The composition of the choice set modulates probability weighting in risky decisions.

Probability distortion-the tendency to underweight larger probabilities and overweight smaller ones-is a robust empirical phenomenon and an important driver of suboptimal choices. We reveal a novel contextual effect on probability distortion that depends on the composition of the choice set. Probability distortion was larger in a magnitude-diverse choice set (in which participants encountered more unique magnitudes than probabilities) but declined, resulting in more veridical weighting, in a probability-diverse choice set (more unique probabilities than magnitudes). This effect was consistent in two, large, independent datasets (N = 481, N = 100) and held for a subset of lotteries that were identical in the two contexts. It also developed gradually as a function of exposure to the choice set, was independent of attentional biases to probability versus magnitude information, and was specific to probability weighting, leaving risk attitudes unaffected. The results highlight the importance of context when processing probabilistic information.

Effect of high-protein diet on pyrimidine synthesis and response to PALA in mouse tissues.

BACKGROUND: High-protein diets have been found to protect mice from the lethal effects of cytotoxic pyrimidine analogues and to reduce the toxicity of the antipyrimidine fluorouracil (5-FU), but the biochemical explanation for these effects is not known. PALA potentiates the chemotherapeutic efficacy of 5-FU, and each of the two agents can produce dose-limiting intestinal toxic effects. We have shown that intraperitoneal infusion of ammonium chloride stimulates intestinal de novo pyrimidine synthesis. This stimulation with excess ammonia, which can also result from high-protein intake, is dependent on the presence of carbamoyl phosphate synthetase I, an enzyme in the liver and intestine but not in most tumors. These findings suggest that a high-protein diet can stimulate pyrimidine synthesis in the liver and intestine but leave it unchanged in tumor tissue. PURPOSE: The purpose of this study was to determine whether varying dietary protein causes pharmacologically relevant and preferential changes in de novo pyrimidine synthesis. METHODS: Mice were fed diets containing 18%, 35%, or 50% casein. Dietary effects on de novo pyrimidine synthesis were measured in the intestine, liver, and B16 mouse melanoma in mice treated with PALA and in untreated mice. De novo synthesis was measured by infusion of [15N]alanine into intact animals, determination of 15N incorporation into uracil by use of gas chromatography-mass spectrometry, and calculation of the fraction of the uracil nucleotide pool formed by de novo synthesis. RESULTS: In mice on a 50% casein diet (high protein), de novo pyrimidine synthesis increased substantially in the liver and intestine, compared with synthesis in mice receiving 18% casein. Increase in pyrimidine synthesis in B16 tumor tissue was negligible. The high-protein diet protected the intestine and liver from depletion of uracil nucleotide pools by PALA, and toxicity in tumor-free animals was reduced, as determined by mortality after PALA treatment. Sensitivity of the B16 tumor to the biochemical and cytotoxic effects of PALA was not diminished. CONCLUSIONS: We propose that the basis for these effects of a high-protein diet is the generation of excess carbamoyl phosphate in tissues containing carbamoyl phosphate synthetase I. This carbamoyl phosphate can stimulate de novo pyrimidine synthesis and compete with drugs that interact with enzymes of the de novo pathway, thereby selectively protecting the liver and intestine. IMPLICATIONS: These data provide a biochemical explanation for reported effects of high-protein diet on toxicity of antipyrimidines like 5-FU. Studies are underway to determine if stimulation of pyrimidine synthesis by excess ammonia improves therapy with 5-FU alone or combined with PALA.

Improved cyclic urea inhibitors of the HIV-1 protease: synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450.

BACKGROUND: Effective HIV protease inhibitors must combine potency towards wild-type and mutant variants of HIV with oral bioavailability such that drug levels in relevant tissues continuously exceed that required for inhibition of virus replication. Computer-aided design led to the discovery of cyclic urea inhibitors of the HIV protease. We set out to improve the physical properties and oral bioavailability of these compounds. RESULTS: We have synthesized DMP 450 (bis-methanesulfonic acid salt), a water-soluble cyclic urea compound and a potent inhibitor of HIV replication in cell culture that also inhibits variants of HIV with single amino acid substitutions in the protease. DMP 450 is highly selective for HIV protease, consistent with displacement of the retrovirus-specific structural water molecule. Single doses of 10 mg kg-1 DMP 450 result in plasma levels in man in excess of that required to inhibit wild-type and several mutant HIVs. A plasmid-based, in vivo assay model suggests that maintenance of plasma levels of DMP 450 near the antiviral IC90 suppresses HIV protease activity in the animal. We did identify mutants that are resistant to DMP 450, however; multiple mutations within the protease gene caused a significant reduction in the antiviral response. CONCLUSIONS: DMP 450 is a significant advance within the cyclic urea class of HIV protease inhibitors due to its exceptional oral bioavailability. The data presented here suggest that an optimal cyclic urea will provide clinical benefit in treating AIDS if it combines favorable pharmacokinetics with potent activity against not only single mutants of HIV, but also multiply-mutant variants.

