The Essentials of Multiomics.

Within the last decade, the science of molecular testing has evolved from single gene and single protein analysis to broad molecular profiling as a standard of care, quickly transitioning from research to practice. Terms such as genomics, transcriptomics, proteomics, circulating omics, and artificial intelligence are now commonplace, and this rapid evolution has left us with a significant knowledge gap within the medical community. In this paper, we attempt to bridge that gap and prepare the physician in oncology for multiomics, a group of technologies that have gone from looming on the horizon to become a clinical reality. The era of multiomics is here, and we must prepare ourselves for this exciting new age of cancer medicine.

Can the Thought of Teilhard de Chardin Carry Us Past Current Contentious Discussions of Gene Editing Technologies?

The advent of CRISPR-Cas9 technology has increased attention, and contention, regarding the use and regulation of genome editing technologies. Public discussions continue to give evidence of this debate falling back into the previous polarized positions of technological enthusiasts versus those who are more cautious in their approach. One response to this contentious relapse could be to view this promising and problematic new technology from a radically different perspective that embraces both the excitement of this technological advance and the prudence necessary to use it well. The thought of Teilhard de Chardin provides this desired perspective, and some insights that may help carry forward public discussions to achieve widely accepted uses and regulations.

Using Ethical Reasoning to Amplify the Reach and Resonance of Professional Codes of Conduct in Training Big Data Scientists.

The use of Big Data--however the term is defined--involves a wide array of issues and stakeholders, thereby increasing numbers of complex decisions around issues including data acquisition, use, and sharing. Big Data is becoming a significant component of practice in an ever-increasing range of disciplines; however, since it is not a coherent "discipline" itself, specific codes of conduct for Big Data users and researchers do not exist. While many institutions have created, or will create, training opportunities (e.g., degree programs, workshops) to prepare people to work in and around Big Data, insufficient time, space, and thought have been dedicated to training these people to engage with the ethical, legal, and social issues in this new domain. Since Big Data practitioners come from, and work in, diverse contexts, neither a relevant professional code of conduct nor specific formal ethics training are likely to be readily available. This normative paper describes an approach to conceptualizing ethical reasoning and integrating it into training for Big Data use and research. Our approach is based on a published framework that emphasizes ethical reasoning rather than topical knowledge. We describe the formation of professional community norms from two key disciplines that contribute to the emergent field of Big Data: computer science and statistics. Historical analogies from these professions suggest strategies for introducing trainees and orienting practitioners both to ethical reasoning and to a code of professional conduct itself. We include two semester course syllabi to strengthen our thesis that codes of conduct (including and beyond those we describe) can be harnessed to support the development of ethical reasoning in, and a sense of professional identity among, Big Data practitioners.

Epigenetic regulator MLL2 shows altered expression in cancer cell lines and tumors from human breast and colon.

BACKGROUND: MLL2, an epigenetic regulator in mammalian cells, mediates histone 3 lysine 4 tri-methylation (H3K4me3) through the formation of a multiprotein complex. MLL2 shares a high degree of structural similarity with MLL, which is frequently disrupted in leukemias via chromosomal translocations. However, this structural similarity is not accompanied by functional equivalence. In light of this difference, and previous reports on involvement of epigenetic regulators in malignancies, we investigated MLL2 expression in established cell lines from breast and colon tissues. We then investigated MLL2 in solid tumors of breast and colon by immunohistochemistry, and evaluated potential associations with established clinicopathologic variables. RESULTS: We examined MLL2 at both transcript and protein levels in established cell lines from breast and colon cancers. Examination of these cell lines showed elevated levels of MLL2. Furthermore, we also identified incomplete proteolytic cleavage of MLL2 in the highly invasive tumor cell lines. To corroborate these results, we studied tumor tissues from patients by immunohistochemistry. Patient samples also revealed increased levels of MLL2 protein in invasive carcinomas of the breast and colon. In breast, cytoplasmic MLL2 was significantly increased in tumor tissues compared to adjacent benign epithelium (p < 0.05), and in colon, both nuclear and cytoplasmic immunostaining was significantly increased in tumor tissues compared to adjacent benign mucosa (p < 0.05). CONCLUSION: Our study indicates that elevated levels of MLL2 in the breast and colon cells are associated with malignancy in these tissues, in contrast to MLL involvement in haematopoietic cancer. In addition, both abnormal cellular localization of MLL2 and incomplete proteolytic processing may be associated with tumor growth/progression in breast and colonic tissues. This involvement of MLL2 in malignancy may be another example of the role of epigenetic regulators in cancer.

