Cellular signalling pathways involved in muscle atrophy in cancer cachexia

Cancer cachexia encompases severe weight loss, characterised by the debilitating atrophy of adipose and skeletal muscle mass. Skeletal muscle proteolysis in cancer cachexia is mediated by a sulphated glycoprotein with a relative molecular mass of 24kDa, termed Proteolysis-Inducing Factor (PIF). PIF induced a significant increase in protein degradation, peaking at 4.2nM PIF (p<0.001), ‘chymotrypsin-like’ activity of the proteasome (p<0.001) and increased expression of components of the ATP-ubiquitin dependent proteolytic pathway. This was attenuated in vitro by pre-incubation with the PKC inhibitor calphostin C (100µM) and NF-kB the inhibitors SN50 (18µM), curcumin (50µM) and resveratrol (30µM), 2 hours prior to the addition of PIF. In vivo studies found the IKK inhibitor resveratrol (1mg/kg) to be successful in attenuating protein degradation (p<0.001) and upregulation of ubiquitin-dependent proteolysis in MAC16 tumour bearing mice. C2C12 myoblasts transfected with mutant IkBα and PKCα inserts did not elicit a PIF-induced response, suggesting the importance of the transcription factor NF-kB and PKC  involvement in PIF signal transduction. 15(S)-HETE acts as an intracellular mediator of PIF and exerts an effect through the activation of PKC and subsequently IKK, which phosphorylates IkBα and allows NF-kB to migrate to the nucleus. This effect was negated with the PKC inhibitor calphostin C (300nM). A commercially produced PIF receptor antibody was raised in rabbits immunised with a peptide containing the partial N-terminal sequence of the PIF receptor. The PIF receptor antibody was successful in attenuating the PIF-induced increase in skeletal muscle catabolism and protein degradation in vitro at 10µg/ml (p<0.001) and 3.47mg/kg in vivo (p<0.001). The data suggest great potential in the development of this antibody as a therapy against cancer cachexia.

Attenuation of muscle atrophy by an N-terminal peptide of the receptor for proteolysis-inducing factor (PIF)

Background: Atrophy of skeletal muscle in cancer cachexia has been attributed to a tumour-produced highly glycosylated peptide called proteolysis-inducing factor (PIF). The action of PIF is mediated through a high-affinity membrane receptor in muscle. This study investigates the ability of peptides derived from the 20 N-terminal amino acids of the receptor to neutralise PIF action both in vitro and in vivo. Methods: Proteolysis-inducing factor was purified from the MAC16 tumour using an initial pronase digestion, followed by binding on DEAE cellulose, and the pronase was inactivated by heating to 80°C, before purification of the PIF using affinity chromatography. In vitro studies were carried out using C2C12 murine myotubes, while in vivo studies employed mice bearing the cachexia-inducing MAC16 tumour. Results: The process resulted in almost a 23?000-fold purification of PIF, but with a recovery of only 0.004%. Both the D- and L-forms of the 20mer peptide attenuated PIF-induced protein degradation in vitro through the ubiquitin-proteosome proteolytic pathway and increased expression of myosin. In vivo studies showed that neither the D- nor the L-peptides significantly attenuated weight loss, although the D-peptide did show a tendency to increase lean body mass. Conclusion: These results suggest that the peptides may be too hydrophilic to be used as therapeutic agents, but confirm the importance of the receptor in the action of the PIF on muscle protein degradation.

Mechanism of induction of muscle protein degradation by angiotensin II

Angiotensin I and II have been shown to directly induce protein degradation in skeletal muscle through an increased activity and expression of the ubiquitin-proteasome proteolytic pathway. This investigation determines the role of the nuclear transcription factor nuclear factor-κB (NF-κB) in this process. Using murine myotubes as a surrogate model system both angiotensin I and II were found to induce activation of protein kinase C (PKC), with a parabolic dose-response curve similar to the induction of total protein degradation. Activation of PKC was required for the induction of proteasome expression, since calphostin C, a highly specific inhibitor of PKC, attenuated both the increase in total protein degradation and in proteasome expression and functional activity increased by angiotensin II. PKC is known to activate I-κB kinase (IKK), which is responsible for the phosphorylation and subsequent degradation of I-κB. Both angiotensin I and II induced an early decrease in cytoplasmic I-κB levels followed by nuclear accumulation of NF-κB. Using an NF-κB luciferase construct this was shown to increase transcriptional activation of NF-κB regulated genes. Maximal luciferase expression was seen at the same concentrations of angiotensin I/II as those inducing protein degradation. Total protein degradation induced by both angiotensin I and II was attenuated by resveratrol, which prevented nuclear accumulation of NF-κB, confirming that activation of NF-κB was responsible for the increased protein degradation. These results suggest that induction of proteasome expression by angiotensin I/II involves a signalling pathway involving PKC and NF-κB. © 2005 Elsevier Inc. All rights reserved.