3-D patterning of silicon by laser-initiated, liquid-assisted colloidal (LILAC) lithography.

We report a comprehensive study of laser-initiated, liquid-assisted colloidal (LILAC) lithography, and illustrate its utility in patterning silicon substrates. The method combines single shot laser irradiation (frequency doubled Ti-sapphire laser, 50fs pulse duration, 400nm wavelength) and medium-tuned optical near-field effects around arrays of silica colloidal particles to achieve 3-D surface patterning of silicon. A monolayer (or multilayers) of hexagonal close packed silica colloidal particles act as a mask and offer a route to liquid-tuned optical near field enhancement effects. The resulting patterns are shown to depend on the difference in refractive index of the colloidal particles (ncolloid) and the liquid (nliquid) in which they are immersed. Two different topographies are demonstrated experimentally: (a) arrays of bumps, centred beneath the original colloidal particles, when using liquids with nliquidncolloid - and explained with the aid of complementary Mie scattering simulations. The LILAC lithography technique has potential for rapid, large area, organized 3-D patterning of silicon (and related) substrates.

Patients with primary hypothyroidism presenting as prolactinomas.

Hyperprolactinemia can occur in patients with primary hypothyroidism. Two women with hypothyroidism who had elevated serum prolactin levels, galactorrhea, amenorrhea, and pituitary computed tomographic scans that demonstrated the presence of "pituitary tumors" were recently evaluated. It was believed that they had prolactinomas, and they were referred for possible surgery. An elevated serum thyroid-stimulating hormone level, however, suggested that they had primary hypothyroidism and probably pituitary enlargement secondary to pituitary hyperplasia. Detailed evaluation of thyroid-stimulating hormone and prolactin secretion was performed. These studies revealed several abnormalities in dopamine-prolactin interactions; however, the primary event responsible for the hyperprolactinemia is unclear. These women were given thyroxine therapy, and subsequent radiologic and endocrine studies documented resolution of their "pseudotumors" and normalization of the serum thyroxine and prolactin levels. Hence, thyroid-stimulating hormone levels should be measured in all patients presenting with a suspected prolactinoma so that any hypothyroidism that is noted is not presumed to be due to secondary hypothyroidism from tumor involvement of the pituitary.

Antiinflammatory 4,5-diarylpyrroles: synthesis and QSAR.

A series of 2-substituted- and 2,3-disubstituted-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1H- pyrroles was synthesized and found to be active in the rat adjuvant arthritis model of inflammation. The most active compounds were the 2-halo derivatives in the order of chloro > bromo > iodo. The same pattern of activity was observed for the 2,3-dihalopyrroles. Quantitative structure-activity relationship studies suggested that the activity could be correlated with the molar refractivity and the inductive field effect of the 2-substituent and the lipophilicity of the 3-substituent.

Understanding vascular ultrasonography.

The technology of imaging has progressed rapidly; thus, physicians must stay abreast of the principles of utilization and the interpretation of these new tests. Most of the information about this technology is presented in subspecialty literature that is not readily accessible or easily interpretable by nonspecialists. Herein we review the current literature on vascular ultrasonography and present the information in a simple, practical manner. The safety, utility, and accuracy of the ultrasound devices are delineated for the study of various vascular conditions.

Double dissociation of function within the hippocampus: spatial memory and hyponeophagia.

Complete and dorsal hippocampal lesions impaired spatial performance on 2 working memory tasks: rewarded alternation on the T maze and matching to position in the water maze. In contrast, ventral hippocampal lesions had no effect on these tasks, even when task difficulty was increased by the introduction of delays. Ventral lesions did resemble complete lesions in reducing anxiety in 3 commonly used tests of anxiety (social interaction, plus-maze, and hyponeophagia). Dorsal lesions also appeared to be anxiolytic in the social interaction and plus-maze tests, but they did not affect hyponeophagia. Complete- and dorsal-lesioned rats displayed hyperactivity, whereas ventral-lesioned rats did not. These results show a double dissociation between dorsal and ventral hippocampal lesions (hyponeophagia vs. spatial memory), suggesting differentiation of function along the septotemporal axis of this structure.

Ventral hippocampal lesions affect anxiety but not spatial learning.

