The New Old (and Old New) Medical Model:Four Decades Navigating the Biomedical and Psychosocial Understandings of Health and Illness

The importance of how disease and illness are conceptualised lies in the fact that such definition is paramount to understand the boundaries and scope of responsibility associated with medical work. In this paper, we aim to provide an overview of the interplay of these understandings in shaping the nature of medical work, philosophically, and in practice. We first discuss the emergence of the biopsychosocial model as an attempt to both challenge and broaden the traditional biomedical model. Then, we outline the main criticisms associated with the biopsychosocial model and note a range of contributions addressing the shortcomings of the model as initially formulated. Despite recurrent criticisms and uneven uptake, the biopsychosocial model has gone on to influence core aspects of medical practice, education, and research across many areas of medicine. One of these areas is adolescent medicine, which provides a particularly good exemplar to examine the contemporary challenges associated with the practical application of the biopsychosocial model. We conclude that a more optimal use of existing bodies of evidence, bringing together evidence-based methodological advances of the biopsychosocial model and existing evidence on the psychosocial needs associated with specific conditions/populations, can help to bridge the gap between philosophy and practice

Purification, Characterization and Distribution of a Calmodulin-Dependent Protein Kinase from Rat Brain Cytosol

Tubulin is a major endogenous substrate for Ca(\u272+)- calmodulin-dependent kinase activity in rat brain cytosol. This dissertation details the purification and characterization of a calmodulin-dependent tubulin kinase from rat brain cytosol. The kinase, purified from chelated brain cytosol by sequential chromatography on phosphocellulose, calmodulin-affinity resin, and Fractogel TSK-55F, contains two calmodulin-binding, autophosphorylating subunits of 52,000 and 63,000 daltons, designated rho and sigma, respectively. The kinase holoenzyme complex has a native molecular weight of 600,000 daltons. Both kinase subunits demonstrate isoelectric points near neutrality. The kinase phosphorylated microtubule-associated protein 2, alpha tubulin and beta tubulin as major substrates. Calmodulin-dependent phosphorylation of these proteins occurred on different sites than Mg(\u272+)/cAMP-dependent phosphorylation. The calmodulin kinase displayed a characteristic pattern of 60% of beta tubulin phosphorylation on threonine residues.The endogenous association of this kinase with tubulin was established through the isolation of a tubulin-calmodulin kinase complex from rat brain cytosol by sequential chromatography on DEAE-cellulose, Sephacryl S-300 and Fractogel TSK-65F. The kinase complexed with tubulin was identical by all criteria including subunit composition, subunit properties, and kinase function to the purified calmodulin-dependent kinase. The association of the kinase with microtubule preparations was also demonstrated. Microtubule preparations contain calmodulin-dependent kinase activity with similar properties to the purified calmodulin kinase. These data suggest that calmodulin-dependent kinase may mediate the destabilizing effects of calmodulin on microtubules.Finally, the major protein component of the postsynaptic density was shown to be essentially identical to the rho subunit of purified calmodulin-dependent kinase. Thus, the apparent pansynaptic localization of this kinase implicates it as an important regulator of cytoskeletal dynamics

Centrosomal AKAP350 modulates the G1/S transition

AKAP350 (AKAP450/AKAP9/CG-NAP) is an A-kinase anchoring protein, which recruits multiple signaling proteins to the Golgi apparatus and the centrosomes. Several proteins recruited to the centrosomes by this scaffold participate in the regulation of the cell cycle. Previous studies indicated that AKAP350 participates in centrosome duplication. In the present study we specifically assessed the role of AKAP350 in the progression of the cell cycle. Our results showed that interference with AKAP350 expression inhibits G1/S transition, decreasing the initiation of both DNA synthesis and centrosome duplication. We identified an AKAP350 carboxyl-terminal domain (AKAP350CTD), which contained the centrosomal targeting domain of AKAP350 and induced the initiation of DNA synthesis. Nevertheless, AKAP350CTD expression did not induce centrosomal duplication. AKAP350CTD partially delocalized endogenous AKAP350 from the centrosomes, but increased the centrosomal levels of the cyclin-dependent kinase 2 (Cdk2). Accordingly, the expression of this AKAP350 domain increased the endogenous phosphorylation of nucleophosmin by Cdk2, which occurs at the G1/S transition and is a marker of the centrosomal activity of the cyclin E-Cdk2 complex. Cdk2 recruitment to the centrosomes is a necessary event for the development of the G1/S transition. Altogether, our results indicate that AKAP350 facilitates the initiation of DNA synthesis by scaffolding Cdk2 to the centrosomes, and enabling its specific activity at this organelle. Although this mechanism could also be involved in AKAP350-dependent modulation of centrosomal duplication, it is not sufficient to account for this process.Fil: Mattaloni, Stella Maris. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Ferretti, Anabela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Tonucci, Facundo Mauro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Favre, Cristian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Goldenring, James R.. Vanderbilt University; Estados UnidosFil: Larocca, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentin

Darinaparsin Is a Multivalent Chemotherapeutic Which Induces Incomplete Stress Response with Disruption of Microtubules and Shh Signaling

Chemotherapeutics and other pharmaceuticals are common sources of cellular stress. Darinaparsin (ZIO-101) is a novel organic arsenical under evaluation as a cancer chemotherapeutic, but the drug's precise mechanism of action is unclear. Stress granule formation is an important cellular stress response, but the mechanisms of formation, maintenance, and dispersal of RNA-containing granules are not fully understood. During stress, small, diffuse granules initially form throughout the cytoplasm. These granules then coalesce near the nucleus into larger granules that disperse once the cellular stress is removed. Complete stress granule formation is dependent upon microtubules. Human cervical cancer (HeLa) cells, pre-treated with nocodazole for microtubule depolymerization, formed only small, diffuse stress granules upon sodium arsenite treatment. Darinaparsin, as a single agent, also induced the formation of small, diffuse stress granules, an effect similar to that of the combination of nocodazole with sodium arsenite. Darinaparsin inhibited the polymerization of microtubules both in vivo and in vitro. Interestingly, upon removal of darinaparsin, the small, diffuse stress granules completed formation with coalescence in the perinuclear region prior to disassembly. These results indicate that RNA stress granules must complete formation prior to disassembly, and completion of stress granule formation is dependent upon microtubules. Finally, treatment of cells with darinaparsin led to a reduction in Sonic hedgehog (Shh) stimulated activation of Gli1 and a loss of primary cilia. Therefore, darinaparsin represents a unique multivalent chemotherapeutic acting on stress induction, microtubule polymerization, and Shh signaling