C-terminal modifications of nonpeptide renin inhibitors: improved oral bioavailability via modification of physicochemical properties.

We describe the development of a series of soluble, potent, and bioavailable nonpeptide renin inhibitors. These inhibitors derived from a series of novel nonpeptide renin inhibitors which were recently identified in our laboratories, by alteration of the nature of the C-terminus (P2') of the molecules. Introduction of basic substituents into modified hydroxyethylene dipeptide isosteres gave inhibitors with improved solubility as well as improved potency against human plasma renin. In addition, these modifications produced inhibitors which displayed markedly improved intraduodenal bioavailability in both the ferret and cynomolgus monkey. We also present data which demonstrate excellent efficacy in the monkey for A-74273 (65), with an intraduodenal bioavailability of 16 +/- 4% in the monkey, compared to 1.7 +/- 0.5% for the dipeptide renin inhibitor enalkiren (A-64662, 75). A-74273 is an example of a nonpeptide inhibitor which possesses a good balance of the desirable properties of potency, solubility, and lipophilicity and which is well absorbed into the intestine.     

Identifying potential indicators of the quality of end-of-life cancer care from administrative data.

PURPOSE: To explore potential indicators of the quality of end-of-life services for cancer patients that could be monitored using existing administrative data. METHODS: Quality indicators were identified and assessed by literature review for proposed indicators, focus groups with cancer patients and family members to assess candidate indicators and generate new ideas, and an expert panel ranking the meaningfulness and importance of each potential indicator using a modified Delphi approach. RESULTS: There were three major concepts of poor quality of end-of-life cancer care that could be examined using currently-available administrative data (such as Medicare claims): institution of new anticancer therapies or continuation of ongoing treatments very near death; a high number of emergency room visits, inpatient hospital admissions, or intensive care unit days near the end of life; and a high proportion of patients never enrolled in hospice, only admitted in the last few days of life, or dying in an acute-care setting. Concepts such as access to psychosocial and other multidisciplinary services and pain and symptom control are important and may eventually be feasible, but they cannot currently be applied in most data systems. Indicators based on limiting the use of treatments with low probability of benefit or indicators based on economic efficiency were not acceptable to patients, family members, or physicians. CONCLUSION: Several promising claims-based quality indicators were identified that, if found to be valid and reliable within data systems, could be useful in identifying health-care systems in need of improving end-of-life services.     

The striatal-enriched protein tyrosine phosphatase gates long-term potentiation and fear memory in the lateral amygdala.

BACKGROUND: Formation of long-term memories is critically dependent on extracellular-regulated kinase (ERK) signaling. Activation of the ERK pathway by the sequential recruitment of mitogen-activated protein kinases is well understood. In contrast, the proteins that inactivate this pathway are not as well characterized. METHODS: Here we tested the hypothesis that the brain-specific striatal-enriched protein tyrosine phosphatase (STEP) plays a key role in neuroplasticity and fear memory formation by its ability to regulate ERK1/2 activation. RESULTS: STEP co-localizes with the ERKs within neurons of the lateral amygdala. A substrate-trapping STEP protein binds to the ERKs and prevents their nuclear translocation after glutamate stimulation in primary cell cultures. Administration of TAT-STEP into the lateral amygdala (LA) disrupts long-term potentiation (LTP) and selectively disrupts fear memory consolidation. Fear conditioning induces a biphasic activation of ERK1/2 in the LA with an initial activation within 5 minutes of training, a return to baseline levels by 15 minutes, and an increase again at 1 hour. In addition, fear conditioning results in the de novo translation of STEP. Inhibitors of ERK1/2 activation or of protein translation block the synthesis of STEP within the LA after fear conditioning. CONCLUSIONS: Together, these data imply a role for STEP in experience-dependent plasticity and suggest that STEP modulates the activation of ERK1/2 during amygdala-dependent memory formation. The regulation of emotional memory by modulating STEP activity may represent a target for the treatment of psychiatric disorders such as posttraumatic stress disorder (PTSD), panic, and anxiety disorders.     

Evaluating anxiety in patients attending optometric practice

Although anxiety is a well-established obstacle to the delivery of effective health care, there have been no attempts to measure it in the optometric consulting room. In this paper, we introduce physiological and psychological techniques that may be used to evaluate anxiety and arousal in the consulting room and present data from a small group of patients attending for a routine eye examination. Specifically, arousal was assessed before, during, and after the examination by measuring skin conductance in five patients. Anxiety was evaluated using the State-Trait Anxiety Inventory. Our data confirm the ability of these techniques to quantify arousal and anxiety in the optometric consulting room and reveal a previously unknown but important facet of the eye examination. We conclude that these techniques are suitable for use in further experimental work and may be used to identify factors capable of reducing anxiety in the optometric consulting room.     

Neuroimaging studies of children with serious emotional disturbances: a selective review.

OBJECTIVES: To critically review and integrate, from a developmental perspective, recent magnetic resonance imaging (MRI) studies of 4 childhood psychiatric disorders: schizophrenia, bipolar disorder (BD), attention-deficit hyperactivity disorder (ADHD), and major depressive disorder (MDD). METHOD: We reviewed published reports in refereed journals. We briefly describe the major findings with respect to the brain morphometry, chemistry, and function of children with psychiatric disorders and synthesize the reports in a summary to update clinicians. RESULTS: Some cortical grey matter abnormalities associated with schizophrenia appear to predate the onset of frank psychosis and continue to advance after the onset of psychosis, at least in more severe cases. Pediatric BD is associated with abnormalities in a circuit, thought to be involved in mood regulation, that encompasses the amygdala, striatum, and ventral PFC. Frontostriatal abnormalities are reported consistently in ADHD, potentially reflecting abnormalities in the development of cognitive control. Children with MDD show prefrontal cortical alterations that may differ in familial and nonfamilial subtypes of MDD. CONCLUSIONS: Results from neuroimaging studies of childhood psychopathology reveal abnormalities in the developmental trajectories observed in healthy children. Although MRI has increased our understanding of the pathophysiology of these disorders, routine neuroimaging for children with severe emotional disturbances is not indicated for diagnostic purposes.