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Biomedical subjects

Daniel E Rusyniak

Publications and source records attributed to Daniel E Rusyniak.

At least 19 recordsLinked to original sources
PubMed2006

Hyperthermic syndromes induced by toxins.

Normal thermogenesis requires a complex interaction between systems that generate and dissipate heat. Serving as director of thermogenesis, the hypothalamus activates the sympathetic nervous system along with the thyroid and adrenal glands to respond to changes in body temperature. Working in concert, these systems result in heat generation by uncoupling of oxidative phosphorylation, combined with impaired heat dissipation through vasoconstriction. In this article, the authors discuss serotonin and sympathomimetic syndromes, neuroleptic malignant syndrome,and malignant hyperthermia and how these syndromes affect the hypothalamic and sympathetic nervous systems, resulting at times in severe hyperthermia. Current treatment recommendations and future trends in treatment are also discussed.

Animals↗
PubMed2006

Heavy metal poisoning: clinical presentations and pathophysiology.

Humans have had a long and tumultuous relationship with heavy metals. Their ubiquitous nature and our reliance on them for manufacturing have resulted at times in exposures sufficient to cause systemic toxicity. Their easy acquisition and potent toxicity have also made them popular choices for criminal poisonings. This article examines the clinical manifestation and pathophysiology of poisoning from lead, mercury, arsenic, and thallium.

Arsenic Poisoning↗
PubMed2005

The role of mitochondrial uncoupling in 3,4-methylenedioxymethamphetamine-mediated skeletal muscle hyperthermia and rhabdomyolysis.

Use of the popular club drug ecstasy (3,4-methylenedioxymethamphetamine, MDMA) can result in life-threatening hyperthermia and rhabdomyolysis. Recent studies show a link between skeletal muscle uncoupling proteins in MDMA-mediated hyperthermia. The mechanisms by which MDMA interacts with skeletal muscle mitochondria are largely unknown. The present study was designed to comprehensively evaluate the effects of MDMA on bioenergetics and toxicity of skeletal muscle. Using (31)P nuclear magnetic resonance (NMR) and serum creatine kinase levels, we demonstrate evidence for uncoupling of oxidative phosphorylation in the skeletal muscle of MDMA (40 mg/kg)-treated rats. In vivo, rats treated with MDMA had significantly elevated serum creatine kinase levels, a marker of rhabdomyolysis, 4 h post-MDMA treatment (955 +/- 132 IU/l) compared with saline-treated controls (373.2 +/- 59 IU/l). beta-ATP signal areas after MDMA treatment showed significant reductions (15%) from the baseline values with corresponding increases in inorganic phosphate (88% increases) and decreases in intracellular pH. Clark electrode experiments on isolated skeletal muscle mitochondria in vitro (1-5 mM MDMA) and ex vivo in MDMA-treated animals demonstrated no evidence of uncoupling of oxidative phosphorylation. In vitro experiments using L6 myotubules cocultured with primary hepatocytes demonstrated the presence of uncoupling protein-3 in the L6 myotubules, but no evidence of a direct effect of MDMA or its potential metabolites on cellular creatine kinase concentrations. These findings suggest that MDMA uncouples skeletal muscle mitochondria in vivo but that this uncoupling is the result of indirect mechanisms.

Animals↗
PubMed2005

Toxin-induced hyperthermic syndromes.

Toxin-induced hyperthermic syndromes are important to consider in the differential diagnosis of patients presenting with fever and muscle rigidity. If untreated, toxin-induced hyperthermia may result in fatal hyperthermia with multisystem organ failure. All of these syndromes have at their center the disruption of normal thermogenic mechanisms, resulting in the activation of the hypothalamus and sympathetic nervous systems.The result of this thermogenic dysregulation is excess heat generation combined with impaired heat dissipation. Although many similarities exist among the clinical presentations and pathophysiologies of toxin-induced hyperthermic syndromes, important differences exist among their triggers and treatments. Serotonin syndrome typically occurs within hours of the addition ofa new serotonergic agent or the abuse of stimulants such as MDMA or methamphetamine. Treatment involves discontinuing the offending agent and administering either a central serotonergic antagonist, such as cyproheptadine or chlorpromazine, a benzodiazepine, or a combination of the two. NMS typically occurs over hours to days in a patient taking a neuroleptic agent; its recommended treatment is generally the combination of a central dopamine agonist, bromocriptine or L-dopa, and dantrolene. In those patients in whom it is difficult to differentiate between serotonin and neuroleptic malignant syndromes, the physical examination may be helpful:clonus and hyperreflexia are more suggestive of serotonin syndrome,whereas lead-pipe rigidity is suggestive of NMS. In patients in whom serotonin syndrome and NMS cannot be differentiated, benzodiazepines represent the safest therapeutic option. MH presents rapidly with jaw rigidity, hyperthermia, and hypercarbia. Although it almost always occurs in the setting of surgical anesthesia, cases have occurred in susceptible individuals during exertion. The treatment of MH involves the use of dantrolene. Future improvements in understanding the pathophysiology and clinical presentations of these syndromes will undoubtedly result in earlier recognition and better treatment strategies.

