bluuebunny/crossref_metadata_2025 huggingface dataset:
Retinoid-Regulated FGF8f Secretion by Osteoblasts Bypasses Retinoid Stimuli to Mediate Granulocytic Differentiation of Myeloid Leukemia Cells
Authors: Chaudhry Parvesh , Yang Xiaochun , Wagner Michael , Jong Ambrose , Wu Lingtao
Published: December 2011

Signaling from the human hematopoietic stem cell (HSC) niche formed by osteoblastic cells regulates hematopoiesis. We previously found that retinoic acid receptor alpha (RARα), a transcription factor activated by retinoic acid (RA), mediates both granulocytic and osteoblastic differentiation. This effect depends on decreased phosphorylation of serine 77 of RARα (RARαS77) by the cyclin-dependent kinase-activating kinase (CAK) complex, a key cell-cycle regulator. In this article, we report that, by suppressing CAK phosphorylation of RARα, RA induces FGF8f to mediate osteosarcoma U2OS cell differentiation in an autocrine manner. By contrast, paracrine FGF8f secreted into osteoblast-conditioned medium by U2OS cells transduced with FGF8f or a phosphorylation-defective RARαS77 mutant, RARαS77A, bypasses RA stimuli to cross-mediate granulocytic differentiation of different types of human leukemic myeloblasts and normal primitive hematopoietic CD34+ cells, possibly through modulating mitogen-activated protein kinase (MAPK) pathways. Further experiments using recombinant human FGF8f (rFGF8f) stimuli, antibody neutralization, and peptide blocking showed that paracrine FGF8f is required for mediating terminal leukemic myeloblast differentiation. These studies indicate a novel regulatory mechanism of granulocytic differentiation instigated by RA from the HSC niche, which links loss of CAK phosphorylation of RARα with paracrine FGF8f-mediated MAPK signaling to mediate leukemic myeloblast differentiation in the absence of RA. Therefore, these findings provide a compelling molecular rationale for further investigation of paracrine FGF8f regulation, with the intent of devising HSC niche-based FGF8f therapeutics for myeloid leukemia, with or without RA-resistance. Mol Cancer Ther; 11(2); 267–76. ©2011 AACR.
Sinistral Portal Hypertension: Clinical Features and Surgical Treatment of Chronic Splenic Vein Occlusion
Authors: Wang Li , Liu Gui-Jie , Chen Yan-Xin , Dong Huai-Ping , Wang Le-Xin
Published: December 2011

Objective: Sinistral, or left-sided, portal hypertension (SPH) is a rare cause of upper gastrointestinal hemorrhage. This retrospective analysis summarizes the clinical features of SPH and the results of surgical treatment. Subjects and Methods: Between 2000 and 2009, patients from our hospital diagnosed with SPH were identified. Diagnosis of SPH was based on evidence of isolated splenic vein thrombosis, splenomegaly, gastroesophageal varices and exclusion of other causes of portal hypertension. Results: Eight males and 5 females were included in the study, with a mean age of 43.5 ± 6.4 years (range: 31–68 years). Liver function was normal in all patients. Causes of SPH were chronic pancreatitis (n = 7), pancreatic cancer (n = 3), pancreatic cysts (n = 2) and neuroendocrine tumor (n = 1). The main clinical manifestations were gastrointestinal hemorrhage in 7 cases (53.8%), upper abdominal pain in 10 (76.9%) and hypersplenism in 12 (92.3%). All patients had splenomegaly and gastroesophageal varices. Twelve patients underwent splenectomy and 1 received surgical removal of a pancreatic cyst. No major gastrointestinal tract rebleed occurred after a mean follow-up of 46 months (±7 months). Two patients died of pancreatic cancer and 1 of acute myocardial infarction during follow-up. Conclusions: SPH should be suspected in patients with upper gastrointestinal varices as well as unexplained splenomegaly with normal liver function. Surgical intervention such as splenectomy offers a good long-term outcome in symptomatic patients.
Prevalence of Impaired Glucose Regulation in Asymptomatic Kuwaiti Young Adults
Authors: Alattar Abdulnabi , Al-Majed Hana , Almuaili Thaier , Almutairi Obaid , Shaghouli Amnah , Altorah Wehad
Published: December 2011

