The Toxicology Investigators Consortium Case Registry—the 2013 Experience

The Toxicology Investigators Consortium (ToxIC) Case Registry was established in 2010 by the American College of Medical Toxicology. The Registry includes all medical toxicology consultations performed at participating sites. This report summarizes the Registry data for 2013. A query of the ToxIC Registry was carried out for the dates of January 1 through December 31, 2013. Specific data reviewed for analysis included demographics (age, gender), source of consultation, reasons for consultation, agents involved in toxicological exposures, signs, symptoms and clinical findings, and treatment. A total of 8,598 cases were entered into the Registry in 2013. Females accounted for 49.2 % of cases, males for 47.7 %, and gender was not reported in 3.1 %. The majority of patients (63.4 %) were adults between the ages of 19 and 65 years. There were 93 fatalities (1.1 %). Most referrals for medical toxicology consultation originated from the emergency department (59.7 %) or inpatient services (16.7 %). Exposures to pharmaceutical products (intentional and unintentional) made up 50.0 % of cases. Illicit drug abuse (8.0 %) and adverse drug reactions (ADRs) (4.8 %) were the next most frequent reasons for consultation. Similar to past years, nonopioid analgesics, sedative-hypnotics, and opioids were the most commonly encountered agents. Symptoms or clinical findings were documented in 71.1 % of patients. Of all cases, 54.6 % required some form of medical treatment (antidotes, antivenom, chelation, specific types of supportive care). This report serves as a comprehensive survey of medical toxicology practice within participating institutions. Prior trends continued to apply this year and indicate analgesic (opioid and nonopioid), sedative-hypnotic/muscle relaxant agents, illicit drug use, and ADRs continue to be major toxicological problems. Cases requiring medical toxicology consultation in 2013 predominantly involved pharmaceuticals and illicit drugs. Reasons for these drug exposures were diverse and included intentional overdose, unintentional exposure, withdrawal syndromes, and ADRs. Nonopioid analgesics, sedative-hypnotic agents, and opioids remained the most frequently encountered agent classes. While over half of cases required some form of medical treatment, fatalities were uncommon.     

The Toxicology Investigators Consortium Case Registry—the 2014 Experience

The Toxicology Investigators Consortium (ToxIC) Case Registry was established in 2010 by the American College of Medical Toxicology. The Registry includes all medical toxicology consultations performed at participating sites. The Registry was queried for all cases entered between January 1 and December 31, 2014. Specific data reviewed for analysis included demographics (age, gender, ethnicity), source of consultation, reasons for consultation, agents involved in toxicological exposures, signs, symptoms, clinical findings, fatalities, and treatment. In 2014, 9172 cases were entered in the Registry across 47 active member sites. Females accounted for 51.1 % of cases. The majority (65.1 %) of cases were adults between the ages of 19 and 65. Caucasians made up the largest identified ethnic group (48.9 %). Most Registry cases originated from the inpatient setting (93.5 %), with a large majority of these consultations coming from the emergency department or inpatient admission services. Intentional and unintentional pharmaceutical exposures continued to be the most frequent reasons for consultation, accounting for 61.7 % of cases. Among cases of intentional pharmaceutical exposure, 62.4 % were associated with a self-harm attempt. Non-pharmaceutical exposures accounted for 14.1 % of Registry cases. Similar to the past years, non-opioid analgesics, sedative-hypnotics, and opioids were the most commonly encountered agents. Clinical signs or symptoms were noted in 81.9 % of cases. There were 89 recorded fatalities (0.97 %). Medical treatment (e.g., antidotes, antivenom, chelators, supportive care) was rendered in 62.3 % of cases. Patient demographics and exposure characteristics in 2014 Registry cases remain similar to prior years. The majority of consultations arose in the acute care setting (emergency department or inpatient) and involved exposures to pharmaceutical products. Among exposures, non-opioid analgesics, sedative/hypnotics, and opioids were the most frequently encountered. A majority of cases required some form of treatment, but fatalities were rare.

