Functional capacity and cognitive performance of adults from Argentina in cardiopulmonary rehabilitation / Capacidad funcional y rendimiento cognitivo de adultos argentinos en rehabilitación cardiopulmonar.

Introduction: Functional capacity is decreased in people with Cardiovascular Diseases and Chronic Respiratory Diseases. These diseases have also been associated with cognitive dysfunction. The study examines the efficacy of a cardiopulmonary rehabilitation program in the recovery of functional capacity and analyzes whether subjects with cardiopulmonary diseases suffer from cognitive dysfunction. Materials and methods: Participated 50 adults with medium-high education who completed a cardiopulmonary rehabilitation program of between 3 and 6 months based on physical education, nutritional education, promotion of healthy habits and medication management. Functional capacity was evaluated with the Duke index at the beginning and end of the program. Memory and language tests were also administered, for the only time, at the beginning of the program, comparing the values obtained with Argentine normative studies. The data was analyzed with the Wilcoxon test, bivariate correlations, and linear regression. Results: Functional capacity increased significantly at the end of the program. In any case, the post-program Duke value suggests that the functional capacity of the patients continues to be affected. On the other hand, a memory test explained 10,8% of the variance in the Duke index, and there are no findings of cognitive dysfunction. Conclusion: The functional capacity of cardiopulmonary patients improved with the rehabilitation program, although this improvement is clinically insufficient. Better memory performance predicted greater functional capacity, which is why it is suggested to add cognitive stimulation workshops to cardiopulmonary rehabilitation programs. This sample with cardiopulmonary disease does not present cognitive dysfunction, probably due to its high cognitive reserve. Introduction: Functional capacity is decreased in people with Cardiovascular Diseases and Chronic Respiratory Diseases. These diseases have also been associated with cognitive dysfunction. The study examines the efficacy of a cardiopulmonary rehabilitation program in the recovery of functional capacity and analyzes whether subjects with cardiopulmonary diseases suffer from cognitive dysfunction. Materials and methods: Participated 50 adults with medium-high education who completed a cardiopulmonary rehabilitation program of between 3 and 6 months based on physical education, nutritional education, promotion of healthy habits and medication management. Functional capacity was evaluated with the Duke index at the beginning and end of the program. Memory and language tests were also administered, for the only time, at the beginning of the program, comparing the values obtained with Argentine normative studies. The data was analyzed with the Wilcoxon test, bivariate correlations, and linear regression. Results: Functional capacity increased significantly at the end of the program. In any case, the post-program Duke value suggests that the functional capacity of the patients continues to be affected. On the other hand, a memory test explained 10,8% of the variance in the Duke index, and there are no findings of cognitive dysfunction. Conclusion: The functional capacity of cardiopulmonary patients improved with the rehabilitation program, although this improvement is clinically insufficient. Better memory performance predicted greater functional capacity, which is why it is suggested to add cognitive stimulation workshops to cardiopulmonary rehabilitation programs. This sample with cardiopulmonary disease does not present cognitive dysfunction, probably due to its high cognitive reserve.

Introducción: La capacidad funcional está disminuida en personas con Enfermedades Cardiovasculares y Enfermedades Respiratorias Crónicas. Estas enfermedades también han sido asociadas a disfunción cognitiva. El estudio examina la eficacia de un programa de rehabilitación cardiopulmonar en la recuperación de la capacidad funcional, y analiza si sujetos con enfermedades cardiopulmonares sufren disfunción cognitiva. Materiales y métodos: Participaron 50 personas adultas con instrucción media-alta que completaron un programa de rehabilitación cardiopulmonar de entre 3 y 6 meses basado en educación física, educación nutricional, promoción de hábitos saludables y manejo de medicación. Se evaluó la capacidad funcional con el índice Duke al iniciar y finalizar el programa. Se administró también, por única vez, al iniciar el programa, pruebas de memoria y de lenguaje, comparando los valores obtenidos con estudios normativos argentinos. Se analizó los datos con test Wilcoxon, correlaciones bivariadas y regresión lineal. Resultados: La capacidad funcional aumentó significativamente al finalizar el programa. De todos modos el valor Duke pos- programa sugiere que la capacidad funcional de los pacientes continúa afectada. Por otro lado, una prueba de memoria explicó el 10,8% de la varianza en el índice Duke, y no hay hallazgos de disfunción cognitiva. Conclusión: La capacidad funcional de los pacientes cardiopulmonares mejoró con el programa de rehabilitación, aunque dicha mejora, es clínicamente insuficiente. Mejor rendimiento de memoria predijo mayor capacidad funcional, por lo que se sugiere añadir talleres de estimulación cognitiva a los programas de rehabilitación cardiopulmonares. Esta muestra con enfermedad cardiopulmonar no presenta disfunción cognitiva, probablemente por su elevada reserva cognitiva.

