Utility of BRAF V600E immunohistochemistry in the diagnosis of mandibular ameloblastomas.

Ameloblastoma, odontogenic keratocyst (OKC), and dentigerous cyst (DC) can have similar radiographic and histological appearances. The purpose of this study was to determine the utility of BRAF immunohistochemistry in discerning mandibular ameloblastomas from OKCs and DCs. This retrospective cohort study included patients treated between 1998 and 2018. Inclusion criteria include incisional biopsy-proven mandibular ameloblastoma, OKC, or DC, and sufficient tissue for immunohistochemistry. The primary predictor variable was the type of lesion. The primary outcome variable was the presence/absence of BRAF V600E immunoreactivity. The cohort consisted of 43 patients (19 female, 24 male; mean age 48 ± 17 years). There were 22 ameloblastomas, 11 OKCs, and 10 DCs. Among ameloblastomas, 68.2% (15/22) stained positive for BRAF V600E; no OKC or DC was positive (P < 0.001). By subtype, the majority of the follicular (83.3%), unicystic (83.3%), desmoplastic (66.7%), and acanthomatous (100%) subtypes were positive, but only 33.3% of the plexiform subtype were positive. BRAF immunohistochemistry may be a useful adjunct in the differentiation of ameloblastoma from OKCs and DCs on incisional biopsies. It may be particularly useful for small samples with a prominent cystic component or equivocal histopathology. Mandibular lesions that are BRAF immunohistochemistry positive are unlikely to be DCs or OKCs.

Simulating microbial processes in extraterrestrial, aqueous environments.

Finding evidence of life elsewhere in the Solar System is dependent on understanding biotic processes that could occur within potentially habitable environments. Here, we describe a suite of high-pressure flow-through reactors that have been developed to investigate biotic and abiotic processes within simulated sub-surface martian and icy moon environments.

Reliability of radiological and cosmetic measurements in hallux valgus.

PURPOSE: To evaluate the reliability of angular, linear, and sesamoid position measurements on preoperative and postoperative radiographs in hallux valgus (HV), as well as cosmetic foot appearance. MATERIAL AND METHODS: Radiographs and photographs from 100 patients undergoing HV surgery were evaluated by two independent observers. RESULTS: Interobserver and intraobserver agreements for HV angle using coefficient of repeatability measures were 4.4 degrees and 3.7 degrees, respectively. Intraclass correlation coefficient measures within and between agreements were 0.97 for HV angle. For intermetatarsal distance, interobserver and intraobserver values were 0.90 and 0.94 when measuring from the midline of each metatarsal and 0.75 and 0.92 when measuring between cortices. Using the visual analog scale to evaluate esthetic appearance, interobserver and intraobserver agreements were 0.59 and 0.79, respectively. Sesamoid position values were also measured. Interobserver and intraobserver kappa values for preoperative and postoperative evaluations with two established methods (Mann or Smith) were 0.47 and 0.70 or 0.65 and 0.75, respectively. CONCLUSION: Intraobserver reliability was higher than interobserver for intermetatarsal distance, cosmetics, and sesamoid position. Angular measurements were more accurate than linear. Esthetic evaluation was less reliable than radiographic, except in the case of sesamoid position measurements.

Efficient, near-complete removal of DNAPL from three-dimensional, heterogeneous porous media using a novel combination of treatment technologies.

Remediation of porous media containing an entrapped dense nonaqueous phase liquid (DNAPL) is extremely difficult due to the heterogeneity and three-dimensional spatial nature of typical natural systems. A novel treatment technology based on surfactant- and gravity-induced mobilization, dense brine containment and collection, and a vapor-phase extraction polishing step is proposed as a means to remediate such systems. Laboratory experiments are performed using the suggested methodology applied to three-dimensional, heterogeneous systems, which are packed based upon a realization from a correlated random field. Entrapped DNAPL is effectively removed as a result of each component of the technology. Following vapor extraction, less than 1% of the original DNAPL mass remained in the system. While these results are very promising, several open issues must be resolved before this technology can be considered mature; both the investigation of some of these issues and a summary of remaining needs are addressed.