Objective: The objective of this study was to determine the prevalence of impaired glucose regulation in a young, asymptomatic Kuwaiti population. Subjects and Methods: A cross-sectional study of 484 Kuwaitis (females: 311, and males: 173, aged 17–24 years), students at a public college for basic education, was conducted. Each participant underwent a 75-gram oral glucose tolerance test, and biochemical testing for hemoglobin A1c (HbA1c), total cholesterol and triglyceride levels. Physical examinations were performed to measure body mass index (BMI), waist circumference and blood pressure. Results: The prevalence of impaired glucose regulation (impaired fasting glucose, impaired glucose tolerance, and elevated HbA1c levels) was 32%, including 4% with newly diagnosed diabetes. Of the 484 participants, 47 (10%) of the population had hypertension and 52 (11%) had dyslipidemia. A total of 244 (50%) were classified as overweight/obese (BMI >25 kg/m2) and 201 (42%) had an elevated waist circumference (≧88 cm in females; ≧102 cm in males). Impaired glucose regulation was significantly related to increased waist circumference (p = 0.021) but not to increased BMI (p = 0.181). Those with impaired glucose regulation also had a higher prevalence of hypertension (p = 0.05), particularly systolic hypertension (p = 0.023). Conclusion: Kuwaiti youth have a high prevalence of impaired glucose regulation and overweight/obesity. Waist circumference, rather than BMI, may be a more appropriate screening tool to predict impaired glucose regulation in Kuwaiti youth.
Are 25(OH)D Levels Related to the Severity of Knee Osteoarthritis and Function?
Authors: Al-Jarallah Khaled F. , Shehab Diaa , Al-Awadhi Adel , Nahar Ibrahim , Haider Mohammad Z. , Moussa Mohamed A.
Published: December 2011

Objective: To investigate the effect of 25-hydroxyvitamin D [25(OH)D] in Kuwaiti patients with primary knee osteoarthritis (OA) and to assess its relation with radiological grading and functional status. Subjects and Methods: In this cross-sectional study, 25(OH)D was measured using radioimmunoassay in 99 patients [90 women and 9 men; mean age 56.5 ± 9.1 years (range: 36–80)] with clinical and radiological findings of primary knee OA. X-ray grading using the Kellgren-Lawrence grading scale and the Osteoarthritis Research Society International (OARSI) Atlas grading scale and functional assessments using Lequesne’s indices were evaluated in relation to the 25(OH)D level. Other variables studied were age at onset of symptoms, body mass index and duration of disease. Results: The age of the patients at the onset and the duration of disease were 51.58 ± 7.14 and 3.88 ± 2.51 years, respectively. Mean scoring for functional assessment was 10.31 ± 4.35 and mean Kellgren-Lawrence radiological grading was 2.43 ± 0.85. Radiological finding according to the OARSI Atlas revealed joint space narrowing of grades 2–3 in 87 (87.9%) patients and the presence of osteophytes in 55 (55.6%) patients. The mean value of 25(OH)D level was 11.4 ± 6.07 ng/ml. Of the 99 patients, 92 (92.9%) were vitamin D deficient. Comparison of 25(OH)D levels to radiological findings and different functional classes showed no significant association. Conclusion: Most of our patients had vitamin D deficiency, but the level of 25(OH)D was not related to the severity of the knee X-ray grading or to the functional assessment in our patients with primary knee OA.
Immunodiagnosis of Tuberculosis: State of the Art
Authors: Pinto Lancelot M. , Grenier Jasmine , Schumacher Samuel G. , Denkinger Claudia M. , Steingart Karen R. , Pai Madhukar
Published: December 2011

Undiagnosed and mismanaged tuberculosis (TB) continues to fuel the global TB epidemic. Rapid, accurate and early diagnosis of TB is therefore a priority to improve TB case detection and interrupt transmission. Although considerable improvements have been made in TB diagnostics, there are two major gaps in the existing diagnostics pipeline: (1) lack of a simple accurate point-of-care test that can be used for rapid diagnosis at the primary care level; (2) lack of a biomarker (or combination of biomarkers) that can be used to identify latently infected individuals who will benefit most from preventive therapy. Currently available commercial serological (antibody detection) tests are inaccurate and do not improve patient outcomes. Despite this evidence, dozens of serological tests are sold and used in countries (e.g. India) with weak regulatory systems, especially in the private sector. Recognizing the threat posed by these suboptimal tests, a World Health Organization (WHO) Expert Group has strongly recommended against the use of serological tests for the diagnosis of pulmonary and extra-pulmonary TB. Another WHO Expert Group has discouraged the use of interferon-γ release assays for active pulmonary TB diagnosis in low- and middle-income countries. All existing tests for latent TB infection appear to have only modest predictive value and further research is needed to identify highly predictive biomarkers.
Clinical, Diagnostic and Therapeutic Approaches to Complications of Brucellosis: An Experience of 12 Years
Authors: Mermut Gülşen , Özgenç Onur , Avcı Meltem , Olut Ali Ilgın , Öktem Ebru , Genç Vecdi Evren , Arı Alpay , Coskuner Seher Ayten
Published: December 2011

