STUDIES ON CONSTANT PARAMAGNETISM : PART II: Diamagnetic compounds containing a transition element.

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STUDIES ON CONSTANT PARAMAGNETISM: PART I.

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Lipidomics Reveals Early Metabolic Changes in Subjects with Schizophrenia: Effects of Atypical Antipsychotics

There is a critical need for mapping early metabolic changes in schizophrenia to capture failures in regulation of biochemical pathways and networks. This information could provide valuable insights about disease mechanisms, trajectory of disease progression, and diagnostic biomarkers. We used a lipidomics platform to measure individual lipid species in 20 drug-naïve patients with a first episode of schizophrenia (FE group), 20 patients with chronic schizophrenia that had not adhered to prescribed medications (RE group), and 29 race-matched control subjects without schizophrenia. Lipid metabolic profiles were evaluated and compared between study groups and within groups before and after treatment with atypical antipsychotics, risperidone and aripiprazole. Finally, we mapped lipid profiles to n3 and n6 fatty acid synthesis pathways to elucidate which enzymes might be affected by disease and treatment. Compared to controls, the FE group showed significant down-regulation of several n3 polyunsaturated fatty acids (PUFAs), including 20:5n3, 22:5n3, and 22:6n3 within the phosphatidylcholine and phosphatidylethanolamine lipid classes. Differences between FE and controls were only observed in the n3 class PUFAs; no differences where noted in n6 class PUFAs. The RE group was not significantly different from controls, although some compositional differences within PUFAs were noted. Drug treatment was able to correct the aberrant PUFA levels noted in FE patients, but changes in re patients were not corrective. Treatment caused increases in both n3 and n6 class lipids. These results supported the hypothesis that phospholipid n3 fatty acid deficits are present early in the course of schizophrenia and tend not to persist throughout its course. These changes in lipid metabolism could indicate a metabolic vulnerability in patients with schizophrenia that occurs early in development of the disease. © 2013 McEvoy et al

The Effects of Cocaine on Different Redox Forms of Cysteine and Homocysteine, and on Labile, Reduced Sulfur in the Rat Plasma Following Active versus Passive Drug Injections

Received: 28 November 2012 / Revised: 19 April 2013 / Accepted: 6 May 2013 / Published online: 16 May 2013 The Author(s) 2013. This article is published with open access at Springerlink.comThe aim of the present studies was to evaluate cocaine-induced changes in the concentrations of different redox forms of cysteine (Cys) and homocysteine (Hcy), and products of anaerobic Cys metabolism, i.e., labile, reduced sulfur (LS) in the rat plasma. The above-mentioned parameters were determined after i.p. acute and subchronic cocaine treatment as well as following i.v. cocaine self-administration using the yoked procedure. Additionally, Cys, Hcy, and LS levels were measured during the 10-day extinction training in rats that underwent i.v. cocaine administration. Acute i.p. cocaine treatment increased the total and protein-bound Hcy contents, decreased LS, and did not change the concentrations of Cys fractions in the rat plasma. In turn, subchronic i.p. cocaine administration significantly increased free Hcy and lowered the total and protein-bound Cys concentrations while LS level was unchanged. Cocaine self-administration enhanced the total and protein-bound Hcy levels, decreased LS content, and did not affect the Cys fractions. On the other hand, yoked cocaine infusions did not alter the concentration of Hcy fractions while decreased the total and protein-bound Cys and LS content. This extinction training resulted in the lack of changes in the examined parameters in rats with a history of cocaine self-administration while in the yoked cocaine group an increase in the plasma free Cys fraction and LS was seen. Our results demonstrate for the first time that cocaine does evoke significant changes in homeostasis of thiol amino acids Cys and Hcy, and in some products of anaerobic Cys metabolism, which are dependent on the way of cocaine administration

MicroRNA let-7 suppresses nasopharyngeal carcinoma cells proliferation through downregulating c-Myc expression

