Propofol-induced unresponsiveness is associated with impaired feedforward connectivity in cortical hierarchy.

BACKGROUND: Impaired consciousness has been associated with impaired cortical signal propagation after transcranial magnetic stimulation (TMS). We hypothesised that the reduced current propagation under propofol-induced unresponsiveness is associated with changes in both feedforward and feedback connectivity across the cortical hierarchy. METHODS: Eight subjects underwent left occipital TMS coupled with high-density EEG recordings during wakefulness and propofol-induced unconsciousness. Spectral analysis was applied to responses recorded from sensors overlying six hierarchical cortical sources involved in visual processing. Dynamic causal modelling (DCM) of induced time-frequency responses and evoked response potentials were used to investigate propofol's effects on connectivity between regions. RESULTS: Sensor space analysis demonstrated that propofol reduced both induced and evoked power after TMS in occipital, parietal, and frontal electrodes. Bayesian model selection supported a DCM with hierarchical feedforward and feedback connections. DCM of induced EEG responses revealed that the primary effect of propofol was impaired feedforward responses in cross-frequency theta/alpha-gamma coupling and within frequency theta coupling (F contrast, family-wise error corrected P<0.05). An exploratory analysis (thresholded at uncorrected P<0.001) also suggested that propofol impaired feedforward and feedback beta band coupling. Post hoc analyses showed impairments in all feedforward connections and one feedback connection from parietal to occipital cortex. DCM of the evoked response potential showed impaired feedforward connectivity between left-sided occipital and parietal cortex (T contrast P=0.004, Bonferroni corrected). CONCLUSIONS: Propofol-induced loss of consciousness is associated with impaired hierarchical feedforward connectivity assessed by EEG after occipital TMS.

Comprehensive analysis of "bath salts" purchased from California stores and the internet.

STUDY OBJECTIVE: To analyze the contents of "bath salt" products purchased from California stores and the Internet qualitatively and quantitatively in a comprehensive manner. METHODS: A convenience sample of "bath salt" products were purchased in person by multiple authors at retail stores in six California cities and over the Internet (U.S. sites only), between August 11, 2011 and December 15, 2011. Liquid chromatography-time-of-flight mass spectrometry was utilized to identify and quantify all substances in the purchased products. RESULTS: Thirty-five "bath salt" products were purchased and analyzed. Prices ranged from $9.95 to 49.99 (U.S. dollars). Most products had a warning against use. The majority (32/35, 91%) had one (n = 15) or multiple cathinones (n = 17) present. Fourteen different cathinones were identified, 3,4-methylenedioxypyrovalerone (MDPV) being the most common. Multiple drugs found including cathinones (buphedrone, ethcathinone, ethylone, MDPBP, and PBP), other designer amines (ethylamphetamine, fluoramphetamine, and 5-IAI), and the antihistamine doxylamine had not been previously identified in U.S. "bath salt" products. Quantification revealed high stimulant content and in some cases dramatic differences in either total cathinone or synthetic stimulant content between products with the same declared weight and even between identically named and outwardly appearing products. CONCLUSION: Comprehensive analysis of "bath salts" purchased from California stores and the Internet revealed the products to consistently contain cathinones, alone, or in different combinations, sometimes in high quantity. Multiple cathinones and other drugs found had not been previously identified in U.S. "bath salt" products. High total stimulant content in some products and variable qualitative and quantitative composition amongst products were demonstrated.

Castor bean seed ingestions: a state-wide poison control system's experience.

