Inhibition of toll-like receptor 4 protects against inflammation-induced mechanobiological alterations to intervertebral disc cells.

Intervertebral disc (IVD) degeneration is associated with elevated levels of inflammatory cytokines implicated in disease aetiology and matrix degradation. Toll-like receptor-4 (TLR4) has been shown to participate in the inflammatory responses of the nucleus pulposus (NP) and its levels are upregulated in disc degeneration. Activation of TLR4 in NP cells leads to significant, persistent changes in cell biophysical properties, including hydraulic permeability and osmotically active water content, as well as alterations to the actin cytoskeleton. The study hypothesis was that inflammation-induced changes to cellular biomechanical properties and actin cytoskeleton of NP cells could be prevented by inhibiting TLR4 signalling. Isolated NP cells from bovine discs were treated with lipopolysaccharide (LPS), the best studied TLR4 agonist, with or without treatment with the TLR4 inhibitor TAK-242. Cellular volume regulation responses to step osmotic loading were measured and the transient volume-response was captured by time-lapse microscopy. Volume-responses were analysed using mixture theory framework to investigate hydraulic permeability and osmotically active intracellular water content. Hydraulic permeability and cell radius were significantly increased with LPS treatment and these changes were blocked in cells treated with TAK-242. LPS-induced remodelling of cortical actin and IL-6 upregulation were also mitigated by TAK-242 treatment. These findings indicated that TLR4 signalling participated in NP cell biophysical regulation and may be an important target for mitigating altered cell responses observed in IVD inflammation and degeneration.

Effects of Inflammation on Multiscale Biomechanical Properties of Cartilaginous Cells and Tissues.

Cells within cartilaginous tissues are mechanosensitive and thus require mechanical loading for regulation of tissue homeostasis and metabolism. Mechanical loading plays critical roles in cell differentiation, proliferation, biosynthesis, and homeostasis. Inflammation is an important event occurring during multiple processes, such as aging, injury, and disease. Inflammation has significant effects on biological processes as well as mechanical function of cells and tissues. These effects are highly dependent on cell/tissue type, timing, and magnitude. In this review, we summarize key findings pertaining to effects of inflammation on multiscale mechanical properties at subcellular, cellular, and tissue level in cartilaginous tissues, including alterations in mechanotransduction and mechanosensitivity. The emphasis is on articular cartilage and the intervertebral disc, which are impacted by inflammatory insults during degenerative conditions such as osteoarthritis, joint pain, and back pain. To recapitulate the pro-inflammatory cascades that occur in vivo, different inflammatory stimuli have been used for in vitro and in situ studies, including tumor necrosis factor (TNF), various interleukins (IL), and lipopolysaccharide (LPS). Therefore, this review will focus on the effects of these stimuli because they are the best studied pro-inflammatory cytokines in cartilaginous tissues. Understanding the current state of the field of inflammation and cell/tissue biomechanics may potentially identify future directions for novel and translational therapeutics with multiscale biomechanical considerations.

Contrary to the literature, vomiting is not a common manifestation associated with plant exposures.

A review of clinical toxicology references and the contemporay literature illustrates that vomiting is reported as a nearly universal symptom associatedwith exposure to cultivated and wild plants. However, the literature fails to put thesymptom of vomiting into a clinical perspectivewith regard to its frequency of occurrence. To clarify this issue a retrospective review of plant exposures was conducted. AAPCC TESS 1997-1999 was queried electronicaly to identify and extract all plant ingestion exposures where vomiting was documented as being related to the exposure. All exposures with documented ipecac syrup use were excluded. Data were stratified through the use through the use of a relational database. Plant ingestion exposures accounted for 229,538 reports and vomiting was reported in 5,917 (2.6%) of exposures. Vomiting was attributed as a related symptom in 753 different plants. It was reported once in 323 plants, 1-3 times in 495 plants (65.7%), and < or = 10 times in 657 (87.4%) of all plants in the database. Ten plants accounted for 32.3% of the reports of vomiting Philodendron, Spathiphyllum, Narcissus, Dieffenbachia, Phytolacca, Epipremnum, Euphorbia, Eucalyptus, Ficus, Hedera) and represented 1.3% of the plants associated with vomiting. Even with the most common plant exposures, vomiting is not a frequent adverse event.

