Planning for the future by western scrub-jays.

Knowledge of and planning for the future is a complex skill that is considered by many to be uniquely human. We are not born with it; children develop a sense of the future at around the age of two and some planning ability by only the age of four to five. According to the Bischof-Köhler hypothesis, only humans can dissociate themselves from their current motivation and take action for future needs: other animals are incapable of anticipating future needs, and any future-oriented behaviours they exhibit are either fixed action patterns or cued by their current motivational state. The experiments described here test whether a member of the corvid family, the western scrub-jay (Aphelocoma californica), plans for the future. We show that the jays make provision for a future need, both by preferentially caching food in a place in which they have learned that they will be hungry the following morning and by differentially storing a particular food in a place in which that type of food will not be available the next morning. Previous studies have shown that, in accord with the Bischof-Köhler hypothesis, rats and pigeons may solve tasks by encoding the future but only over very short time scales. Although some primates and corvids take actions now that are based on their future consequences, these have not been shown to be selected with reference to future motivational states, or without extensive reinforcement of the anticipatory act. The results described here suggest that the jays can spontaneously plan for tomorrow without reference to their current motivational state, thereby challenging the idea that this is a uniquely human ability.

The role of complement in Alzheimer's disease pathology.

Complement proteins are integral components of amyloid plaques and cerebral vascular amyloid in Alzheimer brains. They can be found at the earliest stages of amyloid deposition and their activation coincides with the clinical expression of Alzheimer's dementia. This review will examine the origins of complement in the brain and the role of beta-amyloid peptide (Abeta) in complement activation in Alzheimer's disease, an event that might serve as a nidus of chronic inflammation. Pharmacology therapies that may serve to inhibit Abeta-mediated complement activation will also be discussed.

The mechanism of action of synthetic antithyroid drugs: iodine complexation during oxidation of iodide.

A number of compounds of pharmaceutical importance from a variety of chemical families, including thiocyanates, isothiocyanates, thiourea and derivatives, imidazoles, and various amines, were found to form charge transfer complexes with iodine. Parallel studies were carried out to investigate the actions of these drugs on lactoperoxidase and thyroid activity in vivo in the rat (assays of T3 and T4 and histology of the thyroid gland). The results showed that there was a good correlation between the value of Kc (the formation constant of the iodinated complex) and antithyroid activity in vivo. The higher the electron donor power of the compound, the higher the Kc value and the stronger the action on the thyroid. The results indicated that a number of drugs could have secondary antithyroid activity. Some compounds, such as levamisole, tetramethylthiourea, tetrahydrozoline, phenothiazines, and imipramines, with no action on peroxidase had high Kc values (tetramethylthiourea, 13,825 liters/M) and had strong antithyroid activity in the rat. These results suggest that synthetic antithyroid agents may act either on peroxidase and/or the molecular iodine which may be produced by oxidation of iodides (2I(-)----I2----2I+). It has been shown that oxidation of I- can occur in the absence of thyroglobulin. In the absence of a suitable receptor, significant amounts of I2 may, thus, accumulate. The action of such drugs on molecular iodine may have considerable pharmacological significance.

PD 142676 (CI 1002), a novel anticholinesterase and muscarinic antagonist.

Inhibition of brain acetylcholinesterase (AChE) can provide relief from the cognitive loss associated with Alzheimer's disease (AD). However, unwanted peripheral side effects often limit the usefulness of the available anticholinesterases. Recently, we identified a dihydroquinazoline compound, PD 142676 (CI 1002) that is a potent anticholinesterase and a functional muscarinic antagonist at higher concentrations. Peripherally, PD 142676, unlike other anticholinesterases, inhibits gastrointestinal motility in rats, an effect consistent with its muscarinic antagonist properties. Centrally, the compound acts as a cholinomimetic. In rats, PD 142676 decreases core body temperature. It also increases neocortical arousal, as measured by quantitative electroencephalography, and cortical acetylcholine levels, measured by in vivo microdialysis. The compound improves the performance of C57/B10j mice in a water maze task and of aged rhesus monkeys in a delayed match-to-sample task involving short-term memory. The combined effect of AChE inhibition and muscarinic antagonism distinguishes PD 142676 from other anticholinesterases, and may be useful in treating the cognitive dysfunction of AD and produce fewer peripheral side effects.

Design and synthesis of m1-selective muscarinic agonists: (R)-(-)-(Z)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-methoxyphenyl)-2-propynyl)oxime maleate (CI-1017), a functionally m1-selective muscarinic agonist.