Poisonings in reptiles.

Reptiles are increasingly being kept as pets in American households. The basic principles of emergency medicine are the same for all species, but reptilian species present special diagnostic challenges to veterinary clinicians when they become ill. Reptiles in captivity can become accidentally poisoned in a variety of ways. Veterinarians treating small animal emergencies must make an effort to familiarize themselves with the large body of literature and resources that are developing regarding both nontraditional exotic companion species and advances in toxicology.

On the Viability and Potential Value of Stem Cells for Repair and Treatment of Central Neurotrauma: Overview and Speculations.

Central neurotrauma, such as spinal cord injury or traumatic brain injury, can damage critical axonal pathways and neurons and lead to partial to complete loss of neural function that is difficult to address in the mature central nervous system. Improvement and innovation in the development, manufacture, and delivery of stem-cell based therapies, as well as the continued exploration of newer forms of stem cells, have allowed the professional and public spheres to resolve technical and ethical questions that previously hindered stem cell research for central nervous system injury. Recent in vitro and in vivo models have demonstrated the potential that reprogrammed autologous stem cells, in particular, have to restore functionality and induce regeneration-while potentially mitigating technical issues of immunogenicity, rejection, and ethical issues of embryonic derivation. These newer stem-cell based approaches are not, however, without concerns and problems of safety, efficacy, use and distribution. This review is an assessment of the current state of the science, the potential solutions that have been and are currently being explored, and the problems and questions that arise from what appears to be a promising way forward (i.e., autologous stem cell-based therapies)-for the purpose of advancing the research for much-needed therapeutic interventions for central neurotrauma.

The poison-proof practice.

Toxicology is the medical discipline that studies the often dramatic effects that poisons can have on living organisms. The body of toxicological information that the practicing veterinarian must deal with is growing exponentially. The veterinary clinician must come to understand the source of potential toxicants, circumstances leading up to poisoning episodes, must recognize the clinical signs of a wide variety of poisons, be able to diagnose intoxications, successfully treat and manage exposed animals, and institute strategies that educate the public and help prevent future poisonings. This is a tremendously tall order and can be not a little bit overwhelming. Fortunately, the clinicians are not alone and have tremendous resources in their corner, including veterinary schools, regional poison and drug centers, national veterinary hot lines utilizing board-certified veterinary toxicologists, local toxicologists and an ever-growing body of literature concerning small animal poisoning management. This discussion will investigate ways in which to make this seemingly daunting field much more palatable to small animal practitioners.

Smoke inhalation.

Unfortunately, fires are common events both in urban and rural portions of the United States. Smoke inhalation is the leading fire-related cause of death. The elemental combustion products of fire are light, heat, and smoke. Smoke is a very complex mixture of potentially harmful substances. Although a relatively rare presenting event to small animal hospitals, when animal fire victims do appear, clinicians must know how to recognize the signs of smoke inhalation and how to successfully deal with them. This discussion will investigate the toxic nature of fire smoke, its mechanism of action upon respiratory tissues, the clinical signs displayed, and its diagnosis and treatment. Differential diagnoses of smoke inhalation and prevention and prognosis will also be explored. Veterinary hospitals should have set protocols in place for managing animal victims of smoke inhalation in order to ensure a successful outcome.

Hymenoptera stings.