Rats with cytotoxic ventral hippocampal lesions which removed approximately 50% of the hippocampus (including dentate gyrus) starting from the temporal pole, displayed a reduction in freezing behaviour following the delivery of an unsignalled footshock in an operant chamber. This was more plausibly a result of reduced susceptibility to fear than a result of a lesion-induced increase in general motor activity. There was no consistent difference between sham and lesioned animals in spontaneous locomotor activity, or locomotion following acute or chronic treatment with amphetamine. In contrast, ventral hippocampal lesioned animals were quicker to pass from the black to the white box during a modified version of the light/dark exploration test, and were quicker to begin eating during tests of hyponeophagia. Furthermore, rats with ventral hippocampal lesions defecated less than their sham counterparts both during open field testing and in extinction sessions following contextual conditioning. In contrast to these clear lesion effects, there were no signs of any spatial learning impairment either in the watermaze or on the elevated T-maze. Taken together these results suggest that the ventral hippocampus may play a role in a brain system (or systems) associated with fear and/or anxiety, and provide further evidence for a distinct specialisation of function along the septotemporal axis of the hippocampus.

Atipamezole-precipitated clonidine withdrawal induces c-Fos expression in rat central nervous system.

We sought to identify a clonidine withdrawal syndrome in conscious rats by investigating the effects of a single injection of the specific alpha2-adrenergic antagonist atipamezole (1.5 mg/kg i.p.) after chronic treatment with the alpha2-adrenergic agonist clonidine (200 microg/kg per day via osmotic mini-pump for 7-10 days). Rats treated chronically with clonidine followed by atipamezole injection (clonidine-atipamezole) demonstrated dramatic behavioral effects including shaking, vigorous digging, and whole-body seizure-like movements. Control groups (saline-saline, clonidine-saline and saline-atipamezole) showed no overt unusual behavioral effects following injection. The brains of the clonidine-atipamezole group showed massive c-Fos expression (especially in di- and telencephalon) while the other groups showed either background levels of c-Fos-immunopositive cells (saline-saline and clonidine-saline groups) or a slight increase over background in selected areas (saline-atipamezole group). Maps of c-Fos-immunolabeled cells were generated at five representative coronal planes for each treatment group. C-Fos-immunopositive cells were counted in three representative brainstem structures (locus coeruleus, nucleus of the solitary tract, rostral ventrolateral medulla (RVL)) and in three regions of the thoracic spinal cord (dorsal horn, intermediate zone and ventral horn). In the three brainstem structures the number of c-Fos-positive cells was elevated 8-10-fold in the clonidine-atipamezole group compared to the other groups. No other treatment group was significantly different from the saline-saline group. An increased number of c-Fos-positive neurons was also noted in the dorsal horn and intermediate layers of the thoracic spinal cord in the clonidine-atipamezole group compared to a sham-operated atipamezole-injected group. In the RVL, 59% of c-Fos-positive cells contained alpha2A-adrenergic receptor-like immunoreactivity in clonidine-atipamezole treated (withdrawing) rats. In addition, one-third of the tyrosine hydroxylase (TH)-immunopositive cells in RVL were also c-Fos-positive in clonidine withdrawing rats where no TH-positive cells were also c-Fos-positive in RVL of control groups. Atipamezole injected 10 min after a single injection of clonidine (200 microg/kg, i.p.) produced no behavioral effect and did not increase c-Fos expression in brainstem. Injection of the opiate antagonist naltrexone (100 mg/kg, i.p.) in rats chronically treated with clonidine did not elicit behavioral effects or result in increased c-Fos expression in brainstem. In conclusion, administration of the selective alpha2-antagonist atipamezole to rats chronically treated with the alpha2-adrenergic agonist clonidine triggers a powerful withdrawal syndrome associated with massive CNS expression of c-Fos protein. The intensity of the withdrawal syndrome indicates that chronic exposure to alpha2-adrenergic receptor agonists produces strong dependence.

Cocaine- and alcohol-mediated expression of inducible transcription factors is blocked by pentobarbital anesthesia.

