Caring to achieve the maximum independence possible: a synthesis of qualitative evidence on older adults' adaptation to dependency.

AIMS AND OBJECTIVES: To understand the process of adaptation to dependency in older adults and their families. BACKGROUND: Dependency and family care giving are attracting the attention of policymakers, service providers and researchers. DESIGN: An interpretative synthesis of qualitative studies has been conducted. METHODS: An extensive search without time and idiom limitations was conducted using the main databases (MEDLINE, CINAHL, EMBASE, PsycINFO, SSCI, LILACS, CUIDEN, Cochrane Library and JBI): personal communication from expert panel was used to detect filters strategies to find qualitative studies; these strategies were combined with search terms for dependence in older adults. The studies (2164 potentially relevant papers) were judged by two reviewers based on reading title, abstract, keywords and/or full text (English, Spanish, French and Portuguese) to determine their inclusion. After, 203 papers were critically appraised by two reviewers (disagreements were resolved by discussions). Finally, the synthesis of the 20 studies with best interpretative character was carried out based on the principles and procedures of Grounded Theory. RESULTS: The findings were related to the process of adaptation to dependency, the factors and the strategies used, the emotions, perceptions and feelings of care givers and older adults. The central category that emerged was 'Caring to achieve the maximum independence possible', and this could be seen as a transition period in which older adults and their families progressed in a mutually determined adaptation process. This category is made up of several redefinitions of concepts, phases, adaptation strategies and final responses to the process. CONCLUSIONS: The findings show the interconnected nature of physical, material, social and emotional aspects of care; and the profound social impact of providing and receiving care. Relevance to clinical practice. The nurses can assist families and older adults to enhance adaptation to dependency, anticipating and helping to redefine the concepts of care.

Research protocol: a synthesis of qualitative studies on the process of adaptation to dependency in elderly persons and their families.

BACKGROUND: Dealing with dependency in the elderly and their families leads us to explore the life experience of those involved together with the processes of adaptation to this condition. A number of original studies have been published which, following a qualitative methodology, have dealt with both dimensions. OBJECTIVES: 1) To present a synthesis of the qualitative evidence available on the process of adaptation to dependency in elderly persons and their families; 2) to conduct an in-depth study into the experiences and strategies developed by both to optimise their living conditions; 3) to enable standards of action/intervention to be developed in the caregiving environment.A synthesis of qualitative studies is projected with an extensive and inclusive bibliography search strategy. The primary search will focus on the major databases (CINAHL, MEDLINE, EMBASE, PsycInfo, PSICODOC, Cochrane Library, JBI, EMBASE, LILACS, CUIDEN, CUIDEN qualitative, CUIDATGE, British Nursing Index, SSCI). The secondary search will be conducted in articles taken from the references to studies identified in the articles and reports and the manual search in congresses and foundation papers. Article quality will be assessed by the guide proposed by Sandelowski & Barroso and data extraction done using the QARI data extraction form proposed by the Joanna Briggs Institute for Evidence-Based Practice.The synthesis of the findings will be based on the principles and procedures of grounded theory: coding, identification and relationship between categories, and synthesis using constant comparison as a strategy. DISCUSSION: This synthesis of qualitative evidence will enable us to detect health needs as perceived by the receivers in their own interaction contexts.

Transplantation of a liver with the C282Y mutation into a recipient heterozygous for H63D results in iron overload.

Hemochromatosis is a common hereditary disease associated with progressive iron overload eventually leading to parenchymal damage of the liver, heart, pancreas, and other organs. Liver transplantation has been the single most important therapy to extend long-term survival in patients with a variety of acute and chronic liver diseases. We report a case of inadvertent transplantation of a hemochromatotic liver into a nonhemochromatotic recipient, resulting in rapid iron overload. Neither the recipient nor the donor had iron overload at the time of transplantation, but the donor liver was subsequently found to be homozygous for C282Y mutation. The report includes 8 years follow-up, serial biopsies, and molecular studies. Iron overload in our patient transplanted with a C282Y homozygous liver provides an "in vivo" model for the pathophysiology of hemochromatosis and further supports liver playing a primary role in the maintenance of iron hemostasis rather intestine being the sole regulatory site.

A critical role of Sp1 transcription factor in regulating gene expression in response to insulin and other hormones.

