Disease progression after bone marrow transplantation in a model of multiple sclerosis is associated with chronic microglial and glial progenitor response

Multiple sclerosis (MS), the most common nontraumatic cause of neurologic disability in young adults in economically developed countries, is characterized by inflammation, gliosis, demyelination, and neuronal degeneration in the CNS. Bone marrow transplantation (BMT) can suppress inflammatory disease in a majority of patients with MS but retards clinical progression only in patients treated in the early stages of the disease. Here, we applied BMT in a mouse model of neuroinflammation, experimental autoimmune encephalomyelitis (EAE), and investigated the kinetics of reconstitution of the immune system in the periphery and in the CNS using bone marrow cells isolated from syngeneic donors constitutively expressing green fluorescent protein. This approach allowed us to dissect the contribution of donor cells to the turnover of resident microglia and to the pathogenesis of observed disease relapses after BMT. BMT effectively blocked or delayed EAE development when mice were treated early in the course of the disease but was without effect in mice with chronic disease. We found that there is minimal overall replacement of host microglia with donor cells in the CNS and that newly transplanted cells do not appear to contribute to disease progression. In contrast, EAE relapses are accompanied by the robust activation of endogenous microglial and macroglial cells, which further involves the maturation of endogenous Olig2 glial progenitor cells into reactive astrocytes through the cytoplasmic translocation of Olig2 and the expression of CD44 on the cellular membrane. The observed maturation of large numbers of reactive astrocytes from glial progenitors and the chronic activation of host microglial cells have relevance for our understanding of the resident glial response to inflammatory injury in the CNS. Our data indicate that reactivation of a local inflammatory process after BMT is sustained predominantly by endogenous microglia/macrophages.     

Lower levels of inhibin A and pro-alphaC during the luteal phase after triggering oocyte maturation with a gonadotropin-releasing hormone agonist versus human chorionic gonadotropin

OBJECTIVE: To investigate the effect of triggering oocyte maturation with GnRH agonist on corpus luteum function by measuring luteal phase levels of inhibin A and pro-alphaC. DESIGN: Prospective randomized trial. SETTING: In vitro fertilization (IVF) program at a university hospital. PATIENT(S): Infertile women undergoing IVF-ET treatment. INTERVENTION(S): Controlled ovarian hyperstimulation with FSH and GnRH antagonist, triggering of final oocyte maturation with either hCG (n = 8) or GnRH agonist (n = 8), IVF-ET, and collection of blood samples every 2-3 days during the luteal phase. MEASUREMENTS AND MAIN RESULTS: Luteal phase serum levels of inhibin A and pro-alphaC, P, and E(2). RESULT(S): Levels of inhibin A, pro-alphaC, estrogen, and P were significantly lower from day 4 to day 14 after triggering final oocyte maturation by GnRH agonist compared with hCG. Maximal luteal serum inhibin A and pro-alphaC levels were 91.5 +/- 23.6 and 184.1 +/- 23.5 pg/mL in the GnRH agonist-treated women compared with 464.7 +/- 209.1 and 7,351.6 +/- 934.3 pg/mL in women treated with hCG. CONCLUSION(S): Triggering final oocyte maturation with GnRH agonist instead of hCG in IVF cycles dramatically decreases luteal levels of inhibins, reflecting significant inhibition of the corpus luteum function. This effect may explain, at least in part, the mechanism of ovarian hyperstimulation syndrome prevention by the use of GnRH agonist.     

002 高血压及抗高血压药物与Ⅱ型糖尿病

本文采用前瞻性群体研究旨在确定降压药物的应用与继发Ⅱ型糖尿病的危险之间是否存在独立的相关性。 作者对12 550名(年龄45-64岁)无糖尿病的成年人进行全面健康评价(包括药物的使用及血压测定)。高血压判定标准为收缩压≥140mmH-g(1mmHg=0.1333 kPa)或舒张压≥90mmHg。确定高血压患者3 804例,根据使用降压药物的种类分为血管紧张素转化酶抑制剂(ACEI)162例,β阻滞剂543例,钙拮抗剂96例,噻嗪利尿剂458例,其它单一药物137例,多种药物(≥2种)934例,其余1 474例高血压患者未给予任何抗高血压药物治疗。随访3年及6年后,通过测定空腹血糖浓度[糖尿病判定标准为：空腹血糖≥126m/dl(≥7.0mmol/L)餐后血糖≥200m/dl(≥11.1mmol/L)]评价糖尿病新病例的发生率。     

Links that speak: The global language network and its association with global fame