Objective: To describe the clinical presentations, laboratory findings, prevalence and pattern of complications and the response to treatment of brucellosis in a 12-year period in a Turkish research hospital. Materials and Methods: Between 1996 and 2008, 231 patients were diagnosed with brucellosis and treated in our clinic. Medical records of 189 of the 231 patients with at least one demonstrable complication of the disease were reviewed for anamnesis, diagnosis, complications, treatment and clinical outcomes. Results: The decreasing order of the complications was: hematological, 104 (55%); osteoarticular, 70 (37%); hepatobiliary, 59 (31%), and gastrointestinal, 23 (12%). The most common laboratory findings were anemia, lymphomonocytosis, elevated sedimentation rate and C-reactive protein, and elevated aminotransaminases. Conclusion: The hematological, osteoarticular and hepatobiliary manifestations were predominant. Bursitis, synovitis, glomerulonephritis, cutaneous lesion and deep vein thrombosis were the rare complications observed in our study. In clinical practice, brucellosis should be considered in the differential diagnosis in the presence of infrequent complications.
Comparison of the Antioxidant and Cytotoxic Activities of Phyllanthus virgatus and Phyllanthus amarus Extracts
Authors: Poompachee Kanchana , Chudapongse Nuannoi
Published: December 2011

Objective: To determine the antioxidant activity and cytotoxicity of Phyllanthus virgatus crude extract compared to Phyllanthus amarus.Methods: Phenolic contents of the hydromethanolic extracts were measured using Folin-Ciocalteu reagent. Antioxidant activity was evaluated by the 2,2-diphenyl-1-picrylhydrazyl hydrate free radical scavenging and antilipid peroxidation assays. Cytotoxicity on human hepatoma HepG2 cells was assessed by trypan blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assays. A stereomicroscope was used to observe and photograph the morphology of the cells. Oxygen consumption of the HepG2 cells was measured using a Clark oxygen electrode. Results: The extract of P. virgatus, which contained more phenolic compounds than P. amarus extract, had higher cytotoxicity and showed higher free radical scavenging activity and more inhibition of peroxidation in a linoleic acid system. P. virgatus extract conspicuously increased the oxygen consumption of HepG2 cells, while P. amarus extract had little stimulatory effect. Conclusion: The hydromethanolic extract of P. virgatus had stronger antioxidant and cytotoxic action than P. amarus extract. The stimulation of HepG2 cell respiration by P. virgatus extract suggests the extract alters mitochondrial function; this action could play a role in the cytotoxicity of this plant.
Adenosine-Induced Coronary Artery Spasm: A Case Report
Authors: Ismail Montaser , Asaad Nidal , Al-Suwaidi Jassim
Published: December 2011

Objective: To describe an uncommon complication of intravenous adenosine administration. Clinical Presentation and Intervention: A 41-year-old female patient presented with palpitations due to supraventricular tachycardia. The patient was treated with intravenous adenosine with resolution of the tachycardia. Subsequently, the patient developed chest pain and ST segment elevation in the inferior leads that resolved with sublingual nitroglycerin. Conclusion: This report showed a case of coronary spasm secondary to the administration of adenosine. We therefore recommend that discretion be exercised when giving adenosine, especially to patients with an underlying tendency for vasospastic reactions.
Organizing Pneumonia Associated with Oxaliplatin-Combined Chemotherapy: A Case Report
Authors: Lee Eun Joo , Lee Sang Yeub , In Kwang Ho , Kim Chul Hwan , Park Sanghoon
Published: December 2011