Specificity protein 1 (Sp1) belongs to a family of ubiquitously expressed, C(2)H(2)-type zinc finger-containing DNA binding proteins that activate or repress transcription of many genes in response to physiological and pathological stimuli. There is emerging evidence to indicate that in addition to functioning as 'housekeeping' transcription factors, members of Sp family may be key mediators of gene expression induced by insulin and other hormones. The founding member of the family, Sp1, by virtue of its multi-domain organization, potential for posttranslational modifications and interactions with numerous transcription factors, represents an ideal mediator of nuclear signaling in response to hormones. Insulin regulates the sub-cellular localization, stability and trans-activation potential of Sp1 by dynamically modulating its post-translational modification by O-linked beta-N-acetylglucosamine (O-GlcNAc) or phosphate residues. We briefly review the recent literature demonstrating that an involvement of Sp-family of transcription factors in the regulation of differential gene expression in response to hormones is more common than previously appreciated and may represent a key regulatory mechanism.

Sarcoidosis mimicking primary sclerosing cholangitis requiring liver transplantation.

Sarcoidosis is a systemic granulomatous disease of unknown etiology. The association of the cholestatic pattern usually seen in sarcoidosis, with biliary duct changes resembling primary sclerosing cholangitis (PSC) is rare. Liver transplantation permits the histological evaluation of the complete explanted liver, making the diagnosis more reliable. In conclusion we present our experience with two patients with sarcoidosis requiring liver transplantation, who presented with clinical and radiological findings characteristics of primary sclerosing cholangitis.

[Prevalence of dyslipidemia in a family medicine clinic]. / Prevalencia y comorbilidad de dislipidemias en el primer nivel de atención.

OBJECTIVES: To evaluate the prevalence of dyslipidemia and comorbidity in adults older than 20 years attending to the family medicine clinic number 20 of Instituto Mexicano del Seguro Social and to compare it with the prevalence in Mexico. METHOD: the study was conducted in 2005 by using a cross-sectional design; dyslipidemia was ascertained by measuring total cholesterol and triglycerides. Additional variables were: gender, age, health status, and diagnosis of diabetes, hypertension, overweight, and obesity. A standardization procedure and a dry run were carried out before beginning the data collection phase. RESULTS: The study included 165 participants, 35.2 % had hypercholesterolemia and 63.6 % had hypertriglyceridemia. According to the variables, 20.0% of people aged 40 to 59 years of age; 57.1% of women; 40.9% of overweight, 40.9% of obese and 49.5% of healthy patients had hypertriglyceridemia; while 68.9% of women; 44.8% of patients with hypertension, and 51.7 % of overweight patients had hypercholesterolemia. CONCLUSION: The prevalence of hypertriglyceridemia and hypercholesterolemia were significantly different from previous reports (hypercholesterolemia z< or =2.83; p < 0.001; hypertriglyceridemia z = 7.83; p < 00.1), being higher in women and increasing with aging.

Insulin stimulates and diabetes inhibits O-linked N-acetylglucosamine transferase and O-glycosylation of Sp1.

Insulin stimulates both the biosynthesis of transcription factor Sp1 and its O-linked N-acetylglucosaminylation (O-GlcNAcylation), which promotes nuclear localization of Sp1 and its ability to transactivate calmodulin (CaM) gene transcription. To investigate this further, we incubated H-411E liver cells with insulin (10,000 microU/ml) and quantified the subcellular distribution of O-GlcNAc transferase (OGT) and O-GlcNAc-modified Sp1. We also examined the phosphorylation of Sp1 using both Western blot and incorporation of 32P into Sp1. The results demonstrate that insulin, but not glucagon, stimulates OGT synthesis and enhances cytosolic staining of OGT (histochemical). Insulin increases O-GlcNAc-Sp1, which peaks at 30 min, followed by decline at 4 h. In contrast, insulin initiates phosphorylation of Sp1 early, followed by a continued increase in phosphorylated Sp1 (PO4-Sp1) at 4 h. A reciprocal relationship between O-GlcNAc-Sp1 and PO4-Sp1 was observed. To explore the pathophysiological relevance, we localized OGT in liver sections from streptozotocin (STZ)-induced diabetic rats. We observed that staining of OGT in STZ-induced diabetic rat liver is clearly diminished, but it was substantially restored after 6 days of insulin treatment. We conclude that insulin stimulates CaM gene transcription via a dynamic interplay between O-glycosylation and phosphorylation of Sp1 that modulates stability, mobility, subcellular compartmentalization, and activity.

Paradoxical regulation of Sp1 transcription factor by glucagon.