Toxidromes associated with the most common plant ingestions.

Toxicology and botanical references describe a myriad of symptoms associated with the ingestion of plants. The symptoms are based largely on a limited number of case and anecdotal reports or the personal experience of authors: there is little consistency between and among the references. This project compiled a list of symptoms associated with common plant ingestions. Exposure data from the American Association of Poison Control Centers were queried to identify the 20 most commonly ingested plants and the most frequent symptoms associated with those ingestions; 768,284 plant exposures were analyzed and symptoms occurred in 53,081 patients. The 20 most frequently ingested plants accounted for 54.2% of the reported symptoms. Most plant ingestions were not associated with the development of symptoms.

Dieffenbachia species exposures: an evidence-based assessment of symptom presentation.

The literature often ascribes significant morbidity to Dieffenbachia exposures. However, poison center experience suggests a discordant view from that presented in the literature. This project determined if the symptoms described in the literature were consistent with clinical practice. To profile the symptoms reported in the literature, an extensive literature search using Medline and Webspirs (http:/(/)infoshare.library.pitt.edu/webspirs /webspirs.htm) was conducted to identify publications that described Dieffenbachia toxicity. Standard toxicology references and medical botany texts found in poison centers were used to profile symptoms in the tertiary literature; and an Internet search using the Savvy Search program (http:/(/)www.guaraldi.cs.colostate.edu:20 00) to search simultaneously all other search engines. The symptom information was compared to AAPCC TESS (1993-1996) symptom data reported on Dieffenbachia exposure reports. Twenty-three reference sources profiled the literature perspective on Dieffenbachia exposures. AAPCC TESS contained 10,796 Dieffenbachia exposures, and 34.7% of the reports documented symptoms. Oral irritation was reported in 18.2% of the reports and 92.6% of the queried literature listed this symptom (18.2%/92.6%). Additionally dermal pain = 8.7%/63.0%; vomiting = 2.6%/18.5%; erythema = 2.5%/5.3%; throat irritation = 2.3%/22.2%; dermal edema = 2.2%/3.7%; pruritus = 2.1%/7.4%; ocular irritation = 1.7%/44.4%; rash = 1.2%/29.6%; cough/choke = 1.1%/3.7%; loss of speech = 0%/29.6%; salivation = 0%/29.6%; respiratory obstruction = 0%/48.1%; death = 0%/11.18%. When multiple symptoms occurred the most common toxidrome was oral and throat irritation that occurred in 2.9% of the AAPCC TESS reports. There is similarity between the literature and the clinical experience with regard to the irritant properties of Dieffenbachia species, but there is also significant disparity because the literature fails to put the symptoms into a clinical frequency perspective. In general, the literature portrays Dieffenbachia exposures associated with more morbidity and mortality than what was reported in the AAPCC TESS clinical practice data.

Is the yew really poisonous to you?

