mTORC1-mediated translational elongation limits intestinal tumour initiation and growth.

Inactivation of APC is a strongly predisposing event in the development of colorectal cancer, prompting the search for vulnerabilities specific to cells that have lost APC function. Signalling through the mTOR pathway is known to be required for epithelial cell proliferation and tumour growth, and the current paradigm suggests that a critical function of mTOR activity is to upregulate translational initiation through phosphorylation of 4EBP1 (refs 6, 7). This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP1 (ref. 8), would be ineffective in limiting cancer progression in APC-deficient lesions. Here we show in mice that mTOR complex 1 (mTORC1) activity is absolutely required for the proliferation of Apc-deficient (but not wild-type) enterocytes, revealing an unexpected opportunity for therapeutic intervention. Although APC-deficient cells show the expected increases in protein synthesis, our study reveals that it is translation elongation, and not initiation, which is the rate-limiting component. Mechanistically, mTORC1-mediated inhibition of eEF2 kinase is required for the proliferation of APC-deficient cells. Importantly, treatment of established APC-deficient adenomas with rapamycin (which can target eEF2 through the mTORC1-S6K-eEF2K axis) causes tumour cells to undergo growth arrest and differentiation. Taken together, our data suggest that inhibition of translation elongation using existing, clinically approved drugs, such as the rapalogs, would provide clear therapeutic benefit for patients at high risk of developing colorectal cancer.

Drosophila Larval Models of Invasive Tumorigenesis for In Vivo Studies on Tumour/Peripheral Host Tissue Interactions during Cancer Cachexia.

Cancer cachexia is a common deleterious paraneoplastic syndrome that represents an area of unmet clinical need, partly due to its poorly understood aetiology and complex multifactorial nature. We have interrogated multiple genetically defined larval Drosophila models of tumourigenesis against key features of human cancer cachexia. Our results indicate that cachectic tissue wasting is dependent on the genetic characteristics of the tumour and demonstrate that host malnutrition or tumour burden are not sufficient to drive wasting. We show that JAK/STAT and TNF-α/Egr signalling are elevated in cachectic muscle and promote tissue wasting. Furthermore, we introduce a dual driver system that allows independent genetic manipulation of tumour and host skeletal muscle. Overall, we present a novel Drosophila larval paradigm to study tumour/host tissue crosstalk in vivo, which may contribute to future research in cancer cachexia and impact the design of therapeutic approaches for this pathology.

c-Src drives intestinal regeneration and transformation.

The non-receptor tyrosine kinase c-Src, hereafter referred to as Src, is overexpressed or activated in multiple human malignancies. There has been much speculation about the functional role of Src in colorectal cancer (CRC), with Src amplification and potential activating mutations in up to 20% of the human tumours, although this has never been addressed due to multiple redundant family members. Here, we have used the adult Drosophila and mouse intestinal epithelium as paradigms to define a role for Src during tissue homeostasis, damage-induced regeneration and hyperplasia. Through genetic gain and loss of function experiments, we demonstrate that Src is necessary and sufficient to drive intestinal stem cell (ISC) proliferation during tissue self-renewal, regeneration and tumourigenesis. Surprisingly, Src plays a non-redundant role in the mouse intestine, which cannot be substituted by the other family kinases Fyn and Yes. Mechanistically, we show that Src drives ISC proliferation through upregulation of EGFR and activation of Ras/MAPK and Stat3 signalling. Therefore, we demonstrate a novel essential role for Src in intestinal stem/progenitor cell proliferation and tumourigenesis initiation in vivo.

FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells.

Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours.

Inducible progenitor-derived Wingless regulates adult midgut regeneration in Drosophila.

The ability to regenerate following stress is a hallmark of self-renewing tissues. However, little is known about how regeneration differs from homeostatic tissue maintenance. Here, we study the role and regulation of Wingless (Wg)/Wnt signalling during intestinal regeneration using the Drosophila adult midgut. We show that Wg is produced by the intestinal epithelial compartment upon damage or stress and it is exclusively required for intestinal stem cell (ISC) proliferation during tissue regeneration. Reducing Wg or downstream signalling components from the intestinal epithelium blocked tissue regeneration. Importantly, we demonstrate that Wg from the undifferentiated progenitor cell, the enteroblast, is required for Myc-dependent ISC proliferation during regeneration. Similar to young regenerating tissues, ageing intestines required Wg and Myc for ISC hyperproliferation. Unexpectedly, our results demonstrate that epithelial but not mesenchymal Wg is essential for ISC proliferation in response to damage, while neither source of the ligand is solely responsible for ISC maintenance and tissue self-renewal in unchallenged tissues. Therefore, fine-tuning Wnt results in optimal balance between the ability to respond to stress without negatively affecting organismal viability.