Effect of cancer cachexia on the activity of tripeptidyl-peptidase II in skeletal muscle

The ubiquitin-proteasome proteolytic pathway plays a major role in degradation of myofibrillar proteins in skeletal muscle during cancer cachexia. The end-product of this pathway is oligopeptides and these are degraded by the extralysomal peptidase tripeptidyl-peptidase II (TPPII) together with various aminopeptidases to form tripeptides and amino acids. To investigate if a relationship exists between the activity of the proteasome and TPPII, functional activities have been measured in gastrocnemius muscle of mice bearing the MAC16 tumour, and with varying extents of weight loss. TPPII activity was quantitated using the specific substrate Ala-Ala-Phe-7-amido-4-methylcoumarin, while proteasome activity was determined as the 'chymotrypsin-like' enzyme activity. Both proteasome proteolytic activity and TPPII activity increased in parallel with increasing weight loss, reaching a maximum at 16% weight loss, after which there was a progressive decrease in activity for both proteases with increasing weight loss. In murine myotubes, proteolysis-inducing factor, which is a sulphated glycoprotein produced by cachexia-inducing tumours, induced an increase in activity of both proteasome and TPPII, with an identical dose-response curve, and both activities were inhibited by eicosapentaenoic acid. These results suggest that the activities of both the proteasome and TPPII are regulated in a parallel manner in cancer cachexia, and that both are induced by the same factor and probably have the same intracellular signalling pathways and transcription factors. © 2004 Elsevier Ireland Ltd. All rights reserved.

Isotopic studies of the Guerrero composite terrane, west-central Mexico: Implications for provenance of crustal rocks and genesis of ore metals

A variety of world-class mineral deposits occur in Mesozoic and Tertiary rocks of the Guerrero terrane. New Pb isotope analyses of various crustal units and ores from distinct subterranes of the Guerrero terrane are presented to trace metal sources in these deposits and infer source reservoirs. New Sr and Nd isotope results are provided to gain insight into the provenance of the crustal rocks from the Guerrero terrane. Triassic schist samples from the Arteaga Complex and Triassic-Jurassic phyllite and slate samples from the Tejupilco metamorphic suite contain radiogenic Pb (206Pb/204Pb = 18.701–19.256) relative to bulk earth models. Cretaceous sedimentary rocks of the Zihuatanejo Sequence are more radiogenic (206Pb/204Pb = 18.763–19.437) than samples from the Huetamo Sequence (206Pb/204Pb = 18.630–18.998). Tertiary intrusive rocks from La Verde, Inguaran, La Esmeralda, and El Malacate plot to the right of the average Pb crust evolution curve of Stacey and Kramers (206Pb/204Pb = 18.705–19.033). Ores from the La Verde and La Esmeralda porphyry copper deposits yield isotopic ratios (206Pb/204Pb = 18.678–18.723) that are generally less radiogenic than the host igneous rocks, but plot within the field defined by the sedimentary rocks from the Huetamo Sequence. Tertiary intrusive rocks from the Zimapan and La Negra districts in the Sierra Madre terrane plot above and to the right of the Stacey-Kramers reference line (206Pb/204Pb = 18.804–18.972). Lead isotope ratios of ore minerals from the Zimapan and La Negra skarn mines ( 206Pb/204Pb = 18.775–18.975) resemble those of the associated igneous rocks, implying a magmatic Pb input in the skarn deposits. New Sr and Nd isotope data on metamorphic rocks (87Sr/ 86Sr = 0.707757–0.726494 and 143Nd/144 Nd = 0.512109–0.512653) suggest that the basement of the Guerrero terrane originated from sources that had been derived from an old cratonic area. The narrow ranges and generally low 87Sr/86Sr ratios (0.704860–0.705755) and 143Nd/144Nd values (0.512765–0.512772) above that of bulk earth for igneous rocks from Inguaran, El Malacate, and La Esmeralda suggest a relatively low degree of crustal contamination. However, the isotopic values for the La Verde site (87Sr/86Sr = 0.708784 and 143Nd/144Nd = 0.512640) may indicate the involvement of a more evolved crustal component.

