiting the DMH decreases locomotion and prevents hyperthermia in rats given stimulants in a warm environment. Whether the DMH is involved in mediating exercise-induced fatigue and exhaustion is not known. We hypothesized that disinhibiting neurons in the dorsomedial hypothalamus (DMH) would delay the onset of fatigue and exhaustion in animals exercising in a warm environment. To test this hypothesis, we used automated video tracking software to measure fatigue and exhaustion. In rats, using wearable mini-pumps, we demonstrated that disinhibiting the DMH, via bicuculline perfusion (5 µM), increased the duration of exercise in a warm environment as compared to control animals (25 ± 3 min vs 15 ± 2 min). Bicuculline-perfused animals also had higher temperatures at exhaustion (41.4 ± 0.2 °C vs 40.0 ± 0.4 °C). Disinhibiting neurons in the DMH also increased the time to fatigue. Our data show that the same region of the hypothalamus that is involved in mediating locomotion to stimulants, is also involved in controlling exhaustion and fatigue. These findings have implications for understanding the cause and treatment of stimulant-induced-hyperthermia.
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    Eludicating triggers and neurochemical circuits underlying hot flashes in an ovariectomy model of menopause
    (2016-02-26) Federici, Lauren Michele; Shekhar, Anantha; Goodlett, Charles; Johnson, Philip L.; Oxford, Gerry S.; Rusyniak, Daniel E.
    Menopausal symptoms, primarily hot flashes, are a pressing clinical problem for both naturally menopausal women and breast and ovarian cancer patients, with a high societal and personal cost. Hot flashes are poorly understood, and animal modeling has been scarce, which has substantially hindered the development of non-hormonal treatments. An emerging factor in the hot flash experience is the role of anxiety and stress-related stimuli, which have repeatedly been shown to influence the bother, frequency, and severity of hot flashes. Causal relationships are difficult to determine in a clinical setting, and the use of animal models offers the ability to elucidate causality and mechanisms. The first part of this work details the development and validation of novel animal models of hot flashes using clinically relevant triggers (i.e., compounds or stimuli that cause hot flashes in clinical settings), which also increase anxiety symptoms. These studies revealed that these triggers elicited strong (7-9 °C) and rapid hot flash-associated increases in tail skin temperature in rats. In a surgical ovariectomy rat model of menopause, which typically exhibit anxiety-like behavior, hot flash provocation revealed an ovariectomy-dependent vulnerability, which was attenuated by estrogen replacement in tested models. An examination of the neural circuitry in response to the most robust flushing compound revealed increased cellular activity in key thermoregulatory and emotionally relevant areas. The orexin neuropeptide system was hyperactive and presented as a novel target; pretreatment with selective and dual orexin receptor antagonists significantly diminished or eliminated, respectively, the response to a hot flash provocation in ovariectomized rats. The insertion/deletion polymorphism of the serotonin transporter has been linked to increased anxiety-associated traits in humans, and subsequent studies prolonged hot flashes in SERT+/- rats, which also caused hot flashes in highly symptomatic women. These studies indicate the orexin system may be a novel non-hormonal treatment target, and future studies will determine the therapeutic importance of orexin receptor antagonists for menopausal symptoms.
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    Exercise activates compensatory thermoregulatory reaction in rats: a modeling study
    (American Psychological Society, 2015-12-15) Yoo, Yeonjoo; LaPradd, Michelle; Kline, Hannah; Zaretskaia, Maria V.; Behrouzvaziri, Abolhassan; Rusyniak, Daniel E.; Molkov, Yaroslav I.; Zaretsky, Dmitry V.; Department of Mathematical Sciences, School of Science
    The importance of exercise is increasingly emphasized for maintaining health. However, exercise itself can pose threats to health such as the development of exertional heat shock in warm environments. Therefore, it is important to understand how the thermoregulation system adjusts during exercise and how alterations of this can contribute to heat stroke. To explore this we measured the core body temperature of rats (Tc) running for 15 min on a treadmill at various speeds in two ambient temperatures (Ta = 25°C and 32°C). We assimilated the experimental data into a mathematical model that describes temperature changes in two compartments of the body, representing the muscles and the core. In our model the core body generates heat to maintain normal body temperature, and dissipates it into the environment. The muscles produce additional heat during exercise. According to the estimation of model parameters, at Ta = 25°C, the heat generation in the core was progressively reduced with the increase of the treadmill speed to compensate for a progressive increase in heat production by the muscles. This compensation was ineffective at Ta = 32°C, which resulted in an increased rate of heat accumulation with increasing speed, as opposed to the Ta = 25°C case. Interestingly, placing an animal on a treadmill increased heat production in the muscles even when the treadmill speed was zero. Quantitatively, this "ready-to-run" phenomenon accounted for over half of the heat generation in the muscles observed at maximal treadmill speed. We speculate that this anticipatory response utilizes stress-related circuitry.
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    Functional contributions of a sex-specific population of myelinated aortic baroreceptors in rat and their changes following ovariectomy
    (2014) Santa Cruz Chavez, Grace C.; Schild, John H.; Nicol, Grant D.; Oxford, Gerry S.; Rusyniak, Daniel E.; Vasko, Michael R.
    Gender differences in the basal function of autonomic cardiovascular control are well documented. Consistent baroreflex (BRx) studies suggest that women have higher tonic parasympathetic cardiac activation compared to men. Later in life and concomitant with menopause, a significant reduction in the capacity of the BRx in females increases their risk to develop hypertension, even exceeding that of age-matched males. Loss of sex hormones is but one factor. In female rats, we previously identified a distinct myelinated baroreceptor (BR) neuronal phenotype termed Ah-type, which exhibits functional dynamics and ionic currents that are a mix of those observed in barosensory afferents functionally identified as myelinated A-type or unmyelinated C-type. Interestingly, Ah-type afferents constitute nearly 50% of the total population of myelinated aortic BR in female but less than 2% in male rat. We hypothesized that an afferent basis for sexual dimorphism in BRx function exists. Specifically, we investigated the potential functional impact Ah-type afferents have upon the aortic BRx and what changes, if any, loss of sex hormones through ovariectomy brings upon such functions. We assessed electrophysiological and reflexogenic differences associated with the left aortic depressor nerve (ADN) from adult male, female, and ovariectomized female (OVX) Sprague-Dawley rats. Our results revealed sexually dimorphic conduction velocity (CV) profiles. A distinct, slower myelinated fiber volley was apparent in compound action potential (CAP) recordings from female aortic BR fibers, with an amplitude and CV not observed in males. Subsequent BRx studies demonstrated that females exhibited significantly greater BRx responses compared to males at myelinated-specific intensities. Ovariectomy induced an increased overall temporal dispersion in the CAP of OVX females that may have contributed to their attenuated BRx responses. Interestingly, the most significant changes in depressor dynamics occurred at electrical thresholds and frequencies most closely aligned with Ah-type BR fibers. Collectively, we provide evidence that, in females, two anatomically distinct myelinated afferent pathways contribute to the integrated BRx function, whereas in males only one exists. These functional differences may partly account for the enhanced control of blood pressure in females. Furthermore, Ah-type afferents may provide a neuromodulatory pathway uniquely associated with the hormonal regulation of BRx function.