Discovery of a Novel Series of Imidazopyrazine Derivatives as Potent SHP2 Allosteric Inhibitors.

Protein tyrosine phosphatase SHP2 is an oncogenic protein that can regulate different cytokine receptor and receptor tyrosine kinase signaling pathways. We report here the identification of a novel series of SHP2 allosteric inhibitors having an imidazopyrazine 6,5-fused heterocyclic system as the central scaffold that displays good potency in enzymatic and cellular assays. SAR studies led to the identification of compound , a highly potent SHP2 allosteric inhibitor.

MPGN and mixed cryoglobulinemia in a patient with hepatitis C - new treatment implications and renal outcomes.

Introduction: The association of hepatitis C virus (HCV), cryoglobulinemia, and membranoproliferative glomerulonephritis (MPGN) is well known. Treatment of underlying HCV infection has greatly improved in recent years with the introduction of direct-acting antivirals (DAA), which have demonstrated curative sustained viral response (SVR) rates for select viral genotypes with the added benefit of less drug side effects. However, a mainstay of newer DAAs is sofosbuvir, which is contraindicated in patients with severe renal impairment.

Tools, works of art, psychoanalysis.

The roots of psychoanalysis lie deep within the evolutionary history of human life and intelligence. In this article I will explore a set of evolving relationships between human beings and the artifacts they have created. The psychoanalytic treatment method is one such artifact, despite the apparent reluctance of many psychoanalysts to describe what they do in terms that might be interpreted to minimize the personal element in their work with their patients.

Reducing risk for cardiovascular disease in uninsured women: combined results from two WISEWOMAN projects.

Objective: to evaluate the effectiveness of a cardiovascular disease (CVD) risk factor reduction program for financially disadvantaged women. The program included cholesterol and blood pressure assessments and tailored physical activity and nutrition interventions.

Methods: Women who attended selected National Breast and Cervical Cancer Early Detection Program sites in North Carolina and Massachusetts received either enhanced physical activity and nutrition interventions (EI) or minimum interventions (MI).

Rapid determination of valaciclovir and acyclovir in human biological fluids by high-performance liquid chromatography using isocratic elution.

A rapid high-performance liquid chromatographic assay with isocratic elution is developed for the simultaneous quantification of valaciclovir (VACV) prodrug and its active converted compound, acyclovir (ACV), in biological fluids of treated patients. For serum, the samples are deproteinized with perchloric acid in presence of 1-methylguanosine as the internal standard (IS). For urine and dialysis liquid, the samples are diluted with a mobile phase containing the IS, then filtered.

The prisoner's dilemma: game theory and the therapeutic alliance.

My aim in this paper is to describe how the therapeutic alliance evolves during psychoanalytic treatment. Lindgren has shown that a coevolutionary process can optimize the level of cooperation by the players in the game of prisoner's dilemma. This level is reached when strategies for recognizing reliable patterns in the sequence of moves by the other player have evolved.

VIP-like immunoreactivity within neurons and perivascular neuronal processes of the human cerebral cortex.

Using indirect immunocytochemical techniques, neurons with VIP (Vasoactive Intestinal Polypeptide)-like immunoreactivity (ir) have been demonstrated in the human cerebral cortex of the parietal lobe. In all the cortical layers containing positive neurons, perivascular immunoreactive neuronal processes have been detected: in arterioles, they are located in the adventitial and smooth muscle layers; in capillaries, they establish tight anatomical relations with the endothelium-pericyte layer and the perivascular glial sheath. Bodies of positive neurons have also been seen adhering to capillary walls.

Omeprazole and lansoprazole are not inducers of cytochrome P4501A2 under conventional therapeutic conditions.

Objectives: Claims that substituted benzimidazole molecules induce cytochromes P4501A2 are still controversial. This study was undertaken to evaluate their inducing potency under conventional therapeutic conditions.

Methods: Twelve healthy non-smoking young volunteers were given 20 mg omeprazole or 30 mg lansoprazole daily, in random order, for 2 weeks, separated by a 3 week wash-out period.

Oedipus and the sphinx: triumph and catastrophe.

The downfall of Oedipus in Sophocles' most famous play, Oedipus Tyrannus, is the reversal of his triumphant entry into the city of Thebes 17 years earlier. The oracle at Delphi has told the Thebans that the plague will end only when the murderer of Laius is identified and punished. The unconscious collusion between Oedipus and the Thebans to ignore the unsolved murder breaks down.

Increased metabolism of acetaminophen in chronically alcoholic patients.

The aim of this work was to determine whether the metabolism of acetaminophen increases in chronic alcoholics, and consequently whether the production of its hepatotoxic metabolite is enhanced. For this purpose, the pharmacokinetics of acetaminophen were compared in 12 alcoholic men and 12 healthy controls. After a 12-hr fast, the patients (on the 3rd hospital day) and volunteers were given 1 g of oral acetaminophen at 8.