Non-autonomous crosstalk between the Jak/Stat and Egfr pathways mediates Apc1-driven intestinal stem cell hyperplasia in the Drosophila adult midgut.

Inactivating mutations within adenomatous polyposis coli (APC), a negative regulator of Wnt signaling, are responsible for most sporadic and hereditary forms of colorectal cancer (CRC). Here, we use the adult Drosophila midgut as a model system to investigate the molecular events that mediate intestinal hyperplasia following loss of Apc in the intestine. Our results indicate that the conserved Wnt target Myc and its binding partner Max are required for the initiation and maintenance of intestinal stem cell (ISC) hyperproliferation following Apc1 loss. Importantly, we find that loss of Apc1 leads to the production of the interleukin-like ligands Upd2/3 and the EGF-like Spitz in a Myc-dependent manner. Loss of Apc1 or high Wg in ISCs results in non-cell-autonomous upregulation of upd3 in enterocytes and subsequent activation of Jak/Stat signaling in ISCs. Crucially, knocking down Jak/Stat or Spitz/Egfr signaling suppresses Apc1-dependent ISC hyperproliferation. In summary, our results uncover a novel non-cell-autonomous interplay between Wnt/Myc, Egfr and Jak/Stat signaling in the regulation of intestinal hyperproliferation. Furthermore, we present evidence suggesting potential conservation in mouse models and human CRC. Therefore, the Drosophila adult midgut proves to be a powerful genetic system to identify novel mediators of APC phenotypes in the intestine.

Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation.

OBJECTIVE: Colorectal cancer (CRC) is a major contributor to cancer mortality and morbidity. LIM kinase 2 (LIMK2) promotes tumour cell invasion and metastasis. The objectives of this study were to determine how LIMK2 expression is associated with CRC progression and patient outcome, and to use genetically modified Drosophila and mice to determine how LIMK2 deletion affects gastrointestinal stem cell regulation and tumour development. DESIGN: LIMK2 expression and activity were measured by immunostaining tumours from CRC-prone mice, human CRC cell lines and 650 human tumours. LIMK knockdown in Drosophila or Limk2 deletion in mice allowed for assessment of their contributions to gastrointestinal stem cell homeostasis and tumour development. RESULTS: LIMK2 expression was reduced in intestinal tumours of cancer-prone mice, as well as in human CRC cell lines and tumours. Reduced LIMK2 expression and substrate phosphorylation were associated with shorter patient survival. Genetic analysis in Drosophila midgut and intestinal epithelial cells isolated from genetically modified mice revealed a conserved role for LIMK2 in constraining gastrointestinal stem cell proliferation. Limk2 deletion increased colon tumour size in a colitis-associated colorectal mouse cancer model. CONCLUSIONS: This study revealed that LIMK2 expression and activity progressively decrease with advancing stage, and supports the hypothesis that there is selective pressure for reduced LIMK2 expression in CRC to relieve negative constraints imposed upon gastrointestinal stem cells.

[A survey on the use of fluoroscopy in the treatment of pain: do we perform it correctly?]. / Encuesta acerca de la utilización de fluoroscopia en el tratamiento del dolor. ¿Lo hacemos correctamente?

OBJECTIVES: Fluoroscopy is technique that is commonly used for procedures in the treatment of pain, but despite its importance in healthcare, many specialists do not know how to use it. We conducted a national survey to evaluate its use. MATERIAL AND METHODS: A questionnaire with 15 questions related to the use of fluoroscopy in the treatment of pain was designed and sent to 105 units that diagnosed and treated pain in Spain, in 2008. RESULTS: A total of 63 (60%) questionnaires with valid responses were received. The majority of specialist (66.6%) had not received specific training on fluoroscopy or pain during their residency. Almost all (90%) of specialists who responded performed procedures that required X-rays in the operating theatre. Just over half (54.7%) performed less than 10 procedures a week, and only 12% performed more than 20 procedures per week. As regards radiation protection, the majority (80%) did not use protective glasses, and only 50% wore leaded gloves. Just under half (47%) were situated less than 0.5 metre from the patient. The majority (76%) did not inform about the radiation, nor was it mentioned in the informed consent (80%). CONCLUSIONS: There is a lack of information on the handling of the fluoroscope in the area of pain treatment, and this usually leads to the adoption of insufficient radiation protection measures. The treatments are usually performed in the operating theatre. More than half the specialists perform less 10 procedures per week with x-rays. The control and follow-up of radiation values is insufficient, as is the information and protection offered to the patient.