BACKGROUND: Taxus species, commonly referred to as yew plants, have the reputation of being inordinately toxic. Case reports which chronicle human near-fatal yew berry ingestions and countless fatalities in livestock present a sober profile to the treating toxicologist. Very often, a limited number of adverse reports influence decisions on all exposures to that potential poison. The objective of this investigation was to profile the toxicity of exposures to Taxus spp and determine what percentage of exposures were associated with significant morbidity. METHODS: The individual computerized files of all exposures to Taxus spp were retrieved from American Association of Poison Control Centers (AAPCC) Toxic Exposure Surveillance System (TESS) and placed in a relational database. Reports from 1985-1994 were analyzed. The cases were examined to determine patient demographics, the outcome of exposures, the ultimate disposition of the patients, treatment, and symptoms. AAPCC TESS definitions were used to assess outcomes. RESULTS: The number of exposures identified from the 10-year subset was 11,197. Children less than 12 years of age were involved in 96.4% (< 6 years 92.7%; 6-12 years, 3.7%) of the exposures. When the final outcome of the exposure was documented (n = 7269), no adverse effects occurred in 92.5% and minor effects were experienced in 7.0%. Moderate (more pronounced, but not life-threatening) effects were experienced by 30 individuals and major (life-threatening) effects occurred in 4 people. There were no fatalities. Decontamination therapy, when compared to no therapy, had no impact on patient outcome. 6.3% were admitted for psychiatric or medical care. When symptoms were related to Taxus spp exposures, the most frequent symptoms were gastrointestinal (65.5%), followed by dermal (8.3%), neurological (6.0%), and cardiovascular (6.0%). DISCUSSION: There are limitations to the interpretation of AAPCC TESS data which may lead to bias in favor of positive outcomes. However, the large sample size may minimize the limitations. CONCLUSION: Taxus spp exposures result only rarely in significant morbidity. Consistent with published case reports, the most common symptoms were gastrointestinal. Decontamination had no impact on patient outcome.

Those pesky berries ... are they a source of concern?

Plant exposures constitute the 4th most common call to poison information centers. Within the plant category, exposures to unidentified berries are common and often create panic in the public and indecisiveness by health professionals. Are exposures to unidentified berries associated with morbidity and mortality? Can these berry exposures be managed at home or do they necessitate medical evaluation? The AAPCC Toxic Exposure Surveillance System was queried to identify exposures with the "unidentified berry" code for a 10-y period. Data parameters included frequency, age, outcome, patient disposition, referral pattern, symptom progression and therapeutic intervention. The data were analyzed using descriptive statistics. Unidentified berry exposures included 11,237 incidents, making it the 11th most common plant-related exposure. Children < 6 y-of-age accounted for 88.5% of the exposures, and 88.5% occurred during June-October. There were no fatalities, and morbidity included 1 major outcome in an infant and 26 exposures with moderate outcomes. In exposures with a known outcome, no effects (86.0%) and minor effects (13.6%) accounted for 99.6% of exposures. When a patient was initially asymptomatic, 89.7% did not develop symptoms and 10.2% progressed to have minor symptoms, accounting for 99.9% of all exposures. Poison centers referred 7.5% to a health care facility. There was no apparent benefit conferred by decontamination therapy. Exposures to unidentified berries represent common inquiries to poison information centers. They are associated with low morbidity and no mortality. If no initial symptoms are present, it is unlikely that the patient will develop clinically relevant effects.

American mistletoe exposures.

American mistletoe is generally considered to be extremely toxic. Although there are no data to support this contention, both the lay public and medical professionals often respond very aggressively after ingestion of any portion of this plant. To determine if American mistletoe is deserving of this reputation, the outcomes of 1,754 exposures to this plant were examined. All mistletoe data extracted from the American Association of Poison Control Centers national data collection system for the period of 1985 to 1992 were analyzed according to patient age, gastrointestinal decontamination therapy, patient outcome, and geographic region of the exposure. Pediatric exposures accounted for 92.1% of the cases, and 94.7% of the reported cases were accidental exposures. Of all cases, 99.2% had an outcome associated with no morbidity, and there were no fatalities. Apparently, patient outcome was not influenced by the use of gastrointestinal decontamination techniques-96.2% of treated patients remained asymptomatic versus 96.3% of patients who received no therapy. The accidental ingestion of American mistletoe is not associated with profound toxicity.

Plant exposures ... a national profile of the most common plant genera.