The medically important groups of Hymenoptera are the Apoidea (bees), Vespoidea (wasps, hornets, and yellow jackets), and Formicidae (ants). These insects deliver their venom by stinging their victims. Bees lose their barbed stinger after stinging and die. Wasps, hornets, and yellow jackets can sting multiple times. Most deaths related to Hymenoptera stings are the result of immediate hypersensitivity reactions, causing anaphylaxis. Massive envenomations can cause death in nonallergic individuals. The estimated lethal dose is approximately 20 stings/kg in most mammals. Anaphylactic reactions to Hymenoptera stings are not dose dependent or related to the number of stings. Bee and wasp venoms are made up primarily of protein. Conversely, fire ant venoms are 95% alkaloids. Four possible reactions are seen after insect stings: local reactions, regional reactions, systemic anaphylactic responses, and less commonly, delayed-type hypersensitivity. Clinical signs of bee and wasp stings include erythema, edema, and pain at the sting site. Occasionally, animals develop regional reactions. Onset of life-threatening, anaphylactic signs typically occur within 10 minutes of the sting. Diagnosis of bee and wasp stings stem from a history of potential contact matched with onset of appropriate clinical signs. Treatment of uncomplicated envenomations (stings) consists of conservative therapy (antihistamines, ice or cool compresses, topical lidocaine, or corticosteroid lotions). Prompt recognition and initiation of treatment is critical in successful management of anaphylactic reactions to hymenopteran stings. Imported fire ants both bite and sting, and envenomation only occurs through the sting. Anaphylaxis after imported fire ant stings is treated similarly to anaphylactic reactions after honeybee and vespid stings. The majority of Hymenopteran stings are self-limiting events, which resolve in a few hours without treatment. Because life-threatening anaphylactic reactions can progress rapidly, all animals stung should be closely monitored and observed. In the following review article, we will examine the sources and incidence, toxicokinetics, pathological lesions, clinical signs, diagnosis, treatment, and prognosis for dogs and cats suffering Hymenoptera stings.

"Over-the-counter" drug toxicities in companion animals.

A truly astonishing variety of "over-the-counter" drugs not taken under the auspices of a physician or veterinarian and not regulated by the Federal Drug Administration (FDA) are currently available to the American public. Many of these are widely advertised, readily available, remarkably inexpensive, and universally taken. Although most of the over-the-counter medications are fairly safe, the potential for toxic episodes exists due in large part simply on account of the amounts curious unsupervised animals may ingest. Another part of the problem is that since they are over the counter a large proportion of the public perceives them as totally harmless. In this article, we will investigate the most frequently seen non-prescription intoxications, their mechanism of action, clinical signs, diagnosis management, and prevention.

Plasma 24-metabolite Panel Predicts Preclinical Transition to Clinical Stages of Alzheimer's Disease.

We recently documented plasma lipid dysregulation in preclinical late-onset Alzheimer's disease (LOAD). A 10 plasma lipid panel, predicted phenoconversion and provided 90% sensitivity and 85% specificity in differentiating an at-risk group from those that would remain cognitively intact. Despite these encouraging results, low positive predictive values limit the clinical usefulness of this panel as a screening tool in subjects aged 70-80 years or younger. In this report, we re-examine our metabolomic data, analyzing baseline plasma specimens from our group of phenoconverters (n = 28) and a matched set of cognitively normal subjects (n = 73), and discover and internally validate a panel of 24 plasma metabolites. The new panel provides a classifier with receiver operating characteristic area under the curve for the discovery and internal validation cohort of 1.0 and 0.995 (95% confidence intervals of 1.0-1.0, and 0.981-1.0), respectively. Twenty-two of the 24 metabolites were significantly dysregulated lipids. While positive and negative predictive values were improved compared to our 10-lipid panel, low positive predictive values provide a reality check on the utility of such biomarkers in this age group (or younger). Through inclusion of additional significantly dysregulated analyte species, our new biomarker panel provides greater accuracy in our cohort but remains limited by predictive power. Unfortunately, the novel metabolite panel alone may not provide improvement in counseling and management of at-risk individuals but may further improve selection of subjects for LOAD secondary prevention trials. We expect that external validation will remain challenging due to our stringent study design, especially compared with more diverse subject cohorts. We do anticipate, however, external validation of reduced plasma lipid species as a predictor of phenoconversion to either prodromal or manifest LOAD.

Polar bears: the fate of an icon.