Csk-deficient boundary cells are eliminated from normal Drosophila epithelia by exclusion, migration, and apoptosis.

The construction and maintenance of normal epithelia relies on local signals that guide cells into their proper niches and remove unwanted cells. Failure to execute this process properly may result in aberrant development or diseases, including cancer and associated metastasis. Here, we show that local environment influences the behavior of dCsk-deficient cells. Broad loss of dCsk led to enlarged and mispatterned tissues due to overproliferation, a block in apoptosis, and decreased cadherin-mediated adhesion. Loss of dCsk in discrete patches led to a different outcome: epithelial exclusion, invasive migration, and apoptotic death. These latter phenotypes required sharp differences in dCsk activity between neighbors; dE-cadherin, P120-catenin, Rho1, JNK, and MMP2 mediated this signal. Together, our data demonstrate how the cellular microenvironment plays a central role in determining the outcome of altered dCsk activity, and reveal a role for P120-catenin in a mechanism that protects epithelial integrity by removing abnormal cells.

A role for the epithelial microenvironment at tumor boundaries: evidence from Drosophila and human squamous cell carcinomas.

Recent work has shown an increasing appreciation for the importance of the tumor environment, most commonly the overlying stroma. Less emphasis has been placed on the importance of local communication between transformed cells and their neighbors within the epithelium at tumor boundaries. We previously reported a Drosophila model that highlighted the importance of local interactions within the epithelial microenvironment: Src-transformed cells (Csk-deficient) were influenced by their immediate normal neighbors. The result was a consistent change in 'border cells' at the edge of transformed patches including delocalized p120-catenin and E-cadherin as well as invasive migration through the basal lamina. Here we show that the invasive properties of the boundary cells depend on up-regulation of Drosophila matrix metalloproteinase-1 as assessed by promoter activity, protein levels, in situ enzymatic activity, and tests of genetic modifier activity. Further, we provide evidence that these events at tumor borders may be evolutionarily conserved. We detected changes in 'boundary cells' within histological sections of human squamous cell carcinomas that were similar to those observed in Drosophila: both E-cadherin and p120-catenin exhibited normal junctional localization at the centers of the tumors but were reduced or delocalized at the boundary. Further, matrix metalloproteinase-2 was up regulated within these same boundary cells. These results support the view that local cell-cell interactions within the epithelial microenvironment impact tumor invasion and progression.

Assessment of the different citation systems in the scientific publication of nursing authors from Spanish-speaking countries.

OBJECTIVE: To assess the distribution of citations of nursing authors in Spanish in Google Scholar as well as to compare the possible differences between this source and Web of Science and Scopus. METHOD: This is a descriptive cross-sectional study based on the citation systems offered by Google Scholar, Web of Science, and Scopus. RESULTS: Nursing researchers present a verified mean h-index of 7.82 in Academic Google. 74% of researchers belong to the academic field, compared to 26%, who are in health services. Most of them live in Spain (83%), followed by Colombia (12%), Mexico (4%), and Chile (1%). In Spain, the community with the largest number of researchers is Andalusia (41.5%), followed by Valencia (14.6%), and Madrid (7.3%). CONCLUSION: The Google Scholar citation system requires adjustments in its algorithm for selecting works and citations, and it should also allow some system of confirmation by authors. Nursing can have relatively low h-index values compared to other courses due to short research development.

Drosophila models for cancer research.

Drosophila is a model system for cancer research. Investigation with fruit flies has facilitated a number of important recent discoveries in the field: the hippo signaling pathway, which coordinates cell proliferation and death to achieve normal tissue size; 'social' behaviors of cells, including cell competition and apoptosis-induced compensatory proliferation, that help ensure normal tissue size; and a growing understanding of how oncogenes and tumor suppressors cooperate to achieve tumor growth and metastasis in situ. In the future, Drosophila models can be extended beyond basic research in the search for human therapeutics.