Anesthesia, General↗
PubMed2005

Cerebrovascular and cardiovascular complications of alcohol and sympathomimetic drug abuse.

Alcohol and stimulant abuse represents a major cause of cerebrovascular and cardiovascular disease in young adults. Although mild-to-moderate alcohol consumption has been linked to a decreased risk for stroke and CVD, excessive use is associated with an increased risk for intracranial hemorrhage and cardiomyopathy. Cocaine represents the single largest,cause of medical complications related to illegal drug use. Cocaine has been associated with cerebral infarction, intracranial hemorrhage, myocardial infarction, cardiomyopathy, and cardiac arrhythmias. Abuse of amphetamines is associated with complications similar to those of cocaine. The complications associated with stimulant abuse are thought to be primarily mediated through excess catecholamines, resulting in acute arterial hypertension, vasospasm, thrombosis, and accelerated atherosclerosis. Because many complications of alcohol and stimulant abuse are preventable and reversible, it is important to screen for these in patients with cerebrovascular and cardiovascular disease.

Alcoholism↗
PubMed2005

Historical neurotoxins: what we have learned from toxins of the past about diseases of the present.

Throughout history, humans have fallen victim to a variety of neurotoxins, with exposures coming in the form of tainted products, industrial pollution, drugs of abuse, and even the bread and water that sustain them. Despite this long and tumultuous history, neurotoxic outbreaks still occur with regular frequency. Although many difficulties currently exist in linking many of today's unexplained neurologic disorders to toxins, the past suggests a prominent role for neurotoxins in diseases (such as amyotrophic lateral sclerosis and PD), unexplained peripheral neuropathies, neurodevelopmental disorders, and many psychiatric disturbances.

Animals↗
PubMed2005

Carvedilol reverses hyperthermia and attenuates rhabdomyolysis induced by 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) in an animal model.

OBJECTIVE: Hyperthermia is a potentially fatal manifestation of severe 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) intoxication. No proven effective drug treatment exists to reverse this potentially life-threatening hyperthermia, likely because mechanisms of peripheral thermogenesis are poorly understood. Using a rat model of MDMA hyperthermia, we evaluated the acute drug-induced changes in plasma catecholamines and used these results as a basis for the selection of drugs that could potentially reverse this hyperthermia. DESIGN: Prospective, controlled, randomized animal study. SETTING: A research institute laboratory. SUBJECTS: Male, adult Sprague-Dawley rats. INTERVENTIONS: Based on MDMA-induced changes in plasma catecholamine levels, rats were subjected to the nonselective (beta1 + beta2) adrenergic receptor antagonists propranolol or nadolol or the alpha1- + beta1,2,3-adrenergic receptor antagonist carvedilol before or after a thermogenic challenge of MDMA. MEASUREMENT AND MAIN RESULTS: Plasma catecholamines levels 30 mins after MDMA (40 mg/kg, subcutaneously) were determined by high-pressure liquid chromatography and electrochemical detection. Core temperature was measured by a rectal probe attached to a thermocouple. Four hours after MDMA treatment, blood was drawn and serum creatine kinase levels were measured as a marker of rhabdomyolysis using a Vitros analyzer. MDMA induced a 35-fold increase in norepinephrine levels, a 20-fold increase in epinephrine, and a 2.4-fold increase in dopamine levels. Propranolol (10 mg/kg, intraperitoneally) or nadolol (10 mg/kg, intraperitoneally) administered 30 mins before MDMA had no effect on the thermogenic response. In contrast, carvedilol (5 mg/kg, intraperitoneally) administered 15 mins before or after MDMA prevented this hyperthermic response. Moreover, when administered 1 hr after MDMA, carvedilol completely reversed established hyperthermia and significantly attenuated subsequent MDMA-induced creatine kinase release. CONCLUSION: These data show that alpha1 and beta3-adrenergic receptors may contribute to the mediation of MDMA-induced hyperthermia and that drugs targeting these receptors, such as carvedilol, warrant further investigation as novel therapies for the treatment of psychostimulant-induced hyperthermia and its sequelae.