The synthesis and SAR of a series of (Z)-(+/-)-1-azabicyclo[2.2. 1]heptan-3-one, O-(3-aryl-2-propynyl)oximes are described. The biochemistry and pharmacology of 24Z (PD 142505) and its enantiomers are highlighted. 24Z is functionally an m1-selective muscarinic agonist. Efficacy and m1 selectivity reside in the R enantiomer, (R)-24Z (CI-1017).

Formation of molecular iodine during oxidation of iodide by the peroxidase/H2O2 system. Implications for antithyroid therapy.

The first step in the biogenesis of thyroid hormones is the oxidation of iodides taken up by the thyroid gland. Oxidation of I- by the H2O2/peroxidase system leads to the formation of iodinium ions I+ which bond to thyroglobulin by electrophilic substitution. However, it is not clear whether I- is transformed directly to I+ or whether it passes through a molecular iodine intermediate. This latter possibility is indicated by the oxidation potentials of the reactions. I2 can be detected in vitro from the formation of I3- ions, although this has yet to be confirmed in vivo. The present study was designed to determine, albeit indirectly, whether this reaction occurs in vivo. If I2 is produced, it may form charge transfer complexes with numerous drugs. We also investigated the action of various drugs on lactoperoxidase and assessed their antithyroid activity in the rat by assay of plasma levels of T3, T4, and TSH. We found a good correlation between the value of Kc, the formation constant of the complex of the drug with molecular iodine, and the antithyroid activity in vivo. This correlation was observed in four different classes of compound. The possibility that molecular iodine is produced in the thyroid gland has implications for antithyroid therapy.

Traumatic brain injury elevates the Alzheimer's amyloid peptide A beta 42 in human CSF. A possible role for nerve cell injury.

The increased risk for Alzheimer's Disease (AD) associated with traumatic brain injury (TBI) suggests that environmental insults may influence the development of this age-related dementia. Recently, we have shown that the levels of the beta-amyloid peptide (A beta 1-42) increase in the cerebrospinal fluid (CSF) of patients after severe brain injury and remain elevated for some time after the initial event. The relationships of elevated A beta with markers of blood-brain barrier (BBB) disruption, inflammation, and nerve cell or axonal injury were evaluated in CSF samples taken daily from TBI patients. This analysis reveals that the rise in A beta 1-42 is best correlated with possible markers of neuronal or axonal injury, the cytoskeletal protein tau, neuron-specific enolase (NSE), and apolipoprotein E (ApoE). Similar or better correlations were observed between A beta 1-40 and the three aforementioned markers. These results imply that the degree of brain injury may play a decisive role in determining the levels of A beta 1-42 and A beta 1-40 in the CSF of TBI patients. Inflammation and alterations in BBB may play lesser, but nonetheless significant, roles in determining the A beta level in CSF after brain injury.

Secondary antithyroid action of drugs in relation to structure.

Molecular interactions between iodine and disulfiram, clomethiazole, and tolnaftate were investigated by electron spectroscopy. Iodine forms charge transfer complexes with these molecules, with 1:1 stoichiometry and of the n-sigma type. The formation constants were compared with those obtained with antithyroid molecules. Only disulfiram appears to have any effect on the intrathyroid cycle of iodine.

Biological evaluation of compounds with -NCS- group or derived from thiazole and imidazole. Activity on prostaglandin synthetase complex.

The effects of compounds with activity against thyroid peroxidase were tested on the activity of hydroperoxidase and cyclo-oxygenase of the prostaglandin synthetase complex in-vitro. Active compounds were found to inhibit the peroxidase, and the cyclo-oxygenase function. These compounds were also found to have anti-inflammatory activity as demonstrated by the reduction of carrageenan-induced oedema of the hind paw of the rat. Indomethacin and non-steroidal anti-inflammatory drugs tested under the same conditions were shown to have activity towards the cyclo-oxygenase rather than the peroxidase function of the prostaglandin synthetase complex. A common feature of the active compounds was the presence of an -NCS- linkage or free -SH group.

Antithyroid action of ketoconazole: in-vitro studies and rat in-vivo studies.

Inspection of the chemical structure of ketoconazole indicates that it may have antithyroid activity. The antithyroid action of this drug was demonstrated in-vitro and in-vivo. In-vitro, it was found to form a complex with iodine (formation constant Kc 141 L mol-1), and to inhibit lactoperoxidase (IC50 2 x 10(-4) M). Its effects in-vivo in the rat were assessed by assay of circulating-thyroxine, and from the histological appearance of the thyroid gland. Thyroid gland weight was increased in rats treated with ketoconazole.