Polar bears are one of the most iconic animals on our planet. Worldwide, even people who would never see one are drawn to these charismatic arctic ice hunters. They are the world's largest terrestrial carnivore, and despite being born on land, they spend most of their lives out on the sea ice and are considered a marine mammal. Current global studies estimate there are around 20,000 animals in some 19 discrete circumpolar populations. Aside from pregnant females denning in the winter months to give birth, the white bears do not hibernate. They spend their winters on the sea ice hunting seals, an activity they are spectacularly adapted for. Research on these animals is incredibly difficult because of the inhospitable surroundings they inhabit and how inaccessible they make the bears. For many years, the sum of our understanding of the natural history of polar bears came from tracks, scats, the remains of their kills, abandoned dens, and anecdotal observations of native hunters, explorers, and early biologists. Nonetheless, the last 40 years have seen a much better picture of their biology emerge thanks to, first, dedicated Canadian researchers and, later, truly international efforts of workers from many countries. Veterinarians have contributed to our knowledge of the bears by delivering and monitoring anesthesia, obtaining blood samples, performing necropsies, investigating their reproduction, conducting radiotelemetry studies, and examining their behavior. Recently, new technologies have been developed that revolutionize the study of the lives and natural history of undisturbed polar bears. These advances include better satellite radiotelemetry equipment and the development of remote-controlled miniature devices equipped with high-definition cameras. Such new modalities provide dramatic new insights into the life of polar bears. The remarkable degree of specialized adaptation to life on the sea ice that allowed the bears to be successful is the very reason that the bears are so vulnerable to the effects of climate change. Polar bears have few alternatives if their habitat (the sea ice) and their access to their ringed seal prey rapidly disappear. Predictions that polar bears may be able to adjust and sustain themselves on alternative food sources are not based on reality. Spring breakup of the sea ice is happening much earlier as well as fall freezeup is getting later, thereby prolonging the open water period that the bears are shore bound. If trends continue and the ice continues to disappear, the effect on polar bears would be devastating. Veterinarians must stay involved in polar bear studies and in multidisciplinary conservation studies dealing with threatened and endangered species worldwide. On account of their training, veterinarians can offer a unique skill set that can provide access to a number of technologies critical to conservation efforts. The oath veterinarians take on graduation from veterinary school charges them to be sworn to the "conservation of animal resources" and in the education of the public. We are only as good as the oaths we keep.

Longline fishing (how what you don't know can hurt you).

Longline fishing utilizes monofilament lines that can be as much as 62 miles long. The line itself is buoyed by Styrofoam or plastic floats. Usually, at about every 100ft, a secondary line is attached and hangs down from the mainline. The lines are baited with mackerel, squid, or shark meat and have as many as 10,000 hooks. Every 12-24 hours, the line is hauled in, mechanically rebaited, and set back into the water behind the vessel. The baited hooks can be seen by albatross and other seabirds as they are placed in the water or being hauled out. When the birds dive for the bait, they are hooked, dragged behind the fishing boat, and drown. Spectacularly nonselective, longline fishing techniques also hook many other forms of marine life-"bycatch" (sea turtles, seals, dolphins, penguins, sharks, and many other nontarget finfish). It is estimated that 300,000 seabirds (including 100,000 albatross) die on longlines each year. Albatross are among the longest-lived birds. They can live up to 60 years and some species do not start breeding until they are 10 years old. They have a low reproductive rate and many species only breed every other year. In addition, a species like the Wandering Albatross (Diomedea exulans) rears its chicks for an average of more than 270 days. Albatross pair for life and may take years to find a new partner if their mate is killed. Owing to their incredibly low reproductive rate, albatross are particularly vulnerable to longline fishing. Currently, it is believed that 4 albatross drown per 100,000 hooks set. This is more than 400 birds a week. The current mortality rate for adult birds is not sustainable and for some species, the birds are dying faster that they can repopulate. Currently, 19 of the world's 22 albatross species are threatened with extinction. This year longline fishing ships will set 10 billion hooks worldwide. Various mitigation measures (bird-scaring lines, weighted, faster-sinking line, setting lines deeper out of the bird's sight, reduction in the amount of offal discarded from fishing boats, night fishing, and restriction of longline operations from areas where nesting and foraging birds are congregated during the breeding season, among others) have been proposed and attempted. There is no one panacea for the effects of longlining and mitigation efforts are most successful when used in combination. Some of these mitigation measures have shown very promising results. Some experts feel that government legislation, regulation, and enforcement in conjunction with incentives for the fishing industry to incorporate and implement mitigating techniques have the best chance in ameliorating the problem. The public is surprisingly unaware of this wanton and wasteful exploitation of the ocean's resources, and the worldwide demand for seafood continues to rise. Meanwhile, globally, fishermen voice the same complaints: fewer fish, smaller fish, shorter fishing seasons, bizarre developments in their seasonal appearance and dispersal, and fewer overall species seen. These are all the classic signs of overfishing. Each year it is estimated that some 90 million tons of wild fish are harvested from our planet's oceans. Nearly 30 million tons of this is discarded as the incidental bycatch of nontarget species. If international curbs are not placed upon wasteful fishing practices, we are doomed to learn a painful maxim. "The ocean is not infinite." Veterinarians must become involved in worldwide conservation efforts, acting locally, while thinking globally.