Adrenergic beta-Antagonists↗
PubMed2004

The role of the sympathetic nervous system and uncoupling proteins in the thermogenesis induced by 3,4-methylenedioxymethamphetamine.

Body temperature regulation involves a homeostatic balance between heat production and dissipation. Sympathetic agents such as 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) can disrupt this balance and as a result produce an often life-threatening hyperthermia. The hyperthermia induced by MDMA appears to result from the activation of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-thyroid/adrenal axis. Norepinephrine release mediated by MDMA creates a double-edged sword of heat generation through activation of uncoupling protein (UCP3) along with alpha1- and beta3-adrenoreceptors and loss of heat dissipation through SNS-mediated vasoconstriction. This review examines cellular mechanisms involved in MDMA-induced thermogenesis from UCP activation to vasoconstriction and how these mechanisms are related to other thermogenic conditions and potential treatment modalities.

Animals↗
PubMed2004

UCP3 and thyroid hormone involvement in methamphetamine-induced hyperthermia.

Here, we determined the extent of hypothalamic-pituitary-thyroid (HPT) axis and uncoupling protein-3 (UCP3) involvement in methamphetamine (METH)-induced hyperthermia. Sprague-Dawley rats treated with METH (40mg/kg, s.c.) responded with a hyperthermic response that peaked 1h post-treatment and was sustained through 2h. After METH treatment, thyroparathyroidectomized (TX) animals developed hypothermia that was sustained for the 3h monitoring period. In TX animals supplemented for 5 days with levothyroxine (100microg/kg, s.c.), METH-induced hypothermia was eliminated and the hyperthermic response was restored. Thyroid hormone levels (T3 and T4), measured in euthyroid animals 1h after METH, remained unchanged. As seen in rats, 1h post-METH (20mg/kg, i.p.) treatment, wild-type (WT) mice developed profound hyperthermia that was sustained for 2h. In marked contrast, UCP3-/- animals developed a markedly blunted hyperthermic response at 1h compared to WT animals. Furthermore, UCP3-/- mice could not sustain this slight elevation in temperature. Two hours post-METH treatment, UCP3-/- animal temperature returned to baseline temperatures. UCP3-/- mice were also completely protected against the lethal effects of METH, whereas 40% of WT mice succumbed to the hyperthermia. These findings suggest that thyroid hormone plays a permissive role in the thermogenic effects induced by METH. Furthermore, the findings indicate that UCP3 plays a major role in the development and maintenance of the hyperthermia induced by METH. The relationship of these results to the hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) is also discussed.

Animals↗
PubMed2004

Attenuation of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced rhabdomyolysis with alpha1- plus beta3-adrenoreceptor antagonists.

1. Studies were designed to examine the effects of alpha(1) (alpha(1)AR)- plus beta(3)-adrenoreceptor (beta(3)AR) antagonists on 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced hyperthermia and measures of rhabdomyolysis (creatine kinase (CK)) and renal function (blood urea nitrogen (BUN) and serum creatinine (sCr)) in male Sprague-Dawley rats. 2. MDMA (40 mg x kg(-1), s.c.) induced a rapid and robust increase in rectal temperature, which was significantly attenuated by pretreatment with the alpha(1)AR antagonist prazosin (100 microg x kg(-1), i.p.) plus the beta(3)AR antagonist SR59230A (5 mg x kg(-1), i.p.). 3. CK levels significantly increased (peaking at 4 h) after MDMA treatment and were blocked by the combination of prazosin plus SR59230A. 4. At 4 h after MDMA treatment, BUN and sCr levels were also significantly increased and could be prevented by this combination of alpha(1)AR- plus beta(3)AR-antagonists. 5. The results from this study suggest that alpha(1)AR and beta(3)AR play a critical role in the etiology of MDMA-mediated hyperthermia and subsequent rhabdomyolysis.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2004

Organophosphate poisoning.

Organophosphates are commonly used as pesticides around the world. Exposures to organophosphates cause a significant number of poisonings and deaths each year. Organophosphates bind and inhibit cholinesterase enzymes. Acute toxicity manifests as a cholinergic crisis with excessive glandular secretions, altered mental status, and weakness. Several delayed syndromes have also been associated with organophosphate exposure, including a myasthenic-like syndrome, peripheral neuropathies, neuropsychiatric abnormalities, and extrapyramidal disorders. Clinical features and management of organophosphate poisoning is reviewed with emphasis on those affecting the central and peripheral nervous system.