CONTEXT: Ingestions of the seed of the castor bean plant (Ricinus communis) carries the risk of toxicity from ricin, a potent inhibitor of protein synthesis. OBJECTIVE: We sought to describe characteristics of castor bean seed exposures reported to a state-wide poison control system. METHODS: This was an observational case series. A state-wide poison control system's database was reviewed for exposures to castor bean plant seeds from 2001 to 2011. Case notes were reviewed and data collected, when available, included age, gender, circumstances surrounding exposure, number of castor beans consumed, whether beans were chewed or crushed, symptoms described, laboratory values (aspartate aminotransferase [AST], alanine aminotransferase [ALT], prothrombin time [PT] and international normalized ratio [INR]), duration of follow-up, treatment, and patient outcomes. RESULTS: Eighty-four cases were identified. Ingestions were unintentional in 50 cases (59%) cases and intentional in 34 (40%) cases. A median of 10 seeds (range: 1-20) were ingested in intentional cases versus 1 seed (range: 1-40) in unintentional cases. In 49 (58%) of cases the seeds were reported to have been chewed or crushed. Gastrointestinal symptoms were the most commonly reported symptoms. Vomiting (n = 39), nausea (n = 24), diarrhea (n = 17), and abdominal pain (n = 16) predominated. One patient developed hematochezia and vomiting after reportedly ingesting and intravenously injecting castor bean seeds. Laboratory values were documented in 17 (20%) cases. Only one abnormality was noted; an asymptomatic patient one week following ingestion had AST/ALT of 93 U/L and 164 U/L, respectively. Ricinine was confirmed in the urine of two patients. Twenty-three (27%) cases received activated charcoal. Seventy-two (86%) of cases were calls from health care facilities or referred to health care facilities by the poison control center. Twenty-two (26%) cases were admitted for a median of 2 days (range: 1-10). Admitted cases ingested a median of 8.5 seeds (range: 1-20). Intentional ingestions were followed for median of 37.5 h (range: 0.5-285.5) while unintentional cases were followed for 14 h (range: 1-182). No delayed symptoms, serious outcomes, or deaths were reported. DISCUSSION: Due to the presence of ricin, there is concern for serious outcomes after ingestions of the seeds of the castor bean plant. In this study GI symptoms were most commonly reported but serious morbidity or mortality was not present. The true risk of castor bean plant seed ingestions should continue to be re-evaluated. CONCLUSION: In this retrospective review, gastrointestinal symptoms were the most common symptoms described after reported exposures to castor bean seeds. These exposures were not associated with serious morbidity, mortality, or delayed symptoms.

A retrospective review of isolated gliptin-exposure cases reported to a state poison control system.

BACKGROUND: The dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin, saxagliptin, and linagliptin are approved by the US Food and Drug Administration in the treatment of type-2 diabetes. Given the limited published information regarding human overdoses to these medications, our goal was to characterize such exposures. METHODS: A state poison system database was retrospectively reviewed for all single-agent exposures to sitagliptin, saxagliptin, and linagliptin from 2006 to 2012. Case notes were reviewed and an observational case series was constructed from the data collected including age, weight, gender, circumstances surrounding exposure, symptoms, and outcome. Patients with co-ingestants, confirmed non-exposure, unknown outcomes, or other coding errors were excluded. RESULTS: A total of 197 cases were identified: 135 cases were excluded (123 cases were excluded due to co-ingestants and 12 cases were lost to follow-up); 62 were included for review. No patients experienced hypoglycemia. One of 19 exposed pediatric (0-9 years of age) patients experienced symptoms and was safely managed at home after one episode of emesis. No symptom was experienced following unintentional ingestion by three adolescent (10-18 years of age) patients. Forty single-agent adult exposures to gliptins were included. Thirty-seven involved non-self-harm exposures resulting from double or triple doses; all were safely managed at home without reported symptoms. The majority of these ingestions involved sitagliptin. Three self-harm-adult exposures to gliptins were included for review. All the three were evaluated in a healthcare facility. One patient experienced abdominal discomfort after ingesting 700 mg of sitagliptin and was ultimately discharged from the emergency department. The other two patients experienced no reported symptoms. CONCLUSION: The majority of gliptin-exposed adult and pediatric/adolescent patients were safely managed at home and when evaluated in a healthcare facility, did not require hospitalization. Intentional self-harm-adult gliptin exposures were managed in a healthcare facility but rarely resulted in hospitalization or serious morbidity at doses up to 18 times the adult therapeutic dose. Additional studies are necessary to determine precise triage guidelines for the management of gliptin overdose.

Nontropic actions of neurotrophins: subcortical nerve growth factor gene delivery reverses age-related degeneration of primate cortical cholinergic innervation.

Normal aging is associated with a significant reduction in cognitive function across primate species. However, the structural and molecular basis for this age-related decline in neural function has yet to be defined clearly. Extensive cell loss does not occur as a consequence of normal aging in human and nonhuman primate species. More recent studies have demonstrated significant reductions in functional neuronal markers in subcortical brain regions in primates as a consequence of aging, including dopaminergic and cholinergic systems, although corresponding losses in cortical innervation from these neurons have not been investigated. In the present study, we report that aging is associated with a significant 25% reduction in cortical innervation by cholinergic systems in rhesus monkeys (P < 0.001). Further, these age-related reductions are ameliorated by cellular delivery of human nerve growth factor to cholinergic somata in the basal forebrain, restoring levels of cholinergic innervation in the cortex to those of young monkeys (P = 0.89). Thus, (i) aging is associated with a significant reduction in cortical cholinergic innervation; (ii) this reduction is reversible by growth-factor delivery; and (iii) growth factors can remodel axonal terminal fields at a distance, representing a nontropic action of growth factors in modulating adult neuronal structure and function (i.e., administration of growth factors to cholinergic somata significantly increases axon density in terminal fields). These findings are relevant to potential clinical uses of growth factors to treat neurological disorders.