An investigation into equations for estimating water requirements and the development of new equations for predicting total water intake

The primary purpose of this study was to investigate agreement among five equations by which clinicians estimate water requirements (EWR) and to determine how well these equations predict total water intake (TWI). The Institute of Medicine has used TWI as a measure of water requirements. A secondary goal of this study was to develop practical equations to predict TWI. These equations could then be considered accurate predictors of an individual’s water requirement. ^ Regressions were performed to determine agreement between the five equations and between the five equations and TWI using NHANES 1999–2004. The criteria for agreement was (1) strong correlation coefficients between all comparisons and (2) regression line that was not significantly different when compared to the line of equality (x=y) i.e., the 95% CI of the slope and intercept must include one and zero, respectively. Correlations were performed to determine association between fat-free mass (FFM) and TWI. Clinically significant variables were selected to build equations for predicting TWI. All analyses were performed with SAS software and were weighted to account for the complex survey design and for oversampling. ^ Results showed that the five EWR equations were strongly correlated but did not agree with each other. Further, the EWR equations were all weakly associated to TWI and lacked agreement with TWI. The strongest agreement between the NRC equation and TWI explained only 8.1% of the variability of TWI. Fat-free mass was positively correlated to TWI. Two models were created to predict TWI. Both models included the variables, race/ethnicity, kcals, age, and height, but one model also included FFM and gender. The other model included BMI and osmolality. Neither model accounted for more than 28% of the variability of TWI. These results provide evidence that estimates of water requirements would vary depending upon which EWR equation was selected by the clinician. None of the existing EWR equations predicted TWI, nor could a prediction equation be created which explained a satisfactory amount of variance in TWI. A good estimate of water requirements may not be predicted by TWI. Future research should focus on using more valid measures to predict water requirements.^

Review of the History and Current Status of Cell-Transplant Approaches for the Management of Neuropathic Pain

Treatment of sensory neuropathies, whether inherited or caused by trauma, the progress of diabetes, or other disease states, are among the most difficult problems in modern clinical practice. Cell therapy to release antinociceptive agents near the injured spinal cord would be the logical next step in the development of treatment modalities. But few clinical trials, especially for chronic pain, have tested the transplant of cells or a cell line to treat human disease. The history of the research and development of useful cell-transplant-based approaches offers an understanding of the advantages and problems associated with these technologies, but as an adjuvant or replacement for current pharmacological treatments, cell therapy is a likely near future clinical tool for improved health care.

Potential for Cell-Transplant Therapy with Human Neuronal Precursors to Treat Neuropathic Pain in Models of PNS and CNS Injury: Comparison of hNT2.17 and hNT2.19 Cell Lines

Effective treatment of sensory neuropathies in peripheral neuropathies and spinal cord injury (SCI) is one of the most difficult problems in modern clinical practice. Cell therapy to release antinociceptive agents near the injured spinal cord is a logical next step in the development of treatment modalities. But few clinical trials, especially for chronic pain, have tested the potential of transplant of cells to treat chronic pain. Cell lines derived from the human neuronal NT2 cell line parentage, the hNT2.17 and hNT2.19 lines, which synthesize and release the neurotransmitters gamma-aminobutyric acid (GABA) and serotonin (5HT), respectively, have been used to evaluate the potential of cell-based release of antinociceptive agents near the lumbar dorsal (horn) spinal sensory cell centers to relieve neuropathic pain after PNS (partial nerve and diabetes-related injury) and CNS (spinal cord injury) damage in rat models. Both cell lines transplants potently and permanently reverse behavioral hypersensitivity without inducing tumors or other complications after grafting. Functioning as cellular minipumps for antinociception, human neuronal precursors, like these NT2-derived cell lines, would likely provide a useful adjuvant or replacement for current pharmacological treatments for neuropathic pain.

Perceptions of collaboration between emergency nurses and paramedics

Collaboration between emergency room (ER) nurses and paramedics is vital due to the increasing number of critically ill patients entering the hospital via the "911" system. This descriptive study examined the perception of the collaborative relationship using the Revised Pehl Collaboration Scale (RPCS) and by qualitative data from four free response questions. The results of this study indicated that the overall relationship between the ER nurses and paramedics was friendly but not fully trusting. The content analysis of the free response questions identified that the "report" of patient information was the origin the most conflict. The nurses felt that paramedic patient assessment, patient priorities, and by-pass protocol were problems. Whereas, the paramedics identified the nurses condescending manner and mistrust, not being "listened" to, and overcrowded emergency rooms as the source of conflict. Data was not statistically significant with regards to personal attributes or social demographics from the RPCS.

(Table 1) AMS 14C dates from sediment cores RC12-10 and GYRE97-6PV-20

Proxy records from two piston cores in the Gulf of Mexico (GOM) provide a detailed (50-100 year resolution) record of climate variability over the last 14,000 years. Long-term (millennial-scale) trends and changes are related to the transition from glacial to interglacial conditions and movement of the average position of the Intertropical Convergence Zone (ITCZ) related to orbital forcing. The d18O of the surface-dwelling planktic foraminifer Globigerinoides ruber show negative excursions between 14 and 10.2 ka (radiocarbon years) that reflect influx of meltwater into the western GOM during melting of the Laurentide Ice Sheet. The relative abundance of the planktic foraminifer Globigerinoides sacculifer is related to transport of Caribbean water into the GOM. Maximum transport of Caribbean surface waters and moisture into the GOM associated with a northward migration of the average position of the ITCZ occurs between about 6.5 and 4.5 ka. In addition, abundance variations of G. sacculifer show century-scale variability throughout most of the Holocene. The GOM record is consistent with records from other areas, suggesting that century-scale variability is a pervasive feature of Holocene climate. The frequency of several cycles in the climate records is similar to cycles identified in proxy records of solar variability, indicating that at least some of the century-scale climate variability during the Holocene is due to external (solar) forcing.