Task demands and representation in long-term repetition priming.

The effects of task demands on the representation of letter strings in long-term repetition priming (LTRP) were explored in two lexical decision experiments. The stimuli in both experiments were words and nonwords, some presented horizontally and some vertically. The only difference between the two experiments was the response required by the participant. In Experiment 1, the participants pressed one of two buttons, indicating whether or not a given stimulus was a word. In Experiment 2, the participants pressed one of four buttons, indicating both the lexical status and the orientation of a given stimulus. The results were that in Experiment 1, LTRP was not disrupted by a change in stimulus orientation, whereas in Experiment 2 it was, suggesting that the nature of the stimulus representation utilized in LTRP is partially dependent on the demands of the task.

Combined nicotinic and muscarinic blockade in elderly normal volunteers: cognitive, behavioral, and physiologic responses.

Establishing a pharmacologic model of the memory deficits of Alzheimer's disease could be an important tool in understanding how memory fails. We examined the combined effects of the muscarinic antagonist scopolamine and the nicotinic antagonist mecamylamine in eight normal elderly volunteers (age 61.9 +/- 8.3 yrs, SD). Each received four separate drug challenges (scopolamine (0.4 mg i.v.), mecamylamine (0.2 mg/kg up to 15 mg PO), mecamylamine + scopolamine, and placebo). There was a trend toward increased impairment in explicit memory for the mecamylamine + scopolamine condition as compared to scopolamine alone. Increased impairment was also seen for the mecamylamine + scopolamine condition as compared to scopolamine alone in selected behavioral ratings. Pupil size increased when mecamylamine was added to scopolamine, while systolic blood pressure and pulse changed in concordance with ganglionic blockade. These data together with previous brain-imaging results suggest that this muscarinic-nicotinic drug combination may better model Alzheimer's disease than either drug alone.

Allocating visual attention: tests of a two-process model.

Observers require less time to identify a visual target when its location is cued in advance than when it is not cued, and the magnitude of the improvement depends on the validity of the cue. According to J. Jonides's (1983) 2-process model, there exist 2 possible modes of attentional readiness: a focused-attention mode and a diffuse-attention mode. Observers are assumed to enter the focused-attention mode on a proportion of trials that matches the validity of the cue and to enter the diffuse-attention mode on the remaining trials. The present experiment tested and rejected the response time mixture prediction of the 2-process model. An instance of the class of 1-process models in which perceptual objects are sampled in parallel according to the validity of the cue was evaluated. A stochastic simulation of the model yielded results that paralleled those of the experiment.

An effect of triazolam on visual attention and information processing.

This study explored whether benzodiazepines selectively affect aspects of attention and/or visual information processing, as they do memory. A cued visual-search paradigm was employed, using normal volunteers and a single dose of triazolam. This paradigm provided for a detailed examination of two aspects of visual attention and information processing: 1) controlled versus automatic attention allocation (via central and peripheral cues), and 2) the extent to which processing an item in a non-cued location affects performance (via cue-validity). Triazolam, compared to placebo, significantly increased response time, and Drug Condition interacted with Cue-Validity but not Cue-Type. Based on these data, we argue that triazolam does not affect attention allocation but does affect attentional disengagement and/or attention switching mechanisms.

Toxicological evaluation of mu-agonists. Part I: Assessment of toxicity following 30 days of repeated oral dosing of male and female rats with levo-alpha-acetylmethadol HCl (LAAM).

