Inducing Energetic Switching Using Klotho Improves Vascular Smooth Muscle Cell Phenotype

The cardiovascular disease of atherosclerosis is characterised by aged vascular smooth muscle cells and compromised cell survival. Analysis of human and murine plaques highlights markers of DNA damage such as p53, Ataxia telangiectasia mutated (ATM), and defects in mitochondrial oxidative metabolism as significant observations. The antiageing protein Klotho could prolong VSMC survival in the atherosclerotic plaque and delay the consequences of plaque rupture by improving VSMC phenotype to delay heart attacks and stroke. Comparing wild-type VSMCs from an ApoE model of atherosclerosis with a flox’d Pink1 knockout of inducible mitochondrial dysfunction we show WT Pink1 is essential for normal cell viability, while Klotho mediates energetic switching which may preserve cell survival. Methods: Wild-type ApoE VSMCs were screened to identify potential drug candidates that could improve longevity without inducing cytotoxicity. The central regulator of cell metabolism AMP Kinase was used as a readout of energy homeostasis. Functional energetic switching between oxidative and glycolytic metabolism was assessed using XF24 technology. Live cell imaging was then used as a functional readout for the WT drug response, compared with Pink1 (phosphatase-and-tensin-homolog (PTEN)-induced kinase-1) knockout cells. Results: Candidate drugs were assessed to induce pACC, pAMPK, and pLKB1 before selecting Klotho for its improved ability to perform energetic switching. Klotho mediated an inverse dose-dependent effect and was able to switch between oxidative and glycolytic metabolism. Klotho mediated improved glycolytic energetics in wild-type cells which were not present in Pink1 knockout cells that model mitochondrial dysfunction. Klotho improved WT cell survival and migration, increasing proliferation and decreasing necrosis independent of effects on apoptosis. Conclusions: Klotho plays an important role in VSMC energetics which requires Pink1 to mediate energetic switching between oxidative and glycolytic metabolism. Klotho improved VSMC phenotype and, if targeted to the plaque early in the disease, could be a useful strategy to delay the effects of plaque ageing and improve VSMC survival.     

Apportionment of primary and secondary organic aerosols in southern California during the 2005 study of organic aerosols in riverside (SOAR-1)

Ambient sampling was conducted in Riverside, California during the 2005 Study of Organic Aerosols in Riverside to characterize the composition and sources of organic aerosol using a variety of state-of-the-art instrumentation and source apportionmenttechniques. The secondary organic aerosol (SOA) mass is estimated by elemental carbon and carbon monoxide tracer methods, water soluble organic carbon content, chemical mass balance of organic molecular markers, and positive matrix factorization of high-resolution aerosol mass spectrometer data. Estimates obtained from each ofthese methods indicate that the organic fraction in ambient aerosol is overwhelmingly secondary in nature during a period of several weeks with moderate ozone concentrations and that SOA is the single largest component of PM1 aerosol in Riverside. Average SOA/OA contributions of 70-90% were observed during midday periods, whereas minimum SOA contributions of approximately 45% were observed during peak morning traffic periods. These results are contraryto previous estimates of SOAthroughout the Los Angeles Basin which reported that, other than during severe photochemical smog episodes, SOA was lower than primary OA. Possible reasons for these differences are discussed.     

Prospects for insulin delivery by ex-vivo somatic cell gene therapy

The principle of insulin delivery by ex-vivo somatic cell gene therapy involves the removal of non-B-cell somatic cells (e.g. fibroblasts) from a diabetic patient, and genetically altering them in vitro to produce and secrete insulin. The cells can be grown in culture and returned to the donor as a source of insulin replacement. Cells modified in this way could be evaluated before implantation, and reserve stocks could be cryopreserved. By using the patient's own cells, the procedure should obviate the need for immunosuppression and overcome the problem of tissue supply, while avoiding a recurrence of cell destruction. Ex-vivo somatic cell gene therapy requires an accessible and robust cell type that is amenable to multiple transfections and subject to controlled proliferation. Special problems associated with the use of non-B-cell somatic cells include the processing of proinsulin to insulin, and the conferment of sensitivity to glucose-stimulated proinsulin biosynthesis and regulated insulin release. Preliminary studies using fibroblasts, pituitary cells, kidney (COS) cells and ovarian (CHO) cells suggest that these challenges could be met, and that ex-vivo somatic cell gene therapy offers a feasible approach to insulin replacement therapy.     

Schizophrenia outpatients' perceptions of their parents: Is expressed emotion a factor?