Objective: To report a case of oxaliplatin-combined chemotherapy-induced interstitial lung disease. Clinical Presentation and Intervention: A 57-year-old man was referred complaining of dyspnea and fever after treatment with an oxaliplatin-combined chemotherapeutic agent for metastatic colorectal cancer. Fever development and spontaneous subsidence were observed during the chemotherapeutic course repeatedly until the 9th cycle. A computer-tomographic (CT) scan revealed bilateral, peripherally distributed, patchy consolidation suggestive of an interstitial lung disease. As a confirmative step, video-assisted thoracoscopic surgical biopsy was attempted; the characteristic intraluminal organizing fibrous plug in the bronchioles and alveoli was seen. Corticosteroid therapy was administered, which rapidly improved the patient’s symptoms and chest CT findings. Conclusion: This case showed that oxaliplatin may be implicated in the etiology of interstitial lung disease, since withdrawal of the drug resulted in improvement of interstitial lung disease.
Intermittent Preventive Treatment during Pregnancy with Sulphadoxine-Pyrimethamine May Promote Plasmodium falciparum Gametocytogenesis
Authors: Fehintola F.A. , Balogun S.T. , Adeoye S.B.
Published: December 2011

Objectives: To determine the incidence of gametocytes and the propensity of sulphadoxine-pyrimethamine to promote gametocytogenesis when used as intermittent preventive treatment in pregnancy. Subjects and Methods: This observational non-interventional study assessed the influence of intermittent preventive treatment with sulphadoxine-pyrimethamine on Plasmodium falciparum gametocytaemia among Nigerian pregnant women. A total of 306 pregnant women were enrolled in the study. Results: The 306 pregnant women had 711 events, of which 31 pure gametocytaemic episodes were documented and 27 were recorded among the intermittent preventive treatment users. Only 4 episodes of pure gametocytaemia were recorded in pregnant women who did not receive any dose of sulphadoxine-pyrimethamine (27/129 vs. 4/276, χ2 = 15.9, p = 0.00006). Conclusion: Our findings show that intermittent preventive treatment in pregnancy with sulphadoxine-pyrimethamine may predispose to gametocyte carriage in pregnant women resident in the hyperendemic malaria region of southwest Nigeria. We therefore suggest that the use of insecticide-treated nets be encouraged among pregnant women resident in malaria-endemic sub-Saharan Africa in order to reduce malaria transmission.
Sex-Specific Time Trends in Very Elderly Patients (Aged ≧80 Years) Hospitalized with Myocardial Infarction
Authors: Ovbiagele Bruce
Published: December 2011

Objective: To assess sex-related time trends in the proportion of very elderly patients (age ≧80) hospitalized with myocardial infarction (MI). Subjects and Methods: Data were obtained from all states in the USA that contributed to the Nationwide Inpatient Sample. All patients admitted to hospital between 1997 and 2006 with a primary discharge diagnosis of MI, identified by the International Classification of Diseases, Ninth Revision procedure codes were included. Percentages of MI hospitalizations comprising men and women aged ≧80 were evaluated. Results: Overall, between 1997 and 2006, the absolute number of MI hospitalizations decreased from 732,170 to 674,988, but the percentage of very elderly men rose in a roughly linear pattern by 2.84% from 14.2% in 1997 to 17.1% in 2006 (95% CI 1.9–3.8%, p < 0.001) while among very elderly women, the percentages increased linearly by 4.95% from 31.0% in 1997 to 35.95% in 2006 (95% CI 3.6–6.3%, p < 0.001). Comparing women to men, the rise was 1.74 times larger (95% CI 1.26–2.23, p = 0.03). Conclusions: Over the last decade, the percentage of very elderly women hospitalized with MI in the United States rose at almost twice the rate of similarly aged men. These trends may be expected to exponentially worsen given the aging global population.
Mixed Hearing Loss in Iatrogenic Tympanic Membrane Perforations over the Round Window Niche and the Immediate Effect of Paper Patch Myringoplasty
Authors: Silverstein Herbert , Wycherly Benjamin J. , Darley D. Spencer , Alameda Yadiel A.
Published: December 2011

Objectives: Report the immediate audiologic effect of paper patch myringoplasty to repair iatrogenic tympanic membrane perforations directly over the round window. Methods: Retrospective case-control study of 15 patients treated for inner ear disease with a MicroWick and dexamethasone for 1 month, resulting in 2-mm perforations over the round window. Paper patch myringoplasties were performed to repair the perforations. Audiograms were performed before and immediately after the paper patch myringoplasty. Results: After paper patch placement, there was a significant improvement in air-bone gap at 250 (p < 0.001), 500 (p = 0.003), and 1000 Hz (p = 0.004) and a significant improvement in bone conduction (BC) threshold at 250 (p = 0.002), 500 