Insulin is a potent regulator of Sp1 transcription factor. To examine if glucagon, which usually antagonizes insulin, regulates Sp1, we assessed the levels of Sp1 by Western blotting from H-411E cells exposed to glucagon with or without insulin. Glucagon alone (1.5 x 10(-9) to 1.5 x 10(-5) M) stimulated Sp1 accumulation but inhibited insulin's (10,000 microU/ml) stimulatory effect on Sp1. We also assessed the effect of TNF-alpha, wortmannin, a PI3K inhibitor, and cAMP-dependent protein kinase inhibitor on Sp1 accumulation. While TNF-alpha (5 ng/ml) blocked insulin-stimulated Sp1, it failed to block stimulation of Sp1 by glucagon (1.5 x 10(-5) M). Similarly, wortmannin inhibited insulin- but not glucagon-stimulated Sp1, whereas protein kinase inhibitor had an opposite effect. Thus, insulin acts primarily via PI3K, and glucagon apparently stimulates through a cAMP-dependent pathway. Insulin increased the staining intensity of Sp1 seen exclusively in the nuclei of H-411E cells. Sp1 was demonstrable in both nucleus and cytoplasm after glucagon treatment. Finally, as judged by immunoblotting to specific antibody, insulin but not glucagon, stimulated O-glycosylation of Sp1. Thus, unique signaling mechanisms mediate the response of Sp1 to glucagon in the presence or absence of insulin.

CpG DNA prevents liver injury and shock-mediated death by modulating expression of interleukin-1 receptor-associated kinases.

Tumor necrosis factor-alpha (TNF-alpha) produced by macrophages in response to CpG DNA induces severe liver injury and subsequent death of D-galactosamine (D-GalN)-sensitized mice. In the present study we demonstrate that mice pre-exposed to CpG DNA are resistant to liver injury and death induced by CpG DNA/D-GalN. CpG DNA/D-GalN failed to induce TNF-alpha production and hepatocyte apoptosis in the mice pre-exposed to CpG DNA. In addition, macrophages isolated from the CpG DNA-pretreated mice showed suppressed activation of MAPKs and NF-kappaB and production of TNF-alpha in response to CpG DNA, indicating that the CpG DNA-mediated protection of CpG DNA/D-GalN-challenged mice is due to the hyporesponsiveness of macrophages to CpG DNA. CpG DNA pretreatment in vivo inhibited expression of interleukin-1 receptor-associated kinase (IRAK)-1 while inducing IRAK-M expression in macrophages. Suppressed expression of IRAK-1 was responsible for the macrophage hyporesponsiveness to CpG DNA. However, increased expression of IRAK-M was not sufficient to render macrophages hyporesponsive to CpG DNA but was required for induction of the optimal level of macrophage hyporesponsiveness. Taken together, reduced expression of IRAK-1 and increased expression of IRAK-M after CpG DNA pretreatment resulted in the hyporesponsiveness of macrophages that leads to the protection of mice from hepatic injury and death caused by CpG DNA/D-GalN.

Insulin dynamically regulates calmodulin gene expression by sequential o-glycosylation and phosphorylation of sp1 and its subcellular compartmentalization in liver cells.

O-glycosylation and phosphorylation of Sp1 are thought to modulate the expression of a number of genes in normal and diabetic state. Sp1 is an obligatory transcription factor for constitutive and insulin-responsive expression of the calmodulin gene (Majumdar, G., Harmon, A., Candelaria, R., Martinez-Hernandez, A., Raghow, R., and Solomon, S. S. (2003) Am. J. Physiol. 285, E584-E591). Here we report the temporal dynamics of accumulation of total, O-GlcNAc-modified, and phosphorylated Sp1 in H-411E hepatoma cells by immunohistochemistry with monospecific antibodies, confocal microscopy, and matrix-assisted laser desorption and ionization-time of flight mass spectrometry. Insulin elicited sequential and reciprocal post-translational modifications of Sp1. The O-glycosylation of Sp1 and its nuclear accumulation induced by insulin peaked early (approximately 30 min), followed by a steady decline of O-GlcNAc-modified Sp1 to negligible levels by 240 min. The accumulation of phosphorylated Sp1 in the nuclei of insulin-treated cells showed an opposite pattern, increasing steadily until reaching a maximum around 240 min after treatment. Analyses of the total, O-GlcNAc-modified, or phosphorylated Sp1 by Western blot and mass spectrometry corroborated the sequential and reciprocal control of post-translational modifications of Sp1 in response to insulin. Treatment of cells with streptozotocin (a potent inhibitor of O-GlcNAcase) led to hyperglycosylation of Sp1 that failed to be significantly phosphorylated. The mass spectrometry data indicated that a number of common serine residues of Sp1 undergo time-dependent, reciprocal O-glycosylation and phosphorylation, paralleling its rapid translocation from cytoplasm to the nucleus. Later, changes in the steady state levels of phosphorylated Sp1 mimicked the enhanced steady state levels of calmodulin mRNA seen after insulin treatment. Thus, O-glycosylation of Sp1 appears to be critical for its localization into the nucleus, where it undergoes obligatory phosphorylation that is needed for Sp1 to activate calmodulin gene expression.