The antimicrobial peptide defensin cooperates with tumour necrosis factor to drive tumour cell death in Drosophila.

Antimicrobial peptides (AMPs) are small cationic molecules best known as mediators of the innate defence against microbial infection. While in vitro and ex vivo evidence suggest AMPs' capacity to kill cancer cells, in vivo demonstration of an anti-tumour role of endogenous AMPs is lacking. Using a Drosophila model of tumourigenesis, we demonstrate a role for the AMP Defensin in the control of tumour progression. Our results reveal that Tumour Necrosis Factor mediates exposure of phosphatidylserine (PS), which makes tumour cells selectively sensitive to the action of Defensin remotely secreted from tracheal and fat tissues. Defensin binds tumour cells in PS-enriched areas, provoking cell death and tumour regression. Altogether, our results provide the first in vivo demonstration for a role of an endogenous AMP as an anti-cancer agent, as well as a mechanism that explains tumour cell sensitivity to the action of AMPs.

A Neuronal Relay Mediates a Nutrient Responsive Gut/Fat Body Axis Regulating Energy Homeostasis in Adult Drosophila.

The control of systemic metabolic homeostasis involves complex inter-tissue programs that coordinate energy production, storage, and consumption, to maintain organismal fitness upon environmental challenges. The mechanisms driving such programs are largely unknown. Here, we show that enteroendocrine cells in the adult Drosophila intestine respond to nutrients by secreting the hormone Bursicon α, which signals via its neuronal receptor DLgr2. Bursicon α/DLgr2 regulate energy metabolism through a neuronal relay leading to the restriction of glucagon-like, adipokinetic hormone (AKH) production by the corpora cardiaca and subsequent modulation of AKH receptor signaling within the adipose tissue. Impaired Bursicon α/DLgr2 signaling leads to exacerbated glucose oxidation and depletion of energy stores with consequent reduced organismal resistance to nutrient restrictive conditions. Altogether, our work reveals an intestinal/neuronal/adipose tissue inter-organ communication network that is essential to restrict the use of energy and that may provide insights into the physiopathology of endocrine-regulated metabolic homeostasis.

Stat1-vitamin D receptor interactions antagonize 1,25-dihydroxyvitamin D transcriptional activity and enhance stat1-mediated transcription.

The cytokine gamma interferon (IFN-gamma) and the calcitropic steroid hormone 1,25-dihydroxyvitamin D (1,25D) are activators of macrophage immune function. In sarcoidosis, tuberculosis, and several granulomatoses, IFN-gamma induces 1,25D synthesis by macrophages and inhibits 1,25D induction of 24-hydroxylase, a key enzyme in 1,25D inactivation, causing high levels of 1,25D in serum and hypercalcemia. This study delineates IFN-gamma-1,25D cross talk in human monocytes-macrophages. Nuclear accumulation of Stat1 and vitamin D receptor (VDR) by IFN-gamma and 1,25D promotes protein-protein interactions between Stat1 and the DNA binding domain of the VDR. This prevents VDR-retinoid X receptor (RXR) binding to the vitamin D-responsive element, thus diverting the VDR from its normal genomic target on the 24-hydroxylase promoter and antagonizing 1,25D-VDR transactivation of this gene. In contrast, 1,25D enhances IFN-gamma action. Stat1-VDR interactions, by preventing Stat1 deactivation by tyrosine dephosphorylation, cooperate with IFN-gamma/Stat1-induced transcription. This novel 1,25D-IFN-gamma cross talk explains the pathogenesis of abnormal 1,25D homeostasis in granulomatous processes and provides new insights into 1,25D immunomodulatory properties.

ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid carcinoma.