Prevalence of Toxoplasma gondii antibodies in southern Louisiana swine in 1980 and 1981.

Sera from 1,219 pigs slaughtered in southern Louisiana in 1980 and 1981 were tested, using the indirect hemagglutination test and microtitration system, for Toxoplasma gondii antibodies; 19.19% had titers of greater than or equal to 1:64. Pigs slaughtered in the colder months, November to March, had significantly higher seroprevalences than did pigs slaughtered in the warmer months. Examination of blood samples from 236 sows and gilts on 52 farms revealed a seroprevalence of 24.6%.

Prevalence of trichinosis in southern Louisiana swine.

After an outbreak of human trichinosis in Louisiana involving 45 cases and 1 death in 1979 and 1980, a survey of pigs killed in 21 selected small slaughterhouses in southwestern Louisiana was conducted from November 1980 to September 1981. The sera from 1,225 pigs were examined for trichinella antibodies using an enzyme-linked immunosorbent assay (ELISA); 1,223 diaphragms were subjected to peptic digestion and examined for the presence of Trichinella spiralis larvae. One diaphragm (0.08%) was found to contain T spiralis (26 larvae/g of muscle) and 4 of the slaughterhouse sera were positive (0.33% seroprevalence). Pigs in 52 herds throughout the state were also tested for ELISA antibodies. The ELISA-positive pigs were not found among the 267 pigs tested from the 52 herds.

Synthesis and anti-inflammatory activity of 2-pyridyl-2-thiobenzothiazole derivatives.

A series of novel 2-pyridyl-2-thiobenzothiazole compounds was prepared and investigated by a number of in vitro methods in order to determine their anti-inflammatory properties. Results are discussed with reference to well known NSAIDs. (3-carboxy-2-pyridyl)-2-thiobenzothiazole had the most potent anti-inflammatory activity, being 1.34 times more active than indomethacin used as reference compound.

Synthesis and antithyroid activity of 1,4,5-trialkyl 2-thioimidazole derivatives.

A series of compounds based on the structure of MTI (1-methyl-2-thioimidazole) were synthesized by condensation of alpha-hydroxyketones and alkylthioureas. The alpha-hydroxyketones were obtained by a radical reaction in the presence of sodium and the alkyl ester, while the alkylthioureas were prepared by nucleophilic addition of ammonia on an alkylisothiocyanate. The antithyroid activity of the 13 compounds prepared was evaluated in vitro by determination of the concentrations which led to a 50% inhibition (IC50) of the activity of thyroid peroxidase, and in vivo by assay of thyroid hormones levels and histological examination of the thyroid gland in rats treated chronically with the compounds. 1-methyl-4,5-dipropyl 2-thioimidazole (compound 10) was found to have the highest antithyroid activity of the 13 compounds synthesized.

[Identification of a metabolite of floctafenine in urinary calculi]. / Identification d'un métabolite de la floctafénine dans un calcul urinaire.

There are three 4-amino-quinolines used for their analgesic properties: glafenine, antrafenine and floctafenin. Urinary calculi due to glafenine have been described since 1980. Recently two cases of renal calculi containing antrafenic acid have been reported. We discovered a metabolite of floctafenin in a bladder calculus and describe its identification by infrared spectrophotometry and thin-layer chromatography.

[Aminopenicillin crystalluria: identification by infrared spectrophotometry]. / Cristalluries d'aminopénicillines: identification par spectrophotométrie infrarouge.

Renal stones and crystalluria can be characterized unambiguously by global physical methods. The authors report four cases of crystalluria induced by aminopenicillin (ampicillin and amoxicillin). Identification of these drug-induced crystalluria was made by high-pressure liquid chromatography and infrared spectrophotometry. The physico-chemical data and infrared absorption characteristics can give us diagnostic for various forms of ampicillin and amoxicillin.

Synthesis and inhibitory effects of 1,4,5-trialkyl-2-thioimidazole derivatives on platelet aggregation.

New 1,4,5-trialkyl-2-thioimidazole have been synthesized by the condensation of alpha-hydroxyketones and alkylthioureas. The in vitro platelet aggregation inhibiting effect of prepared compounds on human platelets was studied in the presence of ADP and collagen as inducers. The formation of thromboxane B2(TXB2) was inhibited. 1-isopropyl-4,5-dimethyl-2-thioimidazole has the greatest aggregation inhibiting effect, about 4 times that of aspirin. It highly inhibits the production of TXB2 (68.5% for a final concentration of 0.04 M).