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If Health Maintenance Organizations (HMOs) are to survive and prosper, they must abide by a large volume of potentially disruptive laws and regulations at the federal, state, and local levels. Some have suffered extreme financial loss and even been driven out of business because of legal transgressions. This study explores the ability of middle managers in large and small HMOs to distinguish between legal and illegal practices in light of federal laws. The study uncovered evidence of lack of this ability especially for managers in small HMOs. Various remedial measures are proposed for this problem.

Background: One of the earliest steps in heart formation is the generation of two chambers, as cardiogenic cells deployed in the epithelial sheet of mesoderm converge to form the nascent heart tube. What guides this transformation to organotypic form is not known., Results: We have identified a small molecule, concentramide, and a genetic mutation called heart-and-soul (has) that disrupt heart patterning. Both cause the ventricle to form within the atrium. Here, we show that the has gene encodes PKC lambda. The effect of the has mutation is to disrupt epithelial cell-cell interactions in a broad range of tissues. Concentramide does not disrupt epithelial interactions, but rather shifts the converging heart field rostrally. What is shared between the concentramide and has effects is a reversal of the order of fusion of the anterior and posterior ends of the heart field., Conclusions: The polarity of cardiac tube assembly is a critical determinant of chamber orientation and is controlled by at least two distinct molecular pathways. Combined chemical/genetic dissection can identify nodal points in development, of special importance in understanding the complex patterning events of organogenesis.

Like most businesses, online pharmacy companies will only be successful if they make sure customers are satisfied with the service they receive. But what attributes of service quality lead to satisfaction and dissatisfaction? This study identified 19 Internet pharmacy service quality dimensions in three categories: (1) product cost and availability, (2) customer service, and (3) the online information system. Our analysis uncovered attributes that tend to determine consumer satisfaction and points out ways to improve overall service quality in the Internet pharmacy arena.

Much has been learned about vertebrate development by random mutagenesis followed by phenotypic screening and by targeted gene disruption followed by phenotypic analysis in model organisms. Because the timing of many developmental events is critical, it would be useful to have temporal control over modulation of gene function, a luxury frequently not possible with genetic mutants. Here, we demonstrate that small molecules capable of conditional gene product modulation can be identified through developmental screens in zebrafish. We have identified several small molecules that specifically modulate various aspects of vertebrate ontogeny, including development of the central nervous system, the cardiovascular system, the neural crest, and the ear. Several of the small molecules identified allowed us to dissect the logic of melanocyte and otolith development and to identify critical periods for these events. Small molecules identified in this way offer potential to dissect further these and other developmental processes and to identify novel genes involved in vertebrate development.

The FKBP12-rapamycin associated protein (FRAP, also RAFT, mTOR) belongs to a family of phosphatidylinositol kinase-related kinases. These kinases mediate cellular responses to stresses such as DNA damage and nutrient deprivation in a variety of eukaryotes from yeast to humans. FRAP regulates G(1) cell cycle progression and translation initiation in part by controlling the phosphorylation states of a number of translational and cell cycle regulators. Although FRAP is known to be phosphorylated in vivo and to phosphorylate several proteins (including itself) in vitro, FRAP's phosphorylation sites and substrate specificity are unknown. We report here the identification of a FRAP autophosphorylation site. This site, Ser-2481, is located in a hydrophobic region near the conserved carboxyl-terminal FRAP tail. We demonstrate that the COOH-terminal tail is required for FRAP kinase activity and for signaling to the translational regulator p70(s6k) (ribosomal subunit S6 kinase). Phosphorylation of wild-type but not kinase-inactive FRAP occurs at Ser-2481 in vivo, suggesting that Ser-2481 phosphorylation is a marker of FRAP autokinase activity in cells. FRAP autophosphorylation is blocked completely by wortmannin treatment but not by rapamycin treatment, amino acid deprivation, or serum withdrawal, treatments that lead to acute dephosphorylation of eIF4E-binding protein (4E-BP1) and p70(s6k). Ser-2481 phosphorylation increases slightly upon c-Akt/PKB activation and dramatically upon calyculin A treatment of T-cells. These results suggest that FRAP-responsive dephosphorylation of 4E-BP1 and p70(s6k) occurs through a mechanism other than inhibition of intrinsic FRAP kinase activity.