Electronic supplementary material

The online version of this article (doi:10.1007/s13181-015-0507-7) contains supplementary material, which is available to authorized users.     

Accelerated premature stress-induced senescence of young annulus fibrosus cells of rats by high glucose-induced oxidative stress

Purposes

Diabetes mellitus (DM) is thought to be an important aetiological factor in intervertebral disc degeneration. A glucose-mediated increase of oxidative stress is a major causative factor in development of diseases associated with DM. The aim of this study was to investigate the effect of high glucose on mitochondrial damage, oxidative stress and senescence of young annulus fibrosus (AF) cells.

Methods

AF cells were isolated from four-week-old young rats, cultured, and placed in either 10 % FBS (normal control) or 10 % FBS plus two different high glucose concentrations (0.1 M and 0.2 M) (experimental conditions) for one and three days. We identified and quantified the mitochondrial damage and reactive oxygen species (ROS) (oxidative stress). We also identified and quantified the occurrence of senescence and telomerase activity. Finally, the expressions of proteins were determined related to replicative senescence (p53-p21-pRB) and stress-induced senescence (p16-pRB).

Results

Two high glucoses enhanced the mitochondrial damage in young rat AF cells, which resulted in an excessive generation of ROS in a dose- and time-dependent manner for one and three days compared to normal control. Two high glucose concentrations increased the occurrence of senescence of young AF cells in a dose- and time-dependent manner. Telomerase activity declined in a dose- and time-dependent manner. Both high glucose treatments increased the expressions of p16 and pRB proteins in young rat AF cells for one and three days. However, compared to normal control, the expressions of p53 and p21 proteins were decreased in young rat AF cells treated with both high glucoses for one and three days.

Conclusions

The present study demonstrated that high glucose-induced oxidative stress accelerates premature stress-induced senescence in young rat AF cells in a dose- and time-dependent manner rather than replicative senescence. These results suggest that prevention of excessive generation of oxidative stress by strict blood glucose control could be important to prevent or to delay premature intervertebral disc degeneration in young patients with DM.     

Protective effects of Wuyaoshunqisan against H2O2-induced apoptosis on hippocampal cell line HiB5

Oxidative stress has been implicated in the pathogenesis of different neurodegenerative disorders. To investigate the protective effects of Wuyaoshunqisan against H2O2-induced apoptosis in the central nervous system, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) method, flow cytometric analysis, and the DNA fragmentation assay were performed on cells of the hippocampal cell line HiB5. Through the morphological and biochemical analyses, it was shown that HiB5 cells treated with H2O2 exhibit classical apoptotic features, while the occurrence of such changes is reduced in cells pre-treated with Wuyaoshunqisan prior to H2O2 exposure.     

RET oligonucleotide microarray for the detection of RET mutations in multiple endocrine neoplasia type 2 syndromes.

Multiple endocrine neoplasia type 2 (MEN2) syndromes are inherited in an autosomal dominant fashion with high penetrance. There are three subtypes, namely, MEN2A (multiple endocrine neoplasia type 2A), MEN2B (multiple endocrine neoplasia type 2B), and familial medullary thyroid carcinoma. The variations in the RET gene play an important role in the MEN2 syndromes. In this work, we have developed a RET oligonucleotide microarray of 67 oligonucleotides to quickly detect RET mutations in MEN2 syndromes. The predominant RET mutations are missense mutations and are restricted to nine codons (codons 609, 611, 618, 620, 630, 634, 768, 804, and 918) in MEN2 syndromes. Missense mutations at codons 609, 611, 618, 620, and 634 have been identified in 98% of MEN2A families and in 85% of familial medullary thyroid carcinoma families. More than 95% of MEN2B patients also had a predominant mutation type at codon 918 (Met-->Thr). RET oligonucleotide microarray can detect RET missense mutations at these nine codons. Theoretically, a total of 55 missense mutation types can occur at eight codons (codons 609, 611, 618, 620, 630, 634, 768, and 804). RET oligonucleotide microarray is designed to detect all of these 55 missense mutation types at these eight codons and one predominant type at codon 918. Fifty-six oligonucleotides were designed for the 56 mutation types at nine codons, and 11 oligonucleotides were designed for the wild types and positive controls. We found RET mutations in all eight of the Korean MEN2A families (a total of 75 members; 27 affected members, 19 gene carriers, and 29 unaffected members) using the developed RET oligonucleotide microarray and an automatic sequencing. Because we found only five mutation types from eight MEN2A families, the international collaborations are required to see whether the RET oligonucleotide microarray may be used as a genetic diagnostic tool. Taken together, the RET oligonucleotide microarray can function as a fast and reliable genetic diagnostic device, which simplifies the process of detecting RET mutations.     