Multicenter retrospective study to evaluate the impact of trabectedin plus pegylated liposomal doxorubicin on the subsequent treatment in women with recurrent, platinum-sensitive ovarian cancer.

Debulking surgery, followed by taxane/platinum-based chemotherapy has traditionally been the first-line treatment for advanced ovarian cancer. However, most patients will experience recurrence afterwards, and receive subsequent lines of therapy. It has been proposed that extending the treatment-free interval of platinum can improve the response to a subsequent platinum-based chemotherapy, and reduce associated toxicities in women with recurrent, platinum-sensitive ovarian cancer. The aim was to determine the impact, in clinical practice, of trabectedin with pegylated liposomal doxorubicin (trabectedin/PLD) on the subsequent platinum-based therapy in these patients, and to explore the prognosis for breast cancer gene status and the expression of diverse genes. This was a multicenter, retrospective, postauthorization study that involved 79 patients. Germline or somatic mutations of breast cancer gene 1/2 were present in 21.5%. The median time between trabectedin/PLD and the onset of the subsequent treatment was 6.7 months. The overall response rate during the trabectedin/PLD period was 36.7%. In the subsequent first-line platinum-based therapy, the overall response rate was 51.4%. Progression-free survival and overall survival were 11.8 and 25.4 months, respectively, from the onset of trabectedin/PLD treatment. Partially platinum-sensitive (between 6 and 12 months) and platinum-sensitive patients (treatment-free interval of platinum≥12 months) showed no differences in progression-free survival and overall survival. Grade 3 neutropenia and asthenia were reported in 15.2 and 10.1% of patients, respectively. Most frequent adverse events in more than 10% of patients were neutropenia (45.6%), asthenia (43.0%), nausea (25.3%), and anemia (13.9%). The intercalation with a nonplatinum regimen may improve the response to a subsequent platinum-based therapy in women with recurrent, platinum-sensitive ovarian cancer.

Extracellular Thiol Isomerases and Their Role in Thrombus Formation.

SIGNIFICANCE: The mammalian endoplasmic reticulum (ER) houses a large family of twenty thioredoxin-like proteins of which protein disulfide isomerase (PDI) is the archetypal member. Although the PDI family is best known for its role in oxidative protein folding of secretory proteins in the ER, these thioredoxin-like proteins fulfill ever-expanding roles, both within the secretory pathway and beyond. RECENT ADVANCES: Secreted PDI family proteins have now been shown to serve a critical role in platelet thrombus formation and fibrin generation. Utilizing intravital microscopy to visualize thrombus formation in mice, we have demonstrated the presence of extracellular PDI antigen during thrombus formation following injury of the vascular wall. Inhibition of PDI abrogates thrombus formation in vivo (16, 26, 46, 55). These observations have been extended to other PDI family members, including ERp57 (39, 116, 118, 123) and ERp5 (77). The vascular thiol isomerases are those PDI family members secreted from platelets and/or endothelium (40): PDI, ERp57, ERp5, ERp72, ERp44, ERp29, and TMX3. We focus here on PDI (16, 46, 55), ERp57 (39, 116, 118, 123), and ERp5 (77), which have been implicated in thrombus formation in vivo. CRITICAL ISSUES: It would appear that a system of thiol isomerase redox catalysts has been hijacked from the ER to regulate thrombus formation in the vasculature. FUTURE DIRECTIONS: How this redox system is trafficked to and regulated at the cell surface, the identity of extracellular substrates, why so many thiol isomerases are required, and which thiol isomerase functions are necessary are critical unanswered questions in understanding the role of thiol isomerases in thrombus formation.

Both platelet- and endothelial cell-derived ERp5 support thrombus formation in a laser-induced mouse model of thrombosis.

Protein disulfide isomerase (PDI) and endoplasmic reticulum protein 57 (ERp57) are emerging as important regulators of thrombus formation. Another thiol isomerase, endoplasmic reticulum protein 5 (ERp5), is involved in platelet activation. We show here the involvement of ERp5 in thrombus formation using the mouse laser-injury model of thrombosis and a specific antibody raised against recombinant ERp5. Anti-ERp5 antibody inhibited ERp5-dependent platelet and endothelial cell disulfide reductase activity in vitro. ERp5 release at the thrombus site was detected after infusion of Alexa Fluor 488-labeled anti-ERp5 antibody at 0.05 µg/g body weight, a dose that does not inhibit thrombus formation. Anti-ERp5 at 3 µg/g body weight inhibited laser-induced thrombus formation in vivo by causing a 70% decrease in the deposition of platelets and a 62% decrease in fibrin accumulation compared to infusion of control antibody (P < .01). ERp5 binds to ß3 integrin with an equilibrium dissociation constant (KD) of 21 µM, measured by surface plasmon resonance. The cysteine residues in the ERp5 active sites are not required for binding to ß3 integrin. These results provide evidence for a novel role of ERp5 in thrombus formation, a function that may be mediated through its association with αIIbß3.