The Eros of dreaming.

This paper examines the aspects of dreaming derived from the principle of Eros, the life instinct as described by Freud in Beyond the Pleasure Principle. The life instinct is interpreted in information-processing terms, as the inverse of entropy. The paper emphasizes the role of condensation as a mechanism that binds together the representations of present and past events in the imagery of the dream.

Connectivity and condensation in dreaming.

Converging developments in the cognitive- and neurosciences have brought Freud's hope of a bridge between psychoanalysis and psychophysiology nearer to hand. This paper concerns the relation between dream construction and memory in terms of these new developments. The neural network architecture of memory structures in the brain is described and illustrated with simple examples.

Comparison of performance of healthy volunteers given prazepam alone or combined with ethanol. Relation to drug plasma concentrations.

The interaction between a single dose of 20 mg of prazepam and 0.5 g/kg body weight ethanol was investigated in 12 healthy male volunteers by nine objective performance tests, eight visual analogue self-rating scales and measurement of prazepam and ethanol plasma concentrations, using a double-blind three-way crossover design. The volunteers were each given three treatments (prazepam+ethanol, placebo+ethanol and prazepam alone), separated by a 2-week interval.

Comparative effects on psychomotor performance of the muscle relaxant afloqualone, alone and with ethanol.

The purpose of this study was to investigate the interaction between 40 mg afloqualone, a new centrally acting muscle relaxant and 0.5 g/kg ethanol using a double-blind three-way cross-over trial in which subjects were each given afloqualone with ethanol, ethanol alone and afloqualone alone. We first compared the effects of 40 mg oral afloqualone and 15 mg diazepam (considered as a reference drug) on the psychomotor and cognitive performance and muscular relaxation of 12 healthy male volunteers.

Enhancement of propoxyphene bioavailability by ethanol. Relation to psychomotor and cognitive function in healthy volunteers.

The interaction between a single oral dose of 130 mg propoxyphene and 0.5 g/kg body weight ethanol was investigated in 12 healthy male volunteers by 9 objective performance tests, 8 visual analogue self-rating scales and the measurement of plasma propoxyphene, norpropoxyphene and ethanol concentrations, using a double-blind threeway crossover design. Volunteers were each given one of three treatments, propoxyphene + ethanol, placebo + ethanol and propoxyphene alone, separated by a two week interval.

Comparison of the effect of two prazepam formulations on psychomotor and cognitive function in healthy volunteers.

A double-blind crossover design was used to evaluate the effect of two different formulations of prazepam, on motor and cognitive functions and subjective symptoms. Ten healthy male volunteers received 20 mg of prazepam both in tablet and liquid (as drops) formulation, separated by a 1 week interval. All subjects completed a battery of 9 performance tests 2.

Day residue and screen memory in Freud's dream of the botanical monograph.

Freud's theory of dream construction allowed the censorship to intervene only when a repressed infantile wish emerged from the unconscious. In his (1899) paper on screen memories, however, he proposed a mechanism for the defensive displacement of current events as they are sorted for introduction into permanent memory. I suggest that Freud was actually describing the conflictual process through which the day residue of the dream is formed.

In vivo determination of the caloric value of gum arabic in the male rat--biological data.

Sprague-Dawley male rats were given normal diets (UAR A 03) containing various amounts of gum arabic, sucrose and lignin for eight consecutive weeks. The caloric values of the diets were derived by utilizing the indirect method comparing the slopes from food consumption and weight gain curves. While the data obtained from sucrose diets showed that these diets caused a clear incremental effect on energy production with respect to both test animals and controls, and data from lignin diets were found to produce a negative effect on energy yields, gum arabic diets produced results indicating that at certain levels of intake, gum arabic may contribute energy values slightly superior to those of lignin (0 cal-g), possibly between zero and 1 cal/g.

Recovery of early memories associated with reported dream imagery.

In recent years dreaming has been characterized as an information-processing activity that functions adaptively to match new experience with representations of past events already stored in long-term memory. Nine patients who reported dreams in psychotherapy were asked expressly if the dream imagery recalled a specific event from early in their lives. Of 50 consecutively reported dreams, 46 were associated with early events whose imagery appeared in the dream.

Deconstructing the manifest dream.

A major part of the analyst's task is to discover the basis for the patient's misidentification of his present life situation with significant but threatening events of his earlier life, now repressed and inaccessible to conscious recall. Reconstructing the patient's history is a crucial step in this process of discovery, but the dynamic relation between the present and the past must be reconstructed as well. The structure of the manifest dream contains the key to this relation.