Humans↗
PubMed2004

The effects of ecstasy (MDMA) on rat liver bioenergetics.

OBJECTIVES: Use of the drug ecstasy (3,4-methylenedioxymethamphetamine [MDMA]) can result in life-threatening hyperthermia. Agents that uncouple mitochondrial oxidative phosphorylation are known to cause severe hyperthermia. In the present study, the authors tested the hypothesis that MDMA directly uncouples oxidative phosphorylation in rat liver mitochondria. METHODS: Effects on mitochondrial bioenergetics were assessed both in vitro and ex vivo. In vitro studies consisted of measuring the effects of MDMA (0.1-5.0 mmol/L) on states of respiration in isolated rat liver mitochondria and on mitochondrial membrane potential in a rat liver cell line. In ex vivo studies, mitochondrial rates of respiration were measured in the livers of rats one hour after treatment with MDMA (40 mg/kg subcutaneously). RESULTS: With the in vitro mitochondrial preparations, only concentrations of 5 mmol/L MDMA showed evidence of uncoupling with a slight increase in state 4 respiration and a corresponding decrease in the respiratory control index. MDMA (0.1-5.0 mmol/L) failed to decrease the mitochondrial membrane potential in 3,3-dihexyloxacarbocyanide iodide-stained WB-344 cells after either one or 24 hours of incubation. Ex vivo rates of respiration obtained from the livers of rats one hour after treatment with MDMA (40 mg/kg subcutaneously) showed no evidence of mitochondrial uncoupling. CONCLUSIONS: These data suggest that while high concentrations of MDMA have some mild uncoupling effects in isolated mitochondria, these effects do not translate to cell culture or ex vivo studies in treated animals. These data do not support the view that the hyperthermia induced by MDMA is from a direct effect on mitochondrial oxidative phosphorylation.

Animals↗
PubMed2003

A prospective, randomized, double-blind comparison of buffered versus plain tetracaine in reducing the pain of topical ophthalmic anesthesia.

STUDY OBJECTIVE: We determine whether buffering ocular tetracaine hydrochloride reduces the pain of instillation. METHODS: We conducted a prospective, randomized, double-blind, 2-treatment, 2-period crossover, single center study of healthy volunteers 18 years of age or older. Participants were randomized to receive either 2 drops of buffered or plain tetracaine in a randomly assigned eye. After a mean wash out period of 24 days (range 7 to 54 days), participants returned to have 2 drops of the other medication instilled in the same eye. The participants recorded the pain of instillation on a 100-mm visual analog scale (VAS) immediately and 5 minutes after instillation. Adverse events were also recorded at these intervals. The primary outcome measure was the intensity of pain as measured on a VAS immediately after instillation. RESULTS: Sixty persons were enrolled in the study, with 100% follow up. Immediately after instillation, the adjusted mean VAS score for buffered tetracaine was 29.1 mm, and the adjusted mean VAS score for plain tetracaine was 16.0 mm. The estimated difference was 13.1 mm (95% confidence interval 6.9 to 19.3 mm). CONCLUSION: Buffering of tetracaine hydrochloride significantly increases the pain of its instillation in healthy volunteers, suggesting that pain with instillation of ocular anesthetics is not dependent on low pH.

Administration, Topical↗
PubMed2003

Dimercaptosuccinic acid and Prussian Blue in the treatment of acute thallium poisoning in rats.