Identifying the neurocircuitry involved in behavioral responses to drugs of abuse is an important step towards understanding the mechanisms of drug addiction. The present study sought to distinguish brain regions involved in pharmacological effects of cocaine and ethanol from secondary effects by administering these drugs in the presence or absence of pentobarbital anesthesia. Changes in neuronal activity were assessed by immunohistochemical analysis of expression of an inducible transcription factor (ITF), c-Fos, in the brain of rats habituated to repeated pentobarbital anesthesia or saline administration. Cocaine administration (15 mg/kg, i.v.) in non-anesthetized animals produced a strong induction of c-Fos in the striatum and large number of other brain areas. Ethanol administration (2 g/kg, i.p.) induced c-Fos in a smaller number of characteristic brain areas, including the central nucleus of amygdala and paraventricular nucleus of hypothalamus. However, neither of these drugs was able to induce c-Fos in pentobarbital-anesthetized rats (50 mg/kg, i.v.). The suppressive effects of pentobarbital were not specific to c-Fos, such that pentobarbital also suppressed expression of ITFs FosB and Egr1 in the striatum of cocaine-treated rats. On the other hand, pentobarbital by itself strongly induced c-Fos expression in the lateral habenula of saline-, cocaine-, and ethanol-injected rats. It is not clear whether the suppressive effects of anesthesia on ITF expression in other areas are mediated by activation of lateral habenula, or are independent of this event. Our data suggest that in the absence of conscious awareness of drug-associated cues, cocaine and alcohol activate only a fraction of the neural elements engaged in the unanesthetized state.

Reduction of adverse acute cardiovascular actions of 6-hydroxydopamine in dogs by adrenergic receptor blockade.

Injection of dogs with 50 mg/kg of 6-hydroxydopamine (6-OHDA) caused large increases in blood pressure and heart rate, followed after 1 or 2 hr by severe hypotension. Prior administration of the adrenergic receptor blocking agents phentolamine and propranolol attenuated both the hyper- and hypotensive phases of 6-OHDA. Phentolamine and propranolol did not prevent depletionof norepinephrine or development of the characteristic morphological changes induced in adrenergic fibers by 6-OHDA.

Biomechanical evaluation of posterior cervical stabilization after a wide laminectomy.

STUDY DESIGN: In vitro biomechanical investigation with nondestructive and destructive testing in a human cadaveric model simulating a wide postlaminectomy condition. OBJECTIVES: To determine the relative stability conferred by a posterior cervical spinal rod system and posterior cervical plating. SUMMARY OF BACKGROUND DATA: Posterior cervical plate fixation has been shown to be biomechanically superior to wiring techniques, but lateral mass screws may injure neurovascular structures or facet joints if they are inserted improperly. A cervical rod system has been developed to enhance the safety of lateral mass instrumentation. METHODS: The cervical spines of 12 cadavers underwent biomechanical testing. After completion of the nondestructive intact testing, a wide laminectomy with subtotal facetectomies from C4 to C6 was performed. The specimens in two subgroups (group A, cervical spine rods with unicortical fixation, and group B, reconstruction plates with bicortical fixation) were tested in flexion, lateral bending, and torsion. Finally, destructive testing in flexion was performed. Stiffness, neutral zone, failure moment, energy to failure, and mechanism of failure were determined for each specimen. The data were analyzed using paired t tests and ANOVA. RESULTS: Group B had a greater mean screw torque value. The instrumented constructs had a greater stiffness ratio (instrumented/intact) than the intact specimens in flexion, lateral bending, and torsional testing. Group A had a significantly greater flexural stiffness than Group B. Neutral zone ratio values were significantly lower during flexural testing for the cervical rod construct. Destructive testing resulted in significantly greater failure moment and energy-to-failure values for group A. In the cervical rod construct, failure occurred primarily by superior screw loosening with pull-out from the lateral mass. Reconstruction plates consistently failed with fracture of the lateral mass and superior screw loosening. CONCLUSION: Significantly greater stability was noted in the cervical rod construct during nondestructive and destructive flexural testing.

Primary Ewing's sarcoma of the spine.

Thirty-six patients with primary Ewing's sarcoma of the spine were diagnosed at the Mayo Clinic between 1951 and 1988. The mean age was 17 years (range, 5-40 years). Neurologic symptoms and signs were seen in 58% of the patients. Forty-seven percent of all patients had an open biopsy of the lesion and underwent a decompressive laminectomy. Three of the four patients with thoracic or thoracolumbar involvement had progressive kyphosis after laminectomy. All patients received radiation therapy in various dosages. Sixteen of the patients were registered in the Intergroup Ewing's Sarcoma Study. Intensive combination chemotherapy was administered to 32 of the patients. Nine patients were free of disease at the final follow-up examination (follow-up ranged from 6 to 184 months). The 5-year survival rate was 33%. The mean survival time was 2.9 years. No significant correlation was found between the location of the tumor in the spine and the length of disease-free survival, overall survival, or incidence of metastatic disease. Patients enrolled in the Intergroup Ewing's Sarcoma Study had significantly better rates of disease-free survival and overall survival.

Biomechanical evaluation of anterior cervical spine stabilization.