The identification of PDK1 as a kinase that phosphorylates the AGC family of kinases led to a hunt for 'PDK2', a hypothetical regulated kinase(s) that would be required for full activation of the AGC kinases. Recent findings suggest that the elusive PDK2 may actually be a familiar kinase with an atypical associate.

The FKBP12-rapamycin-associated protein (FRAP; also called RAFT1/mTOR) regulates translation initiation and entry into the cell cycle. Depriving cells of amino acids or treating them with the small molecule rapamycin inhibits FRAP and results in rapid dephosphorylation and inactivation of the translational regulators 4E-BP1(eukaryotic initiation factor 4E-binding protein 1) and p70(s6k) (the 70-kDa S6 kinase). Data published recently have led to the view that FRAP acts as a traditional mitogen-activated kinase, directly phosphorylating 4E-BP1 and p70(s6k) in response to mitogenic stimuli. We present evidence that FRAP controls 4E-BP1 and p70(s6k) phosphorylation indirectly by restraining a phosphatase. A calyculin A-sensitive phosphatase is required for the rapamycin- or amino acid deprivation-induced dephosphorylation of p70(s6k), and treatment of Jurkat I cells with rapamycin increases the activity of the protein phosphatase 2A (PP2A) toward 4E-BP1. PP2A is shown to associate with p70(s6k) but not with a mutated p70(s6k) that is resistant to rapamycin- and amino acid deprivation-mediated dephosphorylation. FRAP also is shown to phosphorylate PP2A in vitro, consistent with a model in which phosphorylation of PP2A by FRAP prevents the dephosphorylation of 4E-BP1 and p70(s6k), whereas amino acid deprivation or rapamycin treatment inhibits FRAP's ability to restrain the phosphatase.

The identification and measurement of service quality are critical factors that are responsible for customer satisfaction. This article identifies 11 attributes that define quality of care and patient satisfaction and reveals various gaps among the patient, physician, and administrator groups in the perceived importance of those dimensions. Managerial implications for patient-focused health care are discussed.

Protein phosphatases participate in the regulation of a variety of cellular processes. Control of their enzymatic activity and specificity is made possible largely by an array of regulatory subunits. Novel serine/threonine phosphatases--PP4 and PP6 in human cells--have been discovered recently, for which regulatory subunits are yet to be identified. We report here the identification of a potential regulatory subunit of these phosphatases. Using the yeast two-hybrid system, we have found that alpha 4, a previously identified phosphoprotein, associates constitutively with the catalytic subunits of PP4, PP6, and both isoforms of PP2A. These interactions have been confirmed by direct binding and do not require phosphorylation of alpha 4, although it is unclear whether alpha 4 phosphorylation has any effect on its association with the phosphatases. The binding activity appears to reside in the N-terminal 50 amino acids of the phosphatases, consistent with a previous observation that the first 55 residues of PPV, a Drosophila homolog of PP6, may harbor the element for regulation. alpha 4 shares 37% sequence homology with Tap42, an S. cerevisiae protein that has been reported to associate with PP2A and Sit4 (yeast homolog of PP6) and comprises a regulatory component in the rapamycin-sensitive Tor signalling pathway. By analogy, alpha 4 and its associated phosphatases may participate in the mammalian rapamycin-sensitive pathway mediated by FRAP.

The identification of 3-phosphoinositide-dependent kinase 1 (PDK1) as one of the elusive 70 kDa S6 kinase kinases has filled a gap in the signaling pathway by which extracellular receptors regulate translation. Will it cause us to reconsider the relationships between previously identified members of the pathway?

PE, a common and serious pulmonary problem, most often results as a complication of DVT in the lower extremities. There are no specific symptoms or signs that allow a clinical diagnosis of PE. The best approach to the diagnosis is controversial and is at least partially dependent on the diagnostic capabilities and expertise available at a given hospital. Pulmonary arteriography is the definitive diagnostic test and should be considered in patients with results of less-than-high probability V-Q scans, those at high risk of bleeding complications with anticoagulation therapy, and those considered candidates for thrombolytic therapy.