Corneal epithelial cellular dysfunction from benzalkonium chloride (BAC) in vitro

PURPOSE: To investigate the functional and morphological toxicity of benzalkonium chloride (BAC) on corneal epithelial cells in vitro. METHODS: Primary corneal epithelial cells were cultured from rabbit cornea. Corneal epithelial cells containing radioactive 51Cr were exposed for 5 min, 10 min, 30 min and 60 min to concentration of BAC 0.001%, 0.005%, 0.01%, 0.05% and 0.1%. Control cells were treated with phosphate buffer solution alone. 51Cr release from epithelial cells into the supernatant was used as an index of epithelial cell lysis. Cell detachment (index of cell dysfunction) was analysed by measuring 51Cr activity in the supernatant and wash fluid. Morphological cell damage was investigated with transmission electron microscopy. RESULTS: With the higher concentration and the longer duration of BAC exposure, corneal epithelial cell lysis was increased significantly (P < 0.05). Cells showed severe damage at BAC concentration over 0.05% during 5 min of exposure. Cell dysfunction appeared markedly at BAC concentrations of 0.005% for 30 min of exposure, but decreased with longer exposure times. There was an increase in significant cytoplasmic damage with longer BAC exposure times, although not with a minimal dose of 0.001%. Disrupted cytoplasmic membranes of corneal epithelial cells appeared at the higher BAC concentration of 0.1%, and at the longer exposure time of 30 min with BAC concentration of at least 0.001%. CONCLUSIONS: BAC can induce corneal epithelial dysfunction, which can damage the corneal epithelial barrier. This effect occurs when BAC is used frequently or for periods over 30 min, even when the BAC concentration is low (0.001%).     

Skin penetration and retention of L-Ascorbic acid 2-phosphate using multilamellar vesicles

Transdermal formulation of L-ascorbic acid 2-phosphate magnesium salt (A2P) was prepared using multilamellar vesicles (MLV). A2P was either physically mixed with or entrapped into three different MLVs of neutral, cationic, and anionic liposome vesicles. For the preparation of neutral MLVs, phosphatidylcholine (PC) and cholesterol (CH) were used. For cationic and anionic MLVs, dioleoyl-trimethylammonium-propane and dimyristoyl glycerophosphate were added as surface charge inducers, respectively, in addition to PC and CH. Particle size of the three A2P-loaded MLVs was submicron, and polydispersity index revealed homogenous distribution of the prepared MLVs except neutral ones. Skin penetration study with hairless mouse skin showed that both physical mixtures of A2P with empty MLVs and A2P-loaded MLVs increased penetration of the drug compared to aqueous A2P solution. During the penetration, however, significant amount of the drug was metabolized into L-ascorbic acid, which has no beneficial effect on stimulation of hair growth. Out of the physical mixtures and A2P-loaded MLVs tested, physical mixture of A2P with empty cationic MLV resulted in the greatest skin penetration and retention in hairless mouse skin.