Languages vary enormously in global importance because of historical, demographic, political, and technological forces. However, beyond simple measures of population and economic power, there has been no rigorous quantitative way to define the global influence of languages. Here we use the structure of the networks connecting multilingual speakers and translated texts, as expressed in book translations, multiple language editions of Wikipedia, and Twitter, to provide a concept of language importance that goes beyond simple economic or demographic measures. We find that the structure of these three global language networks (GLNs) is centered on English as a global hub and around a handful of intermediate hub languages, which include Spanish, German, French, Russian, Portuguese, and Chinese. We validate the measure of a language’s centrality in the three GLNs by showing that it exhibits a strong correlation with two independent measures of the number of famous people born in the countries associated with that language. These results suggest that the position of a language in the GLN contributes to the visibility of its speakers and the global popularity of the cultural content they produce.Of the thousands of languages that have ever been spoken, only a handful have become influential enough to be considered global languages. However, how do we measure the global influence of a language? What are the implications of a world in which only a handful of languages are globally influential?In the past, researchers have used a variety of measures to determine the global influence of a language. Several studies have relied on measures that proxy the global influence of a language using the population and wealth of its speakers (1–4). While wealth and population approximate a language’s influence, as the dissemination of a language has historically required a strong power base (5), such measures fail to capture the global influence of a language: often the speakers of a language, and their wealth, are locally concentrated, making the language locally influential rather than globally influential.An alternative method to measure the global influence of a language is to focus on who speaks that language, and in particular, on how connected the speakers of that language are. In the words of linguist David Crystal, “Why a language becomes a global language has little to do with the number of people who speak it. It is much more to do with who those speakers are.” (5) In the past, Latin was the pan-European language, not because it was the mother tongue of most Europeans, but because it was the language of the Roman Empire and later the language of the Catholic Church, scholars, and educators (5). The use of Latin by well-connected elites set it apart from other languages and helped Latin endure as a universal language for more than 1,000 years.However, can we use these ideas to identify which modern languages are globally influential? If global languages are those connecting international elites, then we can identify the global languages associated with particular elites by mapping their networks of multilingual coexpressions. Examples of multilingual coexpressions include book translations, edits to multiple language editions of Wikipedia, and posting short messages on Twitter (“tweets”) in multiple languages. These coexpressions define networks (Fig. 1) that—even though not representative of the world’s general population—represent a coarse map of the links connecting the elites that participate of these three important global forums, as social connections often require a shared language.Open in a separate windowFig. 1.Visualizations of the three GLNs. The three GLNs contain all language connections that involve at least six users (Twitter and Wikipedia) or six translations and that are significant with P < 0.01.In this paper, we map the global language networks (GLNs) expressed in three large records of linguistic expression, and use the structure of these networks to determine the degree to which each language is global. First, we look at a collection of more than 2.2 million book translations compiled by UNESCO’s Index Translationum project. This dataset allows us to map the network of book translations, which are produced by individuals with a high literary capacity (authors and professional translators) and are shaped by market forces, such as the demand for books in different languages. Each translation from one language to another forms a connection. Next, we map the network of linguistic coexpressions expressed by the community of digitally engaged knowledge specialists that edit Wikipedia. Here, two languages are connected when users that edit an article in one Wikipedia language edition are significantly more likely to also edit an article in another language edition. Finally, we map the network of linguistic coexpressions expressed in Twitter. Here, two languages are connected when users that tweet in a language are also significantly more likely to tweet in another language.These three networks allow us to map the paths of direct and indirect communication between speakers from different languages. Our method formalizes the intuition that certain languages are disproportionately influential because they provide direct and indirect paths of translation among most of the world’s other languages. For example, it is easy for an idea conceived by a Spaniard to reach an Englishman through bilingual speakers of English and Spanish. An idea conceived by a Vietnamese speaker, however, might only reach a Mapudungun speaker in south-central Chile through a circuitous path that connects bilingual speakers of Vietnamese and English, English and Spanish, and Spanish and Mapudungun. In both cases, however, English and Spanish are still involved in the flow of information, indicating that they act as global languages. In the first example, Spanish and English have a direct involvement because communication is flowing among their speakers. In the latter case, the involvement is indirect and emerges from the lack of speakers that can communicate in both Vietnamese and Mapudungun. These indirect connections make multilingual speakers of global languages globally influential, as they mediate the flow of information not only among each other, but also, among people with whom they do not share a language (6).     

Studies of phlebotomine sand fly (Diptera: Psychodidae) populations in limestone areas and caves of western Malaysia

Phlebotomine sand flies were collected using CO2 baited CDC light trap in 2000 and 2001 in limestone areas and caves of western Malaysia. A total of 1,548 specimens were collected comprising 18 species from two genera: Phlebotomus (6 spp) and Sergentomyia (12 spp). Phlebotomus major major (38.9%) was the predominant species followed by Sergentomyia perturbans (20.1%), P. stantoni (15.3%) and others. Biting activity of the sand flies at the Gua Senyum caves, Gua Kota Gelanggi, Batu caves and Gua Kelam were observed using the bare leg landing catch (BLC) technique. Four Phlebotomus spp at Gua Senyum were found to bite humans with a unimodal biting peak (between 01:00 and 04:00 AM). At Gua Kota Gelanggi P. major major was observed to bite humans, but at Batu Caves and Gua Kelam no sand flies were observed to bite humans. Sergentomyia spp did not feed on humans even though high numbers were caught in light traps. The populations of phleobotomine sand flies fluctuated, with several peaks especially among P. major major which peaked in December and was low in February and August. Phlebotomus stantoni was abundant throughout 2001. Most species populations were weakly related to rainfall because they inhabited caves.     