Growth arrest-specific protein 6 is hepatoprotective against murine ischemia/reperfusion injury.

UNLABELLED: Growth arrest-specific gene 6 (GAS6) promotes growth and cell survival during tissue repair and development in different organs, including the liver. However, the specific role of GAS6 in liver ischemia/reperfusion (I/R) injury has not been previously addressed. Here we report an early increase in serum GAS6 levels after I/R exposure. Moreover, unlike wild-type (WT) mice, Gas6(-/-) mice were highly sensitive to partial hepatic I/R, with 90% of the mice dying within 12 hours of reperfusion because of massive hepatocellular injury. I/R induced early hepatic protein kinase B (AKT) phosphorylation in WT mice but not in Gas6(-/-) mice without significant changes in c-Jun N-terminal kinase phosphorylation or nuclear factor kappa B translocation, whereas hepatic interleukin-1ß (IL-1ß) and tumor necrosis factor (TNF) messenger RNA levels were higher in Gas6(-/-) mice versus WT mice. In line with the in vivo data, in vitro studies indicated that GAS6 induced AKT phosphorylation in primary mouse hepatocytes and thus protected them from hypoxia-induced cell death, whereas GAS6 diminished lipopolysaccharide-induced cytokine expression (IL-1ß and TNF) in murine macrophages. Finally, recombinant GAS6 treatment in vivo not only rescued GAS6 knockout mice from severe I/R-induced liver damage but also attenuated hepatic damage in WT mice after I/R. CONCLUSION: Our data have revealed GAS6 to be a new player in liver I/R injury that is emerging as a potential therapeutic target for reducing postischemic hepatic damage.

Growth arrest-specific gene 6 (GAS6). An outline of its role in haemostasis and inflammation.

GAS6 (growth arrest-specific 6) belongs structurally to the family of plasma vitamin K-dependent proteins. GAS6 has a high structural homology with the natural anticoagulant protein S, sharing the same modular composition and having 40% sequence identity. Despite this, the low concentration of GAS6 in plasma and the pattern of tissue expression of GAS6 suggest a distinct function among vitamin-K dependent proteins. Indeed, GAS6 has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family; Tyro3, Axl and MerTK. GAS6 employs a unique mechanism of action, interacting through its vitamin K-dependent GLA (gamma-carboxyglutamic acid) module with phosphatidylserine-containing membranes and through its carboxy-terminal LamG domains with the TAM membrane receptors. During the last years there has been a considerable expansion of our knowledge of the biology of TAM receptors that has lead to a clear picture of their importance in inflammation, haemostasis and cancer, making this system an interesting target in biomedicine. The innate immune response and the coagulation cascade have been shown to be interconnected. Mediators of inflammation are essential in the initiation and propagation of the coagulation cascade, while natural anticoagulants have important anti-inflammatory functions. GAS6 represents a new player in this context, while protein S seems to have new functions beyond its anticoagulant role through its interaction with TAM receptors.

Vitamin K-dependent actions of Gas6.

Gas6 (growth arrest-specific gene 6) is the last addition to the family of plasma vitamin K-dependent proteins. Gas6 was cloned and characterized in 1993 and found to be similar to the plasma anticoagulant protein S. Soon after it was recognized as a growth factor-like molecule, as it interacted with receptor tyrosine kinases (RTKs) of the TAM family; Tyro3, Axl, and MerTK. Since then, the role of Gas6, protein S, and the TAM receptors has been found to be important in inflammation, hemostasis, and cancer, making this system an interesting target in biomedicine. Gas6 employs a unique mechanism of action, interacting through its vitamin K-dependent Gla module with phosphatidylserine-containing membranes and through its carboxy-terminal LG domains with the TAM membrane receptors. The fact that these proteins are affected by anti-vitamin K therapy is discussed in detail.

Gas6 promotes inflammation by enhancing interactions between endothelial cells, platelets, and leukocytes.

The role of Gas6 in endothelial cell (EC) function remains incompletely characterized. Here we report that Gas6 amplifies EC activation in response to inflammatory stimuli in vitro. In vivo, Gas6 promotes and accelerates the sequestration of circulating platelets and leukocytes on activated endothelium as well as the formation and endothelial sequestration of circulating platelet-leukocyte conjugates. In addition, Gas6 promotes leukocyte extravasation, inflammation, and thrombosis in mouse models of inflammation (endotoxinemia, vasculitis, heart transplantation). Thus, Gas6 amplifies EC activation, thereby playing a key role in enhancing the interactions between ECs, platelets, and leukocytes during inflammation.