Plant exposures are the 4th most common cause of poisoning and 85% of those exposures involve the pediatric population. The large number of plant-related exposures and the lack of knowledge about plant toxicity has led to plant paranoia and considerable educational efforts to reduce the number of exposures. These efforts are often dictated by misconceptions and folklore. American Association of Poison Control Centers (AAPCC) data on all plant exposures for the years 1985-1994 were electronically analyzed by plant genus to establish a frequency distribution of all plant exposures in the United States. A total of 912,534 plant exposure cases were analyzed to tabulate the top 100 plant exposures. Philodendron spp were the most common exposures, followed by Dieffenbachia spp, Euphorbia spp, Capsicum spp and Ilex spp. Plant exposures are very common and poison information centers devote significant clinical service and educational effort to manage these exposures and enhance the public's awareness. Awareness of specific plant species and exposure frequency in a poison center region can serve as a basis for staff education and as the cornerstone for the development of appropriate information in poison prevention and education brochures. This can direct better utilization of poison center financial resources.

Environmental injuries.

Environmental injuries and illnesses can happen in home, work, or recreational settings. The variety and severity of these injuries might require the clinician to call on skills from internal medicine, emergency medicine, and toxicology. Diseases of thermoregulation are hypothermia and hyperthermia. In each instance, treatment is based on the need to restore the patient's core temperature to normal and on monitoring for complications. The victim of a fire might suffer inhalation injury in addition to burns, and it is more likely that the inhalation injury will be fatal. Oxygen deprivation and inhalation of irritant or asphyxiant chemicals contribute to injury. Toxic plants can be the source of poisoning emergencies, especially in children. Misinformation and myths that surround common plants can create diagnostic problems (i.e., which plants really are toxic and require emergency measures). Venomous marine organisms can cause a wide range of injury, from cutaneous eruption to fatal envenomation. Most are encountered in a recreational setting, such as water sports, but keepers of home aquariums are subject to stings from venomous fish. Lightning injury can present many diagnostic and treatment dilemmas. An important point in this regard is that lightning injury and high-voltage electrical injury are different in pathology and require different approaches for treatment. A discussion of electrical, chemical, and thermal burns makes such differences apparent.

Poinsettia exposures have good outcomes...just as we thought.

The poinsettia (Euphorbia pulcherrima) is a much-maligned plant which is thought by the public and some health professionals to be extremely toxic. Despite pronouncements by public health officials to the contrary, the poinsettia continues to be recognized as a poisonous plant. To determine if there was any validity to the toxicity claims, 849,575 plant exposures reported to the American Association of Poison Control Centers were electronically analyzed. Poinsettia exposures accounted for 22,793 cases and formed the subset that was analyzed to critically evaluate the morbidity and mortality associated with poinsettia exposures. There were no fatalities among all poinsettia exposures and 98.9% were accidental in nature, with 93.3% involving children. The majority of exposed patients (96.1%) were not treated in a health care facility and 92.4% did not develop any toxicity related to their exposure to the poinsettia. Most patients do not require any type of therapy and can be treated without referral to a health care facility.

Plant exposures: a state profile of the most common species.

Plant exposures are the fourth most common cause of poisoning and 86% of those exposures involve the pediatric population. The large number of plant-related exposures and the lack of knowledge about plant toxicity has led to plant paranoia and considerable educational efforts to reduce the number of exposures. These efforts are often dictated by misconceptions and folklore. AAPCC TESS data on all plant exposures for the years 1985-1994 were electronically analyzed by plant species and state to establish a frequency distribution in the US. Aggregate national data was also tabulated. A total of 912,534 plant exposures were analyzed to tabulate the top 30 plant exposures for each state. Philodendron species were the most common exposures, followed by Dieffenbachia species, Euphorbia pulcherrima, Capsicum annuum and Ilex species. There were considerable differences between states relating to indoor vs outdoor plants and native vs introduced varieties. Plant exposures are common and poison information centers devote significant clinical service and educational effort to manage them and to enhance public awareness. Recognition of specific plant species and exposure frequency in a poison center region can be a basis for staff education and the development of appropriate poison prevention education brochures. This can direct better utilization of poison center's resources.