Adderall® (amphetamine-dextroamphetamine) toxicity.

The American Psychiatric Association estimates that 3-7% of US school-aged children exhibit attention-deficit/hyperactivity disorder (ADHD). Adderall(®) (amphetamine dextroamphetamine) and a variety of brand names and generic versions of this combination are available by prescription to treat ADHD and narcolepsy. Both immediate and sustained release products are used as are single agent amphetamine medication. Knowing the exact agent ingested can provide information of dose labeled and length of clinical effects. These drugs are used off label by college students for memory enhancement, test taking ability, and for study marathons. These agents are DEA Schedule II controlled substances with high potential for abuse. For humans with ADHD or narcolepsy, standard recommended dosage is 5-60 mg daily. Amphetamine and its analogues stimulate the release of norepinephrine affecting both α- and ß-adrenergic receptor sites. α-Adrenergic stimulation causes vasoconstriction and an increase in total peripheral resistance. ß-Adrenergic receptor stimulation leads to an increase in heart rate, stroke volume, and skeletal muscle blood flow. Clinical signs of Adderall(®) overdose in humans and dogs include hyperactivity, hyperthermia, tachycardia, tachypnea, mydriasis, tremors, and seizures. In addition, Adderall intoxication in dogs has been reported to cause hyperthermia, hypoglycemia, hypersegmentation of neutrophils, and mild thrombocytopenia. Diagnosis can be confirmed by detecting amphetamine in stomach contents or vomitus, or by positive results obtained in urine tests for illicit drugs. Treatment is directed at controlling life-threatening central nervous system and cardiovascular signs. Seizures can be controlled with benzodiazepines, phenothiazines, pentobarbital, and propofol. Cardiac tachyarrhythmias can be managed with a ß-blocker such as propranolol. Intravenous fluids counter the hyperthermia, assist in maintenance of renal function, and help promote the elimination of amphetamine and its analogues. Prognosis after poisoning with Adderall(®) depends upon the severity and duration of clinical signs at presentation. Differential diagnoses that should be considered in cases of suspected amphetamine overdose are any other agents that can cause central nervous system stimulation, tremors, and seizures. This article discusses our present understanding of Adderall(®) intoxication and examines 3 dogs presented to our practice after ingestion of large amounts of the drug.

Selective serotonin reuptake inhibitor exposure.