This study evaluated levo-alpha-acetylmethadol hydrochloride (LAAM), a long-acting morphine-like (mu) agonist approved in 1993 to treat opiate dependence. Sprague-Dawley rate (20/sex/group) were gavaged with doses of 3.0-33.5 mg kg-1 for 30 days followed by a 14-day drug-free recovery period. Treatment-related effects included dose-dependent CNS depression, decreased food consumption and body weight gain, reddish urine and abdominal staining. Tolerance developed by day 7. Mortality was dose-dependent; deaths occurred predominantly during the first week. Increased alanine aminotransferase (SGOT, AST) and lactate dehydrogenase (LDH), observed only in high-dose males, were associated with findings in liver. Decreases in spleen/brain weight and increases in brain/body weight ratios were seen in both sexes. Decreases in weights of heart, liver and kidney achieved statistical significance only for high-dose groups. Kidneys of mid- and high-dose groups displayed intertubular mineral/crystal deposition, focal corticomedullary mineralization and focal regenerative tubular epithelium. Centrilobular hypertrophy was observed in livers of high-dose males and mid- and high-dose females. Following the recovery period, decreased body weights and increased brain/body weight ratios occurred in mid-dose males and low-dose females. Weights of liver and kidney and organ/brain weight ratios were decreased in mid-dose males. Histopathological findings observed in kidneys and livers had abated. In summary, acute and repeated administration of LAAM produced a spectrum of activity consistent with its profile as a long-acting pure mu-agonist which stimulates microsomal enzymes in rodents. Renal and hepatic effects seen in initially drug-naive rats treated with morphine-type agonists are not observed in tolerant individuals stabilized on mu-agonists to treat opiate dependence.

Impairments in reflective cognitive functions in alcoholics: a neuropharmacological model.

The ability to make use of reflective cognitive operations in monitoring and evaluating remembered events is impaired in subgroups of nominally cognitively unimpaired, detoxified alcoholics. Alcoholics, relative to controls, make more errors in identifying the source of remembered information (i.e. whether a remembered word was self-generated or was a stimulus word presented by the experimenter), and are impaired in their ability to inhibit confabulatory errors (intrusions). The cognitive-memory impairment expressed in benzodiazepine-treated normal volunteers mimics this impairment in alcoholics. Disturbances in prefrontal and frontal lobe functions may be involved in this selective impairment in cognition in many alcoholics and may also contribute to what accounts for the failures in reflective cognitive operations observed in amnestic patients.

Medications development at the National Institute on Drug Abuse: focus on cocaine.

NIDA's MDD is faced with the formidable task of identifying, characterizing, and developing new chemical entities to combat substance abuse. The primary challenge is to find one or more medications that will be useful in treating cocaine addiction, withdrawal, and abstinence. In addition, a treatment for cocaine overdose is in progress. Methodological approaches include testing compounds that alter endogenous neurotransmitters and compounds that suppress conditioned cues and stimuli. Compounds that appear efficacious in these tasks and that have a satisfactory safety profile will be studied in humans.

Comparison of routes of administration and time course effects of zacopride and buspirone in mice using an automated light/dark test.

The behavioral effects of zacopride and buspirone were assessed in mice in a fully automated 2-compartment light/dark test. A significant increase in time mice spent in the lit area was used as an indication of anxiolytic-like action. Doses of zacopride from 0.0001 to 17.8 mg/kg, IP, and buspirone from 3.16 to 17.8 mg/kg, IP, produced significant increases in time mice spent in the lit area of the chamber. In addition, zacopride and buspirone were compared for oral potency and for duration of action after IP and PO administration. Zacopride and buspirone produced anxiolytic-like activity between doses of 0.001 to 100.0 mg/kg, PO, and 10.0 to 56.2 mg/kg, PO, respectively. The duration of effect of buspirone was 2 to 4 h after IP or PO administration, while that for zacopride was greater than or equal to 16 h by either route of administration. Thus, when compared for anxiolytic-like effects in this test, zacopride is a more potent and longer acting agent than buspirone.

A fully automated light/dark apparatus useful for comparing anxiolytic agents.