Crisis communication in politics: forgiveness as image restoration tool

Crisis communication is a widely treated field. There are lot of works and guides which provide helpful information in order to face crisis situations successfully (Alcat, 2005, Benoit, 1997) and articles about case studies (Nespereira, 2014, Blaney y Benoit 2001). Nonetheless, most of times, these guides are focused on business or corporations (Abeler, 2010) and there are not such information about crisis communications in politics (Gaspar e Ibeas, 2015). The field is smaller if we speak about forgiveness as restoration image tool in politics (Harris 2006). Despite all, we live in “forgiveness era” as Krauze said (1998) where people demand to politicians to apologize when they have mistakes (Harris et al. 2006:716). So, we will try to make an approach to forgiveness in politics as a image restoration tool and analyze its capabilities in order to face crisis management.

TEACHING MENSTRUAL HEALTH AND HYGIENE TO YOUNG WOMEN IN EASTERN UGANDA WITH REUSABLE MENSTRUAL PADS

In order to identify the impact of teaching menstrual health and hygiene with reusable menstrual pads on knowledge retention and school attendance, qualitative and quantitative data was collected from three rural schools in three districts of eastern Uganda: Amuria, Bukedea, and Ngora. Research techniques employed were preliminary and post surveys of 85 young women; average age 16.9 years. Findings include positive and negative results. Participants’ feelings of normalcy and comfort increased and participants had improved understanding of sexual climax and appropriate menstrual management strategies. There was no statistically significant impact of teaching on topics of sexual intercourse or pregnancy. The impact of reusable menstrual pad sanitary technology on school attendance was negative as more young women reported missing up to a full day of school during their menstrual period (χ2 (3, 73) = 7.81, p = 0.05). Study limitations are discussed and future work is suggested.

Next-to-soft radiative corrections in QCD and quantum gravity

The origin of divergent logarithmic contributions to gauge theory cross sections arising from soft and collinear radiation is explored and a general prescription for tackling next-to-soft logarithms is presented. The NNLO Abelian-like contributions to the Drell-Yan K-factor are reproduced using this generalised prescription. The soft limit of gravity is explored where the interplay between the eikonal phase and Reggeization of the graviton is explained using Wilson line techniques. The Wilson line technique is then implemented to treat the set of next-to-soft contributions arising from dressing external partons with a next-to-soft Wilson line.

Un aporte a la comprensión de las estrategias emergentes en las organizaciones a través del concepto de improvisación y la metáfora musical

Este trabajo se inscribe en uno de los grandes campos de los estudios organizacionales: la estrategia. La perspectiva clásica en este campo promovió la idea de que proyectarse hacia el futuro implica diseñar un plan (una serie de acciones deliberadas). Avances posteriores mostraron que la estrategia podía ser comprendida de otras formas. Sin embargo, la evolución del campo privilegió en alguna medida la mirada clásica estableciendo, por ejemplo, múltiples modelos para ‘formular’ una estrategia, pero dejando en segundo lugar la manera en la que esta puede ‘emerger’. El propósito de esta investigación es, entonces, aportar al actual nivel de comprensión respecto a las estrategias emergentes en las organizaciones. Para hacerlo, se consideró un concepto opuesto —aunque complementario— al de ‘planeación’ y, de hecho, muy cercano en su naturaleza a ese tipo de estrategias: la improvisación. Dado que este se ha nutrido de valiosos aportes del mundo de la música, se acudió al saber propio de este dominio, recurriendo al uso de ‘la metáfora’ como recurso teórico para entenderlo y alcanzar el objetivo propuesto. Los resultados muestran que 1) las estrategias deliberadas y las emergentes coexisten y se complementan, 2) la improvisación está siempre presente en el contexto organizacional, 3) existe una mayor intensidad de la improvisación en el ‘como’ de la estrategia que en el ‘qué’ y, en oposición a la idea convencional al respecto, 4) se requiere cierta preparación para poder improvisar de manera adecuada.

Cors Dei, Cors Humanitatis: El Corazón de Pinocho Y El de Las Místicas Cristianas

Centrado en uno de los símbolos más universales, se comenta la importancia del corazón como sede ontológica en la versión española de Rafael Calleja de la novela infantil Pinocchio, de Carlo Collodi, y en los diarios espirituales de un grupo de místicas cristiano-transatlánticas.