Many antidepressants inhibit serotonin or norepinephrine reuptake or both to achieve their clinical effect. The selective serotonin reuptake inhibitor class of antidepressants (SSRIs) includes citalopram, escitalopram (active enantiomer of citalopram), fluoxetine, fluvoxamine, paroxetine, and sertraline. The SSRIs are as effective as tricyclic antidepressants in treatment of major depression with less significant side effects. As a result, they have become the largest class of medications prescribed to humans for depression. They are also used to treat obsessive-compulsive disorder, panic disorders, alcoholism, obesity, migraines, and chronic pain. An SSRI (fluoxetine) has been approved for veterinary use in treatment of canine separation anxiety. SSRIs act specifically on synaptic serotonin concentrations by blocking its reuptake in the presynapse and increasing levels in the presynaptic membrane. Clinical signs of SSRI overdose result from excessive amounts of serotonin in the central nervous system. These signs include nausea, vomiting, mydriasis, hypersalivation, and hyperthermia. Clinical signs are dose dependent and higher dosages may result in the serotonin syndrome that manifests itself as ataxia, tremors, muscle rigidity, hyperthermia, diarrhea, and seizures. Current studies reveal no increase in appearance of any specific clinical signs of serotonin toxicity with regard to any SSRI medication. In people, citalopram has been reported to have an increased risk of electrocardiographic abnormalities. Diagnosis of SSRI poisoning is based on history, clinical signs, and response to therapy. No single clinical test is currently available to confirm SSRI toxicosis. The goals of treatment in this intoxication are to support the animal, prevent further absorption of the drug, support the central nervous system, control hyperthermia, and halt any seizure activity. The relative safety of the SSRIs in overdose despite the occurrence of serotonin syndrome makes them more desirable than other antidepressants. The prognosis in animals that receive treatment is excellent. In one retrospective study, there were no deaths in 313 SSRI-poisoned dogs. No characteristic or classic histopathologic lesions result from SSRI toxicosis. Differential diagnoses for SSRI overdose must include ingestions of other serotonergic medications such as phenylpiperidine opioids (fentanyl and tramadol), mirtazapine, buspirone, amitraz, and chlorpheniramine.

Polyurethane adhesive ingestion.

Polyurethane adhesives are found in a large number of household products in the United States and are used for a variety of purposes. Several brands of these expanding wood glues (those containing diphenylmethane diisocyanate [MDI]) have the potential to form gastrointestinal (GI) foreign bodies if ingested. The ingested adhesive forms an expanding ball of glue in the esophagus and gastric lumen. This expansion is caused by a polymerization reaction using the heat, water, and gastric acids of the stomach. A firm mass is created that can be 4-8 times its original volume. As little as 2 oz of glue have been reported to develop gastric foreign bodies. The obstructive mass is reported to form within minutes of ingestion of the adhesive. The foreign body can lead to esophageal impaction and obstruction, airway obstruction, gastric outflow obstruction, mucosal hemorrhage, ulceration, laceration, perforation of the esophageal and gastric linings, and death. Clinical signs following ingestion include anorexia, lethargy, vomiting, tachypnea, and abdominal distention and pain, and typically develop within 12 hours. Clinical signs may depend upon the size of the mass. If left untreated, perforation and rupture of the esophagus or stomach can occur. The glue mass does not stick to the GI mucosa and is not always detectable on abdominal palpation. Radiographs are recommended to confirm the presence of the "glue-ball" foreign body, and radiographic evidence of the obstruction may be seen as early as 4-6 hours following ingestion. Emesis is contraindicated owing to the risk of aspiration of the glue into the respiratory tree or the subsequent lodging of the expanding glue mass in the esophagus. Likewise, efforts to dilute the glue and prevent the formation of the foreign body through administration of liquids, activated charcoal, or bulk-forming products to push the foreign body through the GI tract have proven ineffective. Even endoscopy performed to remove the foreign body has been shown to be unreliable. The safest, most effective, and successful therapy is surgical intervention to remove the GI foreign body. If performed early enough, complete recovery of the animal can be expected. Differential diagnoses for polyurethane adhesive ingestion include any potential cause of GI obstruction. The public is largely unaware of the hazards that ingestion of this product may produce. Public education efforts are needed to inform pet owners about the hazards of these glues and the overall importance of providing our companion animals with safe, poison-free environments.

The crucial contribution of veterinarians to conservation biology.