The effects of known anxiolytic agents and putative anxiolytic agents were assessed in mice in a fully automated 2-compartment light/dark test. Significant increases in lit area activities (e.g., time spent in the lit area, locomotor activity, rearing behavior) were used as possible indicators of anxiolytic-like action. The measurement found most consistent and useful for assessing antianxiety-like activity was the time mice spent in the lit area. The benzodiazepine, diazepam; the 5-HT1A agent, ipsapirone; and the 5-HT3 receptor antagonist, ondansetron, produced significant anxiolytic-like activity between doses of 1.0 to 10.0 mg/kg, 17.8 to 31.6 mg/kg, and 0.0001 to 1.0 mg/kg respectively. The 5-HT1A receptor agonist, 8-OH DPAT, also exhibited anxiolytic-like action between doses of 0.0005 to 3.16 mg/kg. In contrast, the peripheral 5-HT3 receptor agonist, N-phenylbiguanide; the antidepressant, imipramine; the neuroleptic, chlorpromazine; and the CNS stimulant, S(+)-amphetamine, did not display antianxiety-like activity. The positive results obtained for the three types of compounds (benzodiazepine, 5-HT1A, and 5-HT3) indicate that this fully automated light/dark apparatus may be useful for identifying known and putative anxiolytic agents.

2-Phenyl-3H-imidazo[4,5-b]pyridine-3-acetamides as non-benzodiazepine anticonvulsants and anxiolytics.

A series of 2-phenyl-3H-imidazo[4,5-b]pyridine-3-acetamides were designed and synthesized as non-benzodiazepine anxiolytics based on a molecular disconnection of a typical 1,4-benzodiazepine (BZD). A number of these compounds showed submicromolar potency in a [3H]benzodiazepine binding assay in vitro and good potency in protecting rodents against pentylenetetrazole-induced seizures. Compound 84 appears to be a selective anticonvulsant (pentylenetetrazole) agent when tested against a profile of chemically and electrically induced seizures in mice. In addition, compound 148 appears to be a selective anxiolytic/hypnotic agent on the basis of biochemical and pharmacological characterization. It appears to be a full BZD agonist as assessed by GABA shift ratio and to be effective in punishment and nonpunishment animal models of anxiety. In addition, it shows a lower side-effect profile than diazepam as assessed by rotorod neurotoxicity and potentiation of ethanol-induced sleep time in mice. The chemistry and structure-activity relationships of this series is discussed.

Anxiolytic-like activity of R(+)- and S(-)-zacopride in mice.

The effects of the optical isomers of zacopride were assessed in mice in a fully automated two-compartment light/dark apparatus. A significant increase in time spent in the lit area was used as an indication of anxiolytic-like action. Intraperitoneal (i.p.) doses of R(+)-zacopride from 0.00001 to 10.0 mg/kg and S(-)-zacopride from 0.01 to 1.0 mg/kg produced significant anxiolytic-like activity. Oral (p.o.) doses of the R(+) isomer from 0.00001 to 10.0 mg/kg and S(-)isomer from 0.1 to 1.0 mg/kg also generated antianxiety-like action. In addition, R(+)-zacopride (0.0001 mg/kg) was evaluated for time course effects after i.p. and p.o. administration. By either route of injection, the onset to action of R(+)-zacopride was 0.5 h, while the duration of effect was greater than or equal to 16 h. It was concluded that R(+)-zacopride is a potent and long-acting drug and that it is principally responsible for the anxiolytic-like activity of racemic zacopride.

AHR-12245: a potential anti-absence drug.

AHR-12245, 2-(4-chlorophenyl)-3H-imadazo[4,5-b]pyridine-3-acetamid, ethosuximide, Na valproate, phenytoin, and clonazepam were evaluated in mice and rats with a battery of well-standardized anticonvulsant test procedures. The results obtained indicate that the anticonvulsant profile of AHR-12245 is similar to that for ethosuximide and clonazepam. AHR-12245 is effective in nontoxic intraperitoneal doses in mice by the maximal electroshock seizure (MES), pentylenetatrazol (s.c. PTZ), bicuculline, and picrotoxin tests but ineffective against strychnine-induced seizures; it is effective after nontoxic oral doses in both mice and rats by the s.c. PTZ test and ineffective by the MES test. The candidate antiepileptic substance was also ineffective against seizures induced in amygdala and corneally kindled rats. The PIs for AHR-12245 by the s.c. PTZ test were 4.5 to 12 times higher than those for the prototype agents, except that for clonazepam when administered orally in mice. The in vitro studies indicate that AHR-12245 is a weak inhibitor of benzodiazepine (BDZ) receptor binding but does inhibit adenosine uptake. These results indicate that AHR-12245 is a relatively nontoxic agent with a profile of anticonvulsant action which suggests it should be useful in generalized absence seizures.

