Triglycerides and TG/HDL‑C ratio as surrogate markers for insulin resistance in Nigerian women with polycystic ovary syndrome

Background: Dyslipidemia is one of the most perplexing metabolic consequences in polycystic ovary syndrome (PCOS). Obesity, insulin resistance (IR), and hyperandrogenism, the pervasive features of PCOS, play significant pathophysiological roles in the lipidemic aberrations associated with the syndrome.Objective: This study aimed to assess the diagnostic utility of triglyceride (TG) and triglyceride to high‑density lipoprotein‑cholesterol (TG/HDL‑C) ratio as surrogate markers for identifying IR in infertile Nigerian women with PCOS.Materials and Methods: Eighty‑seven infertile women with PCOS were selected according to the Androgen Excess Society criteria and categorized into two groups. After anthropometric measurements, fasting blood samples were assayed for plasma glucose, serum insulin, total cholesterol, TG, HDL‑C while lipoprotein ratios were calculated. Homeostasis model assessment for IR (HOMA‑IR) was used in defining IR. The areas under the receiver operating characteristic (ROC) curve analysis were used to compare the power of the serum markers, and to obtain the optimal cutoffs of TG and TG/HDL‑C with HOMA‑IR.Results: TGs correlated significantly with HOMA‑IR in the obese PCOS women. However, the areas under the ROC of potential markers showed no significant marker for HOMA‑IR. The highest area under the curve of ROC for TG belongs to the obese group with a sensitivity of 56% and specificity of 53% (TG ≥ 92.5mg/dL) as a marker of IR in obese PCOS women.Conclusion: TG and TG/HDL‑C would not be reliable markers of IR, and a concerted approach in finding surrogate markers will benefit future  investigations. Key words: Insulin resistance; Nigerian women; polycystic ovary syndrome; surrogate marker; triglyceride

Malariometric indices among Nigerian children in a rural setting

Malaria contributes to high childhood morbidity and mortality in Nigeria. To determine its endemicity in a rural farming community in the south-south of Nigeria, the following malariometric indices, namely, malaria parasitaemia, spleen rates, and anaemia were evaluated in children aged 2-10 years. This was a descriptive cross-sectional survey among school-age children residing in a rubber plantation settlement. The children were selected from six primary schools using a multistaged stratified cluster sampling technique. They were all examined for pallor, enlarged spleen, or liver among other clinical parameters and had blood films for malaria parasites. Of the 461 children recruited, 329 (71.4%) had malaria parasites. The prevalence of malaria parasitaemia was slightly higher in the under fives than that of those ≥5 years, 76.2% and 70.3%, respectively. Splenic enlargement was present in 133 children (28.9%). The overall prevalence of anaemia was 35.7%. Anaemia was more common in the under-fives (48.8%) than in those ≥5 years (32.8%). The odds of anaemia in the under fives were significantly higher than the odds of those ≥5 years (OR = 1.95 [1.19-3.18]). Malaria is highly endemic in this farming community and calls for intensification of control interventions in the area with special attention to school-age children

Distinct Functions of Period2 and Period3 in the Mouse Circadian System Revealed by In Vitro Analysis

The mammalian circadian system, which is composed of a master pacemaker in the suprachiasmatic nuclei (SCN) as well as other oscillators in the brain and peripheral tissues, controls daily rhythms of behavior and physiology. Lesions of the SCN abolish circadian rhythms of locomotor activity and transplants of fetal SCN tissue restore rhythmic behavior with the periodicity of the donor's genotype, suggesting that the SCN determines the period of the circadian behavioral rhythm. According to the model of timekeeping in the SCN, the Period (Per) genes are important elements of the transcriptional/translational feedback loops that generate the endogenous circadian rhythm. Previous studies have investigated the functions of the Per genes by examining locomotor activity in mice lacking functional PERIOD proteins. Variable behavioral phenotypes were observed depending on the line and genetic background of the mice. In the current study we assessed both wheel-running activity and Per1-promoter-driven luciferase expression (Per1-luc) in cultured SCN, pituitary, and lung explants from Per2−/− and Per3−/− mice congenic with the C57BL/6J strain. We found that the Per2−/− phenotype is enhanced in vitro compared to in vivo, such that the period of Per1-luc expression in Per2−/− SCN explants is 1.5 hours shorter than in Per2+/+ SCN, while the free-running period of wheel-running activity is only 11 minutes shorter in Per2−/− compared to Per2+/+ mice. In contrast, circadian rhythms in SCN explants from Per3−/− mice do not differ from Per3+/+ mice. Instead, the period and phase of Per1-luc expression are significantly altered in Per3−/− pituitary and lung explants compared to Per3+/+ mice. Taken together these data suggest that the function of each Per gene may differ between tissues. Per2 appears to be important for period determination in the SCN, while Per3 participates in timekeeping in the pituitary and lung