Conservation biology is a relatively new (began in the 1980s), value-based discipline predicated on the belief that biological diversity-from genes to populations to species to communities to ecosystems-is good and extinction is bad. Conservation biology grew from the recognition that the Earth has entered its sixth great extinction event, one that differs from previous great extinctions in that a single species-Homo sapiens-has caused this biodiversity crisis. A diverse, interacting set of variables drive current extinctions. As such, to succeed, conservation efforts usually require broad-based, interdisciplinary approaches. Conservationists increasingly recognize the importance of contributions by veterinary science, among many other disciplines, to collaborative efforts aimed at stemming the loss of biodiversity. We argue that, to improve success rates, many wildlife conservation programs must incorporate veterinarians as part of an interdisciplinary team to assess and address problems. Ideally, veterinarians who participate in conservation would receive specialized training and be willing to work as partners as part of a larger team of experts who effectively integrate their work rather than work independently (i.e., work as interdisciplinary, as opposed to multidisciplinary, teams, respectively). In our opinion, the most successful and productive projects involve interdisciplinary teams involving both biological and nonbiological specialists. Some researchers hold multiple degrees in biology and veterinary medicine or the biological and social sciences. These experts can often offer unique insight. We see at least 3 major areas in which veterinarians can immediately offer great assistance to conservation efforts: (1) participation in wildlife capture and immobilization, (2) leadership or assistance in addressing wildlife health issues, and (3) leadership or assistance in addressing wildlife disease issues, including using wildlife as sentinels to identify new and emerging diseases or epidemics of old diseases. We cover each of these main topics in detail.

Marijuana poisoning.

The plant Cannabis sativa has been used for centuries for the effects of its psychoactive resins. The term "marijuana" typically refers to tobacco-like preparations of the leaves and flowers. The plant contains more than 400 chemicals but the cannabinoid δ-9-tetrahydrocannabinol (THC) is the major psychoactive constituent. "Hashish" is the resin extracted from the tops of flowering plants and generally has a much higher THC concentration. Marijuana is the most commonly used illicit drug in the United States. Currently, several states have passed legislation to decriminalize possession of small amounts of marijuana for both medical and personal use and several other states have similar legislation under consideration. The most common form of marijuana use in humans is inhalation of the smoke of marijuana cigarettes, followed by ingestion. In animals, although secondhand smoke inhalation is possible, the most common source of exposure is through ingestion of the owner's marijuana supply. The minimum lethal oral dose for dogs for THC is more than 3 g/kg. Although the drug has a high margin of safety, deaths have been seen after ingestion of food products containing the more concentrated medical-grade THC butter. There are two specific cannabinoid receptors in humans and dogs, CB1 (primarily in central nervous system) and CB2 (peripheral tissues). In animals, following oral ingestion, clinical effects begin within 60 minutes. All of the neuropharmacologic mechanisms by which cannabinoids produce psychoactive effects have not been identified. However, CB1 activity is believed to be responsible for the majority of cannabinoid clinical effects. Highly lipid soluble, THC is distributed in fat, liver, brain, and renal tissue. Fifteen percent of THC is excreted into the urine and the rest is eliminated in the feces through biliary excretion. Clinical signs of canine intoxication include depression, hypersalivation, mydriasis, hypermetria, vomiting, urinary incontinence, tremors, hypothermia, and bradycardia. Higher dosages may additionally cause nystagmus, agitation, tachypnea, tachycardia, ataxia, hyperexcitability, and seizures. Treatment of marijuana ingestion in animals is largely supportive. Vital signs including temperature and heart rate and rhythm must be continually monitored. Stomach content and urine can be tested for cannabinoids. Gas chromatography and mass spectrometry can be utilized for THC detection but usually may take several days and are not practical for initiation of therapy. Human urine drug-screening tests can be unreliable for confirmation of marijuana toxicosis in dogs owing to the interference of a large number of the metabolites in canine urine. False negatives may also arise if testing occurs too recently following THC ingestion. Thus, the use of human urine drug-screening tests in dogs remains controversial. No specific antidote presently exists for THC poisoning. Sedation with benzodiazepines may be necessary if dogs are severely agitated. Intravenous fluids may be employed to counter prolonged vomiting and to help control body temperature. Recently, the use of intralipid therapy to bind the highly lipophilic THC has been utilized to help reduce clinical signs. The majority of dogs experiencing intoxication after marijuana ingestion recover completely without sequellae. Differential diagnoses of canine THC toxicosis include human pharmaceuticals with central nervous system stimulatory effects, drugs with central nervous system depressant effects, macrolide parasiticides, xylitol, and hallucinogenic mushrooms.