The differential activities of R (+)- and S(-)-zacopride as 5-HT3 receptor antagonists.

R(+)- and S(-)-zacopride were assessed as potential 5-HT3 receptor antagonists in behavioural and biochemical tests. The S(-)isomer was more potent than the R(+)isomer to antagonise the hyperactivity induced by the injection of amphetamine or the infusion of dopamine into the nucleus accumbens in the rat. In contrast, the R(+)isomer was more potent to reduce the aversive behaviour of mice to a brightly illuminated environment and in a marmoset human threat test, to facilitate social interaction in rats, to increase performance in a mouse habituation test and prevent a scopolamine-induced impairment, and to antagonise the inhibitory effect of 2-methyl-5-hydroxytryptamine to reduce [3H]acetylcholine release in slices of the rat entorhinal cortex. In binding assays, [3H]S(-)-zacopride and [3H]R(+)-zacopride labelled homogenous populations of high-affinity binding sites in the rat entorhinal cortex, R(+)-zacopride compete for a further 10 to 20% of the binding of [3H]R(+)/S(-)-zacopride or [3H]R(+)-zacopride in excess of that competed for by (S)(-)-zacopride. It is concluded that both isomers of zacopride have potent but different pharmacological activities, with the possibility of different recognition sites to mediate their effects.

Mechanisms of attentional priority.

When a single abrupt onset occurs in a multielement visual display, it captures attention, possibly by generating an attentional interrupt that designates onsets as being of high priority. In 3 experiments, the mechanisms subserving attentional priority setting were investigated. Subjects searched for a prespecified target letter among multiple distractor letters, half of which had abrupt onsets and half of which did not. The target, when present, was equally often an onset element and a no-onset element. Several models for attentional priority, differing in how many onset elements have priority over no-onset elements, were assessed. The data support a model in which approximately 4 onset stimuli are processed before any no-onset stimuli are processed. Two attentional priority mechanisms are proposed: (a) queuing of a limited number of high-priority elements and (b) temporally modulated decay of attentional priority tags.

The in vivo and in vitro activity of AHR-13268D, a new antiallergic/antihistaminic agent.

AHR-13268D (4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1- piperidinyl]propoxy]benzoic acid, sodium salt) is a potent, long-acting water soluble, antiallergic and antihistaminic agent. AHR-13268D protects sensitive guinea pigs from collapse induced by aerosolized antigen; 1, 5, and 24 h ED50s in the test were 0.27, 0.25, 0.93 mg/kg, PO, respectively. AHR-13268D was also active when given as an aerosol, the 1 h ED50 = 0.29%. In the rat passivefoot anaphylaxis test. AHR-13268D was slightly more active (1.55 times) than AHR-5333B when given orally 1 h prior to challenge and equipotent to cromolyn when given intravenously immediately prior to challenge. AHR-13268D displayed potent, long-acting antihistaminic activity in naive guinea pigs; the 1, 5, and 24 h oral ED50s being in the range of 0.3 mg/kg. AHR-13268D (10 to 20 mg/kg, PO) attenuated the skin responses to ascaris antigen in sensitive dogs and did not alter the EEG pattern or sleep/wake patterns of cats at doses in vast excess of its antihistaminic activity. In vitro, AHR-13268D was a potent inhibitor of histamine release from rat peritoneal mast cells (IC50 = 0.51 nM) and was as potent as the reference 5-LO inhibitor phenidone in inhibiting antigen-induced contractions of guinea pig ileum in the presence of pyrilamine, atropine, and imidazole (IC50 approximately 300 microM). AHR-13268B was bioavailable (approximately 88%) from capsules or from oral solutions.