INTRODUCTION: Despite being banned as a pesticide, thallium still results in human and animal poisonings. Current recommended treatments include the use of the chemical Prussian Blue. Limitations in its availability may result in Prussian Blue not being obtainable in the thallium-poisoned patient. The chelator 2,3-Dimercaptosuccinic acid (DMSA) is currently FDA-approved for use in childhood lead poisoning and has been reported to be beneficial in treating other heavy metal poisonings. The objective of this study was to determine the efficacy of DMSA as a treatment for thallium poisoning by studying mortality and whole-brain concentrations in thallium poisoned rats. MATERIAL AND METHODS: Rats were gavaged with 30 mg/kg of thallium. After 24 hours they were randomized to DMSA (n = 20) 50 mg/kg twice daily for 5 days, Prussian Blue (n = 20) 50 mg/kg twice daily for 5 days, or control (n = 30). Animals were monitored twice daily for weight loss and mortality. Animals losing greater than 20% of their starting weight were euthanized and counted as a mortality. All surviving rats at 120 hours had their brains harvested and digested and underwent subsequent thallium analysis. RESULTS: The rate of survival in DMSA-treated animals compared to control was 45% vs. 21%, p = 0.07. Mean whole-brain thallium concentrations between DMSA and control rats were 3.4 vs. 3.0 microg/g, p = 0.06. Prussian Blue-treated rats had significantly improved survival (70% vs. 21%, p < 0.01) and lower whole-brain thallium concentrations (1.6 vs. 3.0 microg/g, p < 0.01 tissue) compared to controls. CONCLUSION: DMSA failed to reduce brain thallium concentrations in rats poisoned with thallium and had an indeterminate effect on mortality while Prussian Blue significantly reduces both brain thallium concentrations and mortality.

Acute Disease↗
PubMed2003

Hyperbaric oxygen therapy in acute ischemic stroke: results of the Hyperbaric Oxygen in Acute Ischemic Stroke Trial Pilot Study.

BACKGROUND AND PURPOSE: Hyperbaric oxygen therapy (HBO) has promise as a treatment for acute stroke. This study was conducted to evaluate the efficacy, safety, and feasibility of using HBO in acute ischemic stroke. METHODS: We conducted a randomized, prospective, double-blind, sham-controlled pilot study of 33 patients presenting with acute ischemic stroke who did not receive thrombolytics over a 24-month period. Patients were randomized to treatment for 60 minutes in a monoplace hyperbaric chamber pressurized with 100% O2 to 2.5-atm absolute (ATA) in the HBO group or 1.14 ATA in the sham group. Primary outcomes measured included percentage of patients with improvement at 24 hours (National Institutes of Health Stroke Scale [NIHSS]) and 90 days (NIHSS, Barthel Index, modified Rankin Scale, Glasgow Outcome Scale). Secondary measurements included complications of treatment and mortality at 90 days. RESULTS: Baseline demographics were similar in both groups. There were no differences between the groups at 24 hours (P=0.44). At 3 months, however, a larger percentage of the sham patients had a good outcome defined by their stroke scores compared with the HBO group (NIHSS, 80% versus 31.3%; P=0.04; Barthel Index, 81.8% versus 50%; P=0.12; modified Rankin Scale, 81.8% versus 31.3%; P=0.02; Glasgow Outcome Scale, 90.9% versus 37.5%; P=0.01) with loss of statistical significance in a intent-to-treat analysis. CONCLUSIONS: Although our HBO protocol appears feasible and safe, it does not appear to be beneficial and may be harmful in patients with acute ischemic stroke.

Acute Disease↗
PubMed2002

Absinthe: return of the Green Fairy.

Among the most popular and intriguing intoxicants of the Victorian Age, absinthe had all but disappeared after it was banned in nearly all developed countries in the early 1900s. A number of great artists and writers from the late 1800s used absinthe as a social drink, including Vincent van Gogh and Toulouse-Lautrec. A recent resurgence of absinthe use has occurred in Europe and is rapidly spreading to the United States. Despite its increasing popularity limited information exists on the mechanism of action and neurotoxicity of absinthe. This paper reviews some of the historical aspects of absinthe and aims to shed light on the mechanism of action and neurotoxicology of this the Green Fairy.

Absinthe↗
PubMed2002

Thallium and arsenic poisoning in a small midwestern town.

Thallium and arsenic have been used as a means of criminal poisoning. Although both manifest characteristically with peripheral neuropathies, thallium is associated with alopecia and arsenic with gastrointestinal symptoms. We describe the symptoms, physical findings, diagnostic test results, and outcomes in a group of men poisoned with thallium and arsenic. Seven patients had evidence of elevated thallium levels, and 2 patients had elevated arsenic and thallium levels. The most commonly reported symptoms included myalgias, arthralgias, paresthesias, and dysesthesias. Five patients developed alopecia. All patients with symptoms and peripheral neuropathies had characteristic blackening of their hair roots. Initially treated with dimercaptosuccinic acid, patients were switched to multiple-dose activated charcoal after testing revealed thallium poisoning. By 6 months, all patients' symptoms and peripheral neuropathies improved, but 5 patients had ongoing psychiatric problems. Thallium remains a means of criminal poisoning and should be considered in any patient with a rapidly progressing peripheral neuropathy with or without alopecia.

Alopecia↗