Patients with hereditary medullary thyroid carcinoma (MTC) associated with multiple endocrine neoplasia (MEN) types 2A and 2B and familial MTC (FMTC) have mutations in the RET proto-oncogene. Approximately 40 percent of patients with papillary thyroid carcinoma (PTC) typically have either intrachromosomal or extrachromosomal rearrangements that join the promoter and NH(2)-terminal domains of unrelated genes to the COOH-terminal fragment of RET. The RET point mutations associated with MEN2A, MEN2B, or FMTC, or the chromosomal breakpoints and translocations associated with PTC, typically activate the RET receptor tyrosine kinase (RTK). RET kinase inhibitors are likely to be beneficial for patients with hereditary MTC, where currently there is no effective chemotherapy or radiation therapy. Recently, the low molecular weight tyrosine kinase inhibitor ZD6474 was found to block the enzymatic activity of RET-derived oncoproteins in cultured cell lines. We have developed a Drosophila model for MEN2A and MEN2B diseases by targeting oncogenic forms of RET to the developing Drosophila eye. Here we show that, when fed orally, ZD6474 suppressed RET-mediated phenotypes within the context of this in vivo model. Importantly, ZD6474 showed high efficacy and very low toxicity. This compound failed to significantly suppress an activated form of another RTK, the Drosophila epidermal growth factor receptor, nor did it suppress the activity of downstream components of the RET/Ras pathway. Our results support the view that targeting chemical kinase inhibitors such as ZD6474 to tissues with oncogenic forms of RET is a useful treatment strategy for RET-dependent carcinomas.

Bursicon-α subunit modulates dLGR2 activity in the adult Drosophila melanogaster midgut independently to Bursicon-ß.

Bursicon is the main regulator of post molting and post eclosion processes during arthropod development. The active Bursicon hormone is a heterodimer of Burs-α and Burs-ß. However, adult midguts express Burs-α to regulate the intestinal stem cell niche. Here, we examined the potential expression and function of its heterodimeric partner, Burs-ß in the adult midgut. Unexpectedly, our evidence suggests that Burs-ß is not significantly expressed in the adult midgut. burs-ß mutants displayed the characteristic developmental defects but showed wild type-like adult midguts, thus uncoupling the developmental and adult phenotypes seen in burs-α mutants. Gain of function data and ex vivo experiments using a cAMP biosensor, demonstrated that Burs-α is sufficient to drive stem cell quiescence and to activate dLGR2 in the adult midgut. Our evidence suggests that the post developmental transactivation of dLGR2 in the adult midgut is mediated by Burs-α and that the ß subunit of Bursicon is dispensable for these activities.

Assessment of the different citation systems in the scientific publication of nursing authors from Spanish-speaking countries / Avaliação dos diferentes sistemas de citação na publicação científica de autores de enfermagem em espanhol / Evaluación de los diferentes sistemas de citación en la publicación científica de autores enfermeros en español

ABSTRACT Objective: To assess the distribution of citations of nursing authors in Spanish in Google Scholar as well as to compare the possible differences between this source and Web of Science and Scopus. Method: This is a descriptive cross-sectional study based on the citation systems offered by Google Scholar, Web of Science, and Scopus. Results: Nursing researchers present a verified mean h-index of 7.82 in Academic Google. 74% of researchers belong to the academic field, compared to 26%, who are in health services. Most of them live in Spain (83%), followed by Colombia (12%), Mexico (4%), and Chile (1%). In Spain, the community with the largest number of researchers is Andalusia (41.5%), followed by Valencia (14.6%), and Madrid (7.3%). Conclusion: The Google Scholar citation system requires adjustments in its algorithm for selecting works and citations, and it should also allow some system of confirmation by authors. Nursing can have relatively low h-index values compared to other courses due to short research development.

RESUMO Objetivo: Avaliar a distribuição de citações de autores de enfermagem em espanhol no Google Scholar, bem como comparar as possíveis diferenças entre esta fonte e Web of Science e Scopus. Método: Estudo descritivo transversal baseado nos sistemas de citação oferecidos pelo Google Scholar, Web of Science e Scopus. Resultados: Pesquisadores da área de enfermagem apresentam índice h médio verificado no Google Acadêmico de 7,82. 74% dos pesquisadores pertencem à área acadêmica, contra 26% que estão agrupados nos serviços de saúde. A maioria deles está localizada na Espanha (83%), seguida pela Colômbia (12%), México (4%) e Chile (1%). Na Espanha, a comunidade com maior número de pesquisadores é a Andaluzia (41,5%), seguida da Comunidade Valenciana (14,6%) e Madrid (7,3%). Conclusão: O sistema de citações do Google Scholar requer ajustes em seu algoritmo de seleção de obras e citações, devendo também permitir algum sistema de confirmação por parte dos autores. A enfermagem pode ter valores relativamente baixos do índice h em comparação com outras disciplinas devido ao curto desenvolvimento da pesquisa.