Aims: This study aimed at evaluating the potential anti-proliferative effects of the microRNA let-7 family in nasopharyngeal carcinoma (NPC) cells. In addition, the association between let-7 suppression and DNA hypermethylation is examined. Materials and methods: Levels of mature let-7 family members (-a,-b,-d,-e,-g, and-i) in normal nasopharyngeal cells (NP69 and NP460) and nasopharyngeal carcinoma cells (HK1 and HONE1) were measured by real-time quantitative PCR. Cell-proliferation assay and c-Myc immunohistochemical staining were performed on NPC cells transfected with let-7 precursor molecules. In addition, expression changes in let-7 family members in response to demethylating agents (5-azacytidine and zebularine) were also examined. Results: In comparison with the normal nasopharyngeal cells, let-7 (-a,-b,-d,-e,-g, and-i) levels were reduced in nasopharyngeal carcinoma cells. Ectopic expression of the let-7 family in nasopharyngeal carcinoma cells resulted in inhibition of cell proliferation through downregulation of c-Myc expression. Demethylation treatment of nasopharyngeal carcinoma cells caused activation of let-7 expression in poorly differentiated nasopharyngeal carcinoma cells only. Conclusion: Our results suggested that miRNA let-7 might play a role in the proliferation of NPC. DNA methylation is a potential regulatory pathway, which is affected when let-7 is suppressed in NPC cells. However, the extent of DNA hypermethylation/hypomethylation in regulating let-7 expression requires further elucidation. © The Author(s) 2010. This article is published with open access at Springerlink.com.published_or_final_versionSpringer Open Choice, 21 Feb 201

Selenoproteins Are Essential for Proper Keratinocyte Function and Skin Development

Dietary selenium is known to protect skin against UV-induced damage and cancer and its topical application improves skin surface parameters in humans, while selenium deficiency compromises protective antioxidant enzymes in skin. Furthermore, skin and hair abnormalities in humans and rodents may be caused by selenium deficiency, which are overcome by dietary selenium supplementation. Most important biological functions of selenium are attributed to selenoproteins, proteins containing selenium in the form of the amino acid, selenocysteine (Sec). Sec insertion into proteins depends on Sec tRNA; thus, knocking out the Sec tRNA gene (Trsp) ablates selenoprotein expression. We generated mice with targeted removal of selenoproteins in keratin 14 (K14) expressing cells and their differentiated descendents. The knockout progeny had a runt phenotype, developed skin abnormalities and experienced premature death. Lack of selenoproteins in epidermal cells led to the development of hyperplastic epidermis and aberrant hair follicle morphogenesis, accompanied by progressive alopecia after birth. Further analyses revealed that selenoproteins are essential antioxidants in skin and unveiled their role in keratinocyte growth and viability. This study links severe selenoprotein deficiency to abnormalities in skin and hair and provides genetic evidence for the role of these proteins in keratinocyte function and cutaneous development

Subendocardial contractile impairment in chronic ischemic myocardium: assessment by strain analysis of 3T tagged CMR

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to quantify myocardial strain on the subendocardial and epicardial layers of the left ventricle (LV) using tagged cardiovascular magnetic resonance (CMR) and to investigate the transmural degree of contractile impairment in the chronic ischemic myocardium.</p> <p>Methods</p> <p>3T tagged CMR was performed at rest in 12 patients with severe coronary artery disease who had been scheduled for coronary artery bypass grafting. Circumferential strain (C-strain) at end-systole on subendocardial and epicardial layers was measured using the short-axis tagged images of the LV and available software (Intag; Osirix). The myocardial segment was divided into stenotic and non-stenotic segments by invasive coronary angiography, and ischemic and non-ischemic segments by stress myocardial perfusion scintigraphy. The difference in C-strain between the two groups was analyzed using the Mann-Whitney U-test. The diagnostic capability of C-strain was analyzed using receiver operating characteristics analysis.</p> <p>Results</p> <p>The absolute subendocardial C-strain was significantly lower for stenotic (-7.5 ± 12.6%) than non-stenotic segment (-18.8 ± 10.2%, p < 0.0001). There was no difference in epicardial C-strain between the two groups. Use of cutoff thresholds for subendocardial C-strain differentiated stenotic segments from non-stenotic segments with a sensitivity of 77%, a specificity of 70%, and areas under the curve (AUC) of 0.76. The absolute subendocardial C-strain was significantly lower for ischemic (-6.7 ± 13.1%) than non-ischemic segments (-21.6 ± 7.0%, p < 0.0001). The absolute epicardial C-strain was also significantly lower for ischemic (-5.1 ± 7.8%) than non-ischemic segments (-9.6 ± 9.1%, p < 0.05). Use of cutoff thresholds for subendocardial C-strain differentiated ischemic segments from non-ischemic segments with sensitivities of 86%, specificities of 84%, and AUC of 0.86.</p> <p>Conclusions</p> <p>Analysis of tagged CMR can non-invasively demonstrate predominant impairment of subendocardial strain in the chronic ischemic myocardium at rest.</p

The prognostic relevance of interactions between venous invasion, lymph node involvement and distant metastases in renal cell carcinoma after radical nephrectomy