Hyperglycemia regulates thioredoxin-ROS activity through induction of thioredoxin-interacting protein (TXNIP) in metastatic breast cancer-derived cells MDA-MB-231

<p>Abstract</p> <p>Background</p> <p>We studied the RNA expression of the genes in response to glucose from 5 mM (condition of normoglycemia) to 20 mM (condition of hyperglycemia/diabetes) by microarray analysis in breast cancer derived cell line MDA-MB-231. We identified the thioredoxin-interacting protein (TXNIP), whose RNA level increased as a gene product particularly sensitive to the variation of the level of glucose in culture media. We investigated the kinesis of the TXNIP RNA and protein in response to glucose and the relationship between this protein and the related thioredoxin (TRX) in regulating the level of reactive oxygen species (ROS) in MDA-MB-231 cells.</p> <p>Methods</p> <p>MDA-MB-231 cells were grown either in 5 or 20 mM glucose chronically prior to plating. For glucose shift (5/20), cells were plated in 5 mM glucose and shifted to 20 mM at time 0. Cells were analyzed with Affymetrix Human U133A microarray chip and gene expression profile was obtained. Semi-quantitative RT-PCR and Western blot was used to validate the expression of TXNIP RNA and protein in response to glucose, respectively. ROS were detected by CM-H2DCFDA (5–6-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate) and measured for mean fluorescence intensity with flow cytometry. TRX activity was assayed by the insulin disulfide reducing assay.</p> <p>Results</p> <p>We found that the regulation of TXNIP gene expression by glucose in MDA-MB-231 cells occurs rapidly within 6 h of its increased level (20 mM glucose) and persists through the duration of the conditions of hyperglycemia. The increased level of TXNIP RNA is followed by increased level of protein that is associated with increasing levels of ROS and reduced TRX activity. The inhibition of the glucose transporter GLUT1 by phloretin notably reduces TXNIP RNA level and the inhibition of the p38 MAP kinase activity by SB203580 reverses the effects of TXNIP on ROS-TRX activity.</p> <p>Conclusion</p> <p>In this study we show that TXNIP is an oxidative stress responsive gene and its expression is exquisitely regulated by glucose level in highly metastatic MDA-MB-231 cells.</p

Killer whales and marine mammal trends in the North Pacific : a re-examination of evidence for sequential megafauna collapse and the prey-switching hypothesis

This paper is not subject to U.S. copyright. The definitive version was published in Marine Mammal Science 23 (2007): 766–802, doi:10.1111/j.1748-7692.2006.00093.x.Springer et al. (2003) contend that sequential declines occurred in North Pacific populations of harbor and fur seals, Steller sea lions, and sea otters. They hypothesize that these were due to increased predation by killer whales, when industrial whaling's removal of large whales as a supposed primary food source precipitated a prey switch. Using a regional approach, we reexamined whale catch data, killer whale predation observations, and the current biomass and trends of potential prey, and found little support for the prey-switching hypothesis. Large whale biomass in the Bering Sea did not decline as much as suggested by Springer et al., and much of the reduction occurred 50–100 yr ago, well before the declines of pinnipeds and sea otters began; thus, the need to switch prey starting in the 1970s is doubtful. With the sole exception that the sea otter decline followed the decline of pinnipeds, the reported declines were not in fact sequential. Given this, it is unlikely that a sequential megafaunal collapse from whales to sea otters occurred. The spatial and temporal patterns of pinniped and sea otter population trends are more complex than Springer et al. suggest, and are often inconsistent with their hypothesis. Populations remained stable or increased in many areas, despite extensive historical whaling and high killer whale abundance. Furthermore, observed killer whale predation has largely involved pinnipeds and small cetaceans; there is little evidence that large whales were ever a major prey item in high latitudes. Small cetaceans (ignored by Springer et al.) were likely abundant throughout the period. Overall, we suggest that the Springer et al. hypothesis represents a misleading and simplistic view of events and trophic relationships within this complex marine ecosystem

A beer a minute in Texas football: Heavy drinking and the heroizing of the antihero in Friday Night Lights

This article applies a qualitative framing analysis to the first three seasons of the television series Friday Night Lights, focusing particularly on its incorporation of heavy drinking into narrative representations of the player whose character is most consistently central to the game of football as fictionally mediated in small-town Texas over the course of those three seasons. The analysis suggests that over the course of that period Friday Night Lights embeds nuanced social meanings in its framing of alcohol use by that player and other characters so as to associate it with multiple potential outcomes. Yet among those outcomes, the most dominant framing works to, in effect, reverse a progression through which media representations historically evolved from a heroic model toward an antihero model, with heavy drinking central to that narrative process of meaning-making in such messages.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