The impact of GP IIb/IIIa inhibitors during primary percutaneous coronary intervention in acute myocardial infarction patients

The use of glycoprotein (GP) IIb/IIIa inhibitors during percutaneous coronary interventions (PCI) in the acute phase of myocardial infarction (AMI) is still a matter of debate. The aim of the present study was to compare the outcomes of patients with acute ST-segment elevation myocardial infarction who underwent primary PCI and were concomitantly treated with GP IIb/IIIa inhibitors with those who were not treated with these drugs. Between January 1996 and November 2003, a total of 418 consecutive patients underwent PCI in the setting of ST-segment elevation AMI. At the operator's discretion, 287 patients were concomitantly treated with GP IIb/IIIa inhibitors and 115 patients were not. Angiographic success and final TIMI 3 flow in the infarct-related artery was achieved more frequently in patients treated with GP IIb/IIIa inhibitors (90% vs. 77%; p=0.001). The in-hospital composite endpoint of death, reinfarction and bleeding complications was significantly better in patients treated with GP IIb/IIIa inhibitors (4% vs. 12%; p=0.005). Furthermore, the adjusted 12-month survival rate was significantly better in these patients (RR: 2.99, CI: 1.29-6.9; p=0.01). Therefore, adjunctive therapy with GP IIbIIIa inhibitors during primary PCI is associated with improved short-term outcomes and one-year survival without an increased risk of bleeding.     

Orthostatic hypotension as a risk factor for incident heart failure: the atherosclerosis risk in communities study

Heart failure causes significant morbidity and mortality. Distinguishing risk factors for incident heart failure can help identify at-risk individuals. Orthostatic hypotension may be a risk factor for incident heart failure; however, this association has not been fully explored, especially in nonwhite populations. The Atherosclerosis Risk in Communities Study included 12363 adults free of prevalent heart failure with baseline orthostatic measurements. Orthostatic hypotension was defined as a decrease of systolic blood pressure ≥20 mmHg or diastolic blood pressure ≥10 mmHg with position change from supine to standing. Incident heart failure was identified from hospitalization or death certificate disease codes. Over 17.5 years of follow-up, orthostatic hypotension was associated with incident heart failure with multivariable adjustment (hazard ratio: 1.54 [95% CI: 1.30-1.82]). This association was similar across race and sex groups. A stronger association was identified in younger individuals ≤55 years old (hazard ratio: 1.90 [95% CI: 1.41-2.55]) than in older individuals >55 years old (hazard ratio: 1.37 [95% CI: 1.12-1.69]; interaction P=0.034). The association between orthostatic hypotension and incident heart failure persisted with exclusion of those with diabetes mellitus, coronary heart disease, and those on antihypertensives or psychiatric or Parkinson disease medications. However, exclusion of those with hypertension somewhat attenuated the association (hazard ratio: 1.34 [95% CI: 1.00-1.80]). We identified orthostatic hypotension as a predictor of incident heart failure among middle-aged individuals, particularly those 45 to 55 years of age. This association may be partially mediated through hypertension. Orthostatic measures may enhance risk stratification for future heart failure development.     

Serum uric acid and risk of ischemic stroke: the ARIC Study

AIMS: Since serum uric acid (UA) is strongly associated with cardiovascular risk factors, it has been debated whether serum UA is a stroke risk factor or whether UA may be simply "marking" subjects with other, causal risk factors. We therefore investigated the relation between UA and ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) Study. METHODS AND RESULTS: Of 15,792 ARIC participants, 13,413 who were free of recognized stroke or coronary heart disease (CHD) at baseline and had a baseline UA measurement were included in the analysis. We followed the participants for ischemic stroke incidence (N=381) over 12.6 years. Although serum UA was independently and positively related to ischemic stroke incidence when we adjusted for age, sex, race, and education, the positive relation was weakened when additionally adjusted for possible confounding variables. The positive multivariate-adjusted association between serum UA and ischemic stroke was observed among subjects not using diuretics (adjusted relative hazard in the highest quartile versus the lowest: relative hazard (RH)=1.49; 95% confidence interval (CI): 1.00-2.23) (P for trend: 0.02), but not among diuretic users (P for interaction: 0.08). CONCLUSION: Our findings suggest that UA is an independent predictor of ischemic stroke among subjects not using diuretics, but that elevated UA itself may not cause ischemic stroke.