The factors that mediate the association between expressed emotion (EE) and relapse in schizophrenia patients are still unknown. Many researchers hypothesize that interactions with high-EE individuals are stressful for patients, leaving them vulnerable to relapse. It would be useful to investigate whether patients perceive interactions with high-EE parents as stressful. In this study, associations were examined between levels of EE in parents and the types of personal memories patients had about these parents. EE ratings were obtained for both parents of 27 schizophrenia outpatients, and patients were asked to describe "happy, nonstressful" memories and "unhappy, stressful" memories during 2 interviews. Patients recounted fewer nonstressful memories and more stressful memories about high- versus low-EE parents. Implications of these results are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differences in anaerobic performance between boys and men

The purpose of this study was to compare the anaerobic performance of 11-12 year old prepubescent boys (stage 1; n = 18) using a maximal effort 90 s cycling test to that of adult men (n = 19). Performance was separated into short-term anaerobic power (SAP; work in 10 s), intermediate-term anaerobic capacity (IAC; work in 30 s) and long-term anaerobic capacity (LAC; work in 90 s). Resistance on the Monark cycle ergometer was chosen as the highest tolerable load for the 90 s test and set at 2.6 and 3.8 J. rev-1.kg body mass-1 for boys and men, respectively. Power drop-off (%PD) was determined as the change in 5 s power outputs from 0-90 s. Blood lactates were measured at rest (pretest; BL) and at 2 (BL2) and 5 (BL5) min post test. Absolute and relative (to weight or thigh volume) scores for SAC, IAC and LAC were 33-40% lower in the boys compared to the men (p < 0.001). The men demonstrated significantly greater %PD over the 90 s (32.2%) compared to the 25.3% PD of the boys (p < 0.001), suggesting that the development of fatigue was greater in the men even though power and work outputs were high. Resting BL values were similar for both groups. Mean BL2 and BL5 were higher (p < 0.01) in the men (13.5, SD = 3.4; 12.5, SD = 2.8 mmol.l-1) than in the boys (9.1, SD = 1.7; 8.3, SD = 1.6 mmol.l-1). The anaerobic performance of the boys compared to the men cannot be completely explained by the lower resistance setting used. Although the boys were 50% lighter than the men, their resistance was 70% of that used for the men. The results do not support the contention that children and adults have similar abilities in short term, exhaustive work when corrected for size. Prepubescent boys appear to be limited in their ability to perform short-term as well as intermediate and long term anaerobic exercise compared to adult males.     

Effect of novel mixed ETA/ETB antagonists on responses to ET-1 in human small muscular pulmonary arteries

Selective ETA and ETB receptor antagonists do not fully inhibit responses to ET-1 in human small pulmonary arteries. Here, we have compared the influence of the novel mixed ETA/ETB antagonists SB/217242, SB/234551 and SB/209670 on ET-1-mediated vasoconstriction in these vessels. ET-1 was a potent vasoconstrictor (pEC50: 8.14+/-0.05, n=5) and the concentration-response curve to ET-1 was biphasic in nature. All three mixed antagonists (1 microM) inhibited the responses to ET-1, abolishing the biphasic form of the concentration response curve. The order of potency was SB 209670>SB 234551>/=SB 217242 with estimated pKb values of 8.0+/-0.20, 6.8+/-0.17 and 6. 6+/-0.11 respectively (n=3-5).     

Comparative affective reactivity of different types of communication disturbances in schizophrenia.

Twenty-nine schizophrenic outpatients provided speech samples on affectively positive and negative topics. These samples were assessed for several different types of communication failures by using the Communication Disturbances Index. Frequencies of overinclusive references, ambiguous word meanings, and ambiguous referents increased in the affectively negative condition; frequencies of missing referents and instances of syntactic unclarity did not change across affective conditions. Degree of overall affective reactivity of speech was associated with severity of the core positive schizophrenic syndrome. These findings support the idea that different types of schizophrenic communication disturbances are associated with different underlying pathophysiological processes, that some are more reactive to affect than others, and that affective reactivity of these symptoms is associated with the positive schizophrenic process. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reference performance and positive and negative thought disorder: A follow-up study of manics and schizophrenics.

Manic (n?=?22) and schizophrenic (n?=?28) patients were examined with clinical and linguistic measures of language performance at an acute admission and at a follow-up. It was found that the frequency of incompetent references and the severity of negative thought disorder were stable independent traits of schizophrenics. Furthermore, low levels of verbal productivity, indexed both clinically and linguistically, predicted the likelihood that schizophrenic subjects would be psychotic at follow-up. The language performance of manic patients was not temporally stable, although high levels of reference failures at index predicted psychosis at follow-up. These results are evaluated in terms of their implications for differentiating state-specific aspects of speech competence from potential vulnerability markers in these two types of patients. (PsycINFO Database Record (c) 2010 APA, all rights reserved)