The evolution of the upright posture and gait—a review and a new synthesis

During the last century, approximately 30 hypotheses have been constructed to explain the evolution of the human upright posture and locomotion. The most important and recent ones are discussed here. Meanwhile, it has been established that all main hypotheses published until the last decade of the past century are outdated, at least with respect to some of their main ideas: Firstly, they were focused on only one cause for the evolution of bipedality, whereas the evolutionary process was much more complex. Secondly, they were all placed into a savannah scenario. During the 1990s, the fossil record allowed the reconstruction of emerging bipedalism more precisely in a forested habitat (e.g., as reported by Clarke and Tobias (Science 269:521–524, 1995) and WoldeGabriel et al. (Nature 412:175–178, 2001)). Moreover, the fossil remains revealed increasing evidence that this part of human evolution took place in a more humid environment than previously assumed. The Amphibian Generalist Theory, presented first in the year 2000, suggests that bipedalism began in a wooded habitat. The forests were not far from a shore, where our early ancestor, along with its arboreal habits, walked and waded in shallow water finding rich food with little investment. In contrast to all other theories, wading behaviour not only triggers an upright posture, but also forces the individual to maintain this position and to walk bipedally. So far, this is the only scenario suitable to overcome the considerable anatomical and functional threshold from quadrupedalism to bipedalism. This is consistent with paleoanthropological findings and with functional anatomy as well as with energetic calculations, and not least, with evolutionary psychology. The new synthesis presented here is able to harmonise many of the hitherto competing theories

Characterization of ERK Docking Domain Inhibitors that Induce Apoptosis by Targeting Rsk-1 and Caspase-9

<p>Abstract</p> <p>Background</p> <p>The extracellular signal-regulated kinase-1 and 2 (ERK1/2) proteins play an important role in cancer cell proliferation and survival. ERK1/2 proteins also are important for normal cell functions. Thus, anti-cancer therapies that block all ERK1/2 signaling may result in undesirable toxicity to normal cells. As an alternative, we have used computational and biological approaches to identify low-molecular weight compounds that have the potential to interact with unique ERK1/2 docking sites and selectively inhibit interactions with substrates involved in promoting cell proliferation.</p> <p>Methods</p> <p>Colony formation and water soluble tetrazolium salt (WST) assays were used to determine the effects of test compounds on cell proliferation. Changes in phosphorylation and protein expression in response to test compound treatment were examined by immunoblotting and <it>in vitro </it>kinase assays. Apoptosis was determined with immunoblotting and caspase activity assays.</p> <p>Results</p> <p><it>In silico </it>modeling was used to identify compounds that were structurally similar to a previously identified parent compound, called <b>76</b>. From this screen, several compounds, termed <b>76.2</b>, <b>76.3</b>, and <b>76.4 </b>sharing a common thiazolidinedione core with an aminoethyl side group, inhibited proliferation and induced apoptosis of HeLa cells. However, the active compounds were less effective in inhibiting proliferation or inducing apoptosis in non-transformed epithelial cells. Induction of HeLa cell apoptosis appeared to be through intrinsic mechanisms involving caspase-9 activation and decreased phosphorylation of the pro-apoptotic Bad protein. Cell-based and <it>in vitro </it>kinase assays indicated that compounds <b>76.3 </b>and <b>76.4 </b>directly inhibited ERK-mediated phosphorylation of caspase-9 and the p90Rsk-1 kinase, which phosphorylates and inhibits Bad, more effectively than the parent compound <b>76</b>. Further examination of the test compound's mechanism of action showed little effects on related MAP kinases or other cell survival proteins.</p> <p>Conclusion</p> <p>These findings support the identification of a class of ERK-targeted molecules that can induce apoptosis in transformed cells by inhibiting ERK-mediated phosphorylation and inactivation of pro-apoptotic proteins.</p

Melanoma: A model for testing new agents in combination therapies

Treatment for both early and advanced melanoma has changed little since the introduction of interferon and IL-2 in the early 1990s. Recent data from trials testing targeted agents or immune modulators suggest the promise of new strategies to treat patients with advanced melanoma. These include a new generation of B-RAF inhibitors with greater selectivity for the mutant protein, c-Kit inhibitors, anti-angiogenesis agents, the immune modulators anti-CTLA4, anti-PD-1, and anti-CD40, and adoptive cellular therapies. The high success rate of mutant B-RAF and c-Kit inhibitors relies on the selection of patients with corresponding mutations. However, although response rates with small molecule inhibitors are high, most are not durable. Moreover, for a large subset of patients, reliable predictive biomarkers especially for immunologic modulators have not yet been identified. Progress may also depend on identifying additional molecular targets, which in turn depends upon a better understanding of the mechanisms leading to response or resistance. More challenging but equally important will be understanding how to optimize the treatment of individual patients using these active agents sequentially or in combination with each other, with other experimental treatment, or with traditional anticancer modalities such as chemotherapy, radiation, or surgery. Compared to the standard approach of developing new single agents for licensing in advanced disease, the identification and validation of patient specific and multi-modality treatments will require increased involvement by several stakeholders in designing trials aimed at identifying, even in early stages of drug development, the most effective way to use molecularly guided approaches to treat tumors as they evolve over time