CpG DNA-mediated induction of acute liver injury in D-galactosamine-sensitized mice: the mitochondrial apoptotic pathway-dependent death of hepatocytes.

Unmethylated CpG motifs present in bacterial DNA (CpG DNA) induce innate inflammatory responses, including rapid induction of proinflammatory cytokines. Although innate inflammatory responses induced by CpG DNA and other pathogen-associated molecular patterns are essential for the eradication of infectious microorganisms, excessive activation of innate immunity is detrimental to the host. In this study, we demonstrate that CpG DNA, but not control non-CpG DNA, induces a fulminant liver failure with subsequent shock-mediated death by promoting massive apoptotic death of hepatocytes in D-galactosamine (D-GalN)-sensitized mice. Inhibition of mitochondrial membrane permeability transition pore opening or caspase 9 activity in vivo protects D-GalN-sensitized mice from the CpG DNA-mediated liver injury and death. CpG DNA enhanced production of proinflammatory cytokines in D-GalN-sensitized mice via a TLR9/MyD88-dependent pathway. In addition, CpG DNA failed to induce massive hepatocyte apoptosis and subsequent fulminant liver failure and death in D-GalN-sensitized mice that lack TLR9, MyD88, tumor necrosis factor (TNF)-alpha, or TNF receptor I but not interleukin-6 or -12p40. Taken together, our results provide direct evidence that CpG DNA induces a severe acute liver injury and shock-mediated death through the mitochondrial apoptotic pathway-dependent death of hepatocytes caused by an enhanced production of TNF-alpha through a TLR9/MyD88 signaling pathway in D-GalN-sensitized mice.

O-glycosylation of Sp1 and transcriptional regulation of the calmodulin gene by insulin and glucagon.

Both insulin and glucagon stimulate steady-state levels of Sp1 transcription factor, but only insulin stimulates transcription of the calmodulin (CaM) gene in liver. Because O-glycosylation of Sp1 by O-linked N-acetylglucosamine (O-GlcNAc) is thought to regulate its ability to activate transcription, we assayed the levels of Sp1 with anti-Sp1 and anti-O-GlcNAc antibodies in Western blots by use of extracts of H-411E liver cells treated with insulin (10,000 microU/ml) or glucagon (1.5 x 10(-5) M). We also assessed subcellular localization of the native and glycosylated Sp1 in H411E cells treated with either hormone in the presence of deoxynorleucine (DON, an indirect inhibitor of O-glycosylation) or streptozotocin (STZ, an indirect stimulator of O-glycosylation). Insulin stimulated both total and O-GlcNAc-modified Sp1 primarily in the nucleus and induced CaM gene transcription (P < 0.0001). In contrast, glucagon promoted accumulation of Sp1 in the cytoplasm but not the nucleus, without significantly stimulating (P = not significant) either its O-glycosylation or transcription of the CaM gene. DON inhibited O-glycosylation of Sp1 and its ability to migrate to the nucleus and transactivate CaM gene transcription. In contrast, cotreatment of cells with STZ and glucagon enhanced O-glycosylation of Sp1, promoting its migration to the nucleus and resulting in increased CaM gene transcription. Thus O-glycosylation of Sp1 by insulin, but not glucagon, apparently enhances its (Sp1) nuclear recruitment and results in activation of CaM gene transcription.

La crisis de la autopsia / The autopsy in crisis

In the Western world the autopsy rate is declining at an alarming rate. In the United States of America the rate in some academic hospitals is less than 7 percent of all hospital deaths. This decline has been documented and deplored in many countries, articles and books. Suggestions on how to resuscitate the autopsy range from mandatory in all hospital deaths to economic bonuses to the doctors obtaining the highest autopsy rate. All in vain, the autopsy decline continues. Pathologists deploring this decline blamed clinical colleagues, new social attitudes, the litigious nature of modern society, but few have questioned a procedure little changed in more than a century. Perhaps the time has come to abandon the ÒclassicÓ autopsy and rethink the procedure so as to make it useful, alluring and indispensable for the contemporary, concerned clinician