RESUMEN Objetivo: Evaluar la distribución de citas de autores enfermeros en español en Google Académico, así como comparar las posibles diferencias entre esta fuente y Web of Science y Scopus. Método: Estudio descriptivo transversal basado en los sistemas de citas ofrecidos por Google Académico, Web of Science y Scopus. Resultados: Los investigadores del área de enfermería presentan un índice h verificado medio de 7.82 en Google Académico. El 74% de los investigadores pertenece al ámbito académico, frente a un 26% que se aglutina en los servicios de salud. La mayoría de ellos se ubican en España (83%), seguido de Colombia (12%), Méjico (4%) y Chile (1%). En España, la comunidad que mayor número de investigadores aglutina es Andalucía (41,5%), seguida de la Comunidad Valencia (14,6%) y Madrid (7,3%). Conclusión: El sistema de citación de Google Académico precisa de ajustes en su algoritmo de selección de trabajos y citas, además debería permitir algún sistema de confirmación por parte de los autores. Enfermería puede tener valores relativamente bajos del índice h frente a otras disciplinas debido al breve desarrollo investigador.

HIV-protease inhibitors impair vitamin D bioactivation to 1,25-dihydroxyvitamin D.

BACKGROUND: A high prevalence of bone demineralization occurs in people living with HIV/AIDS. The contribution of HIV itself and its treatment is still unclear. Protease inhibitors (PIs) are potent inhibitors of the cytochrome p450 enzyme system. Three cytochrome p450 mixed function oxygenases control serum levels of 1,25-dihydroxyvitamin D (1,25(OH) D ), which is responsible for vitamin D actions in target tissues including bone. The 25- and 1alpha-hydroxylases regulate 1,25(OH) D synthesis and 24-hydroxylase 1,25(OH) D catabolism. OBJECTIVE: To assess whether HIV-protease inhibitors (ritonavir, indinavir, nelfinavir) impair the activity of the main enzymes involved in 1,25(OH) D homeostasis. DESIGN AND METHODS: Studies were conducted in the human hepatocyte (H3B)- and monocyte (THP-1) cell lines, expressing 25-hydroxylase and 1alpha-hydroxylase, respectively. The 24-hydroxylase expression was induced in macrophages by exposure to 1,25(OH) D. Conversion rates of vitamin D to 25-hydroxyvitamin D [25(OH)D ]; 25(OH)D to 1,25(OH) D or 24,25(OH) D, and 1,25(OH) D degradation were quantified in untreated and HIV-PI-treated cells after C -cartridge extraction and high-performance liquid chromatography purification of 25(OH)D - 24,25(OH) D - and 1,25(OH) D fractions. RESULTS: The PIs impair hepatocyte 25(OH)D - and macrophage 1,25(OH) D synthesis in a reversible, dose-dependent manner. Furthermore, PIs inhibit 1,25(OH) D -degradation in macrophages with lower potency than that elicited on 1alpha-hydroxylase. Thus, reduced macrophage 1,25(OH) D production is the net effect of PIs action. CONCLUSIONS: In intact cells, HIV-PIs markedly suppress the activities of 25- and 1alpha-hydroxylase, which are critical in 1,25(OH) D synthesis, while exerting mild inhibition of 24-hydroxylase, responsible for 1,25(OH) D catabolism. If PIs elicit a similar potency in inhibiting these critical steps for 1,25(OH) D homeostasis, defective 1,25(OH) D production could contribute to the bone demineralization in HIV patients.

[Patient with tricuspid atresia undergoing orthopedic surgery: anesthetic considerations]. / Paciente con atresia tricúspide para cirugía ortopédica: cuidados anestésicos.

We describe a 52-year-old patient with rheumatoid arthritis, interventricular communication and pulmonary stenosis. After an accidental fall she was scheduled for total hip replacement. The main objective of anesthetic management was to preserve pulmonary blood circulation at arterial pressures that would assure adequate tissue perfusion. Other objectives were to maintain hydration to prevent decreases in hematocrit levels, avoid systemic embolization and allow for antibiotic prophylaxis.