<p>Abstract</p> <p>Background</p> <p>To investigate a possible prognostic significance of interactions between lymph node invasion (LNI), synchronous distant metastases (SDM), and venous invasion (VI) adjusted for mode of detection, Eastern Cooperative Oncology Group performance status (ECOG PS), erythrocyte sedimentation rate (ESR) and tumour size (TS) in 196 patients with renal cell carcinoma treated with radical nephrectomy.</p> <p>Methods</p> <p>Median follow-up was 5.5 years (mean 6.9 years; range 0.01–19.4). The mode of detection, ECOG PS, ESR and TS were obtained from the patients' records. Vena cava invasion and distant metastases were detected by preoperative imaging. The surgical specimens were examined for pathological stage, LNI and VI.</p> <p>Results</p> <p>The univariate analyses showed significant impact of VI, LNI, SDM, ESR and TS (p < 0.001), as well as mode of detection (p = 0.003) and ECOG PS (p = 0.002) on cancer specific survival. In multivariate analyses LNI was significantly associated with survival only in patients without SDM or VI (p < 0.001) with a hazard ratio of 9.0. LNI lost its prognostic significance when SDM or VI was present.</p> <p>Conclusion</p> <p>Our findings underline the prognostic importance of the status of the lymph nodes. LNI, SDM, ESR, and VI were independently associated with cancer specific survival after radical nephrectomy. LNI provided the strongest prognostic information for patients without SDM or VI whereas SDM and VI had strongest impact on survival when there was no nodal involvement.</p

The role of potential vorticity anomalies in the Somali Jet on Indian summer monsoon intraseasonal variability

The climate of the Indian subcontinent is dominated by rainfall arising from the Indian summer monsoon (ISM) during the summer season (June to September). Intraseasonal variability during the monsoon is characterized by periods of heavy rainfall interspersed by drier periods, known as active and break events respectively. Understanding and predicting such events is of vital importance for forecasting human impacts such as water resources. The Somali Jet is a key regional feature of this circulation. In the present study, we find that the spatial structure of Somali Jet potential vorticity (PV) anomalies varies considerably during active and break periods. Analysis of these anomalies shows a mechanism whereby sea surface temperature (SST) anomalies propagate north/northwestwards through the Arabian Sea, caused by a positive feedback loop joining anomalies in SST, convection, modification of PV by diabatic heating and mixing in the atmospheric boundary layer, wind stress curl, and upwelling processes. The feedback mechanism is consistent with observed coupled ocean-atmosphere system variability timescales of approximately 20 days. This research suggests that better understanding and prediction of monsoon subseasonal variability in the South Asian monsoon may be gained by analysis of the day-to-day dynamical evolution of PV in the Somali Jet

Response of Estrogen Receptor-Positive Breast Cancer Tumorspheres to Antiestrogen Treatments

Estrogen signaling plays a critical role in the pathogenesis of breast cancer. Because the majority of breast carcinomas express the estrogen receptor ERα, endocrine therapy that impedes estrogen-ER signaling reduces breast cancer mortality and has become a mainstay of breast cancer treatment. However, patients remain at continued risk of relapse for many years after endocrine treatment. It has been proposed that cancer recurrence may be attributed to cancer stem cells (CSCs)/tumor-initiating cells (TICs). Previous studies in breast cancer have shown that such cells can be enriched and propagated in vitro by culturing the cells in suspension as mammospheres/tumorspheres. Here we established tumorspheres from ERα-positive human breast cancer cell line MCF7 and investigated their response to antiestrogens Tamoxifen and Fulvestrant. The tumorsphere cells express lower levels of ERα and are more tumorigenic in xenograft assays than the parental cells. Both 4-hydroxytamoxifen (4-OHT) and Fulvestrant attenuate tumorsphere cell proliferation, but only 4-OHT at high concentrations interferes with sphere formation. However, treated tumorsphere cells retain the self-renewal capacity. Upon withdrawal of antiestrogens, the treated cells resume tumorsphere formation and their tumorigenic potential remains undamaged. Depletion of ERα shows that ERα is dispensable for tumorsphere formation and xenograft tumor growth in mice. Surprisingly, ERα-depleted tumorspheres display heightened sensitivity to 4-OHT and their sphere-forming capacity is diminished after the drug is removed. These results imply that 4-OHT may inhibit cellular targets besides ERα that are essential for tumorsphere growth, and provide a potential strategy to sensitize tumorspheres to endocrine treatment