STUDY DESIGN: An in vitro biomechanical study. OBJECTIVES: To simulate a severe compressive flexion injury for determination of the relative stability of different anterior instrumentation systems in a porcine model and to validate this model in human cadaveric specimens. SUMMARY OF BACKGROUND DATA: Anterior plate fixation is useful for high-grade mechanical insufficiency of the cervical spine and may prevent the need for a second procedure. METHODS: The cervical spines of 45 porcine and 12 cadaveric specimens were subjected to nondestructive flexion, lateral bending, and torsional testing on a modified universal testing machine. A corpectomy was performed with release of the posterior ligamentous structures. The specimens were stabilized with one of three anterior plate constructs. The nondestructive testing was repeated to evaluate structural stability (stiffness and neutral zone). Finally, destructive testing examined failure moment, energy to failure, and mechanism of failure. RESULTS: The instrumented specimens had flexural and lateral bending and torsional stiffness values that were similar to or greater than those of their paired intact specimens. The cervical spine locking plate had a significantly higher flexural stiffness ratio (plated:intact), torsional stiffness ratio, lower flexural neutral zone ratio, higher failure moment, and higher energy to failure than did the Caspar plate. CONCLUSIONS: The cervical spine locking plate is theoretically safer than the Caspar system because the posterior vertebral body cortex is not breached by the fixation screws, and the screws are less likely to back out anteriorly and irritate the esophagus. According to these results, the cervical spine locking plate system is biomechanically equivalent to and in some cases more stable than the Caspar system for fixation of a severe compressive flexion injury.

Capping the cost of compliance with the Kyoto Protocol and recycling revenues into land-use projects.

There is the concern among some countries that compliance costs with commitments under the Kyoto Protocol may be unacceptably high. There is also the concern that technical difficulties with the inclusion of land use, land-use change, and forestry activities in non-Annex I countries might lead to an effective exclusion of such activities from consideration under the Protocol. This paper is proposing a mechanism that addresses both these concerns. In essence, it is suggested that parties should be able to purchase fixed-price offset certificates if they feel they cannot achieve compliance through other means alone, such as by improved energy efficiency, increased use of renewable energy, or use of the flexible mechanisms in the Kyoto Protocol. These offset certificates would act as a price cap for the cost of compliance for any party to the Protocol. Revenues from purchase of the offset certificates would be directed to forest-based activities in non-Annex I countries such as forest protection that may carry multiple benefits including enhancing net carbon sequestration.

Forehead reflectance photoplethysmography to monitor heart rate: preliminary results from neonatal patients.

Around 5%-10% of newborn babies require some form of resuscitation at birth and heart rate (HR) is the best guide of efficacy. We report the development and first trial of a device that continuously monitors neonatal HR, with a view to deployment in the delivery room to guide newborn resuscitation. The device uses forehead reflectance photoplethysmography (PPG) with modulated light and lock-in detection. Forehead fixation has numerous advantages including ease of sensor placement, whilst perfusion at the forehead is better maintained in comparison to the extremities. Green light (525 nm) was used, in preference to the more usual red or infrared wavelengths, to optimize the amplitude of the pulsatile signal. Experimental results are presented showing simultaneous PPG and electrocardiogram (ECG) HRs from babies (n = 77), gestational age 26-42 weeks, on a neonatal intensive care unit. In babies ⩾32 weeks gestation, the median reliability was 97.7% at ±10 bpm and the limits of agreement (LOA) between PPG and ECG were +8.39 bpm and -8.39 bpm. In babies <32 weeks gestation, the median reliability was 94.8% at ±10 bpm and the LOA were +11.53 bpm and -12.01 bpm. Clinical evaluation during newborn deliveries is now underway.

High-frequency limit of neural stimulation with ChR2.

Optogenetic technology based on light activation of genetically targeted single component opsins such as Channelrhodopsin-2 (ChR2) has been changing the way neuroscience research is conducted. This technology is becoming increasingly important for neural engineering as well. The efficiency of neural stimulation with ChR2 drops at high frequencies, often before the natural limit of the neuron is reached. This study aims to investigate the underlying mechanisms that limit the efficiency of the stimulation at high frequencies. The study analyzes the dynamics of the spikes induced by ChR2 in comparison to control stimulations using patch clamp current injection. It shows that the stimulation dynamics is limited by two mechanisms: 1) a frequency independent reduction in the conductance-to-irradiance yield due to the ChR2 light adaptation process and 2) a frequency dependent reduction in the conductance-to-current yield due to a decrease in membrane re-polarization level between spikes that weakens the ionic driving force. The effect of the first mechanism can be minimized by using ChR2 mutants with lower irradiance threshold. In contrast the effect of the second mechanism is fundamentally limited by the rate the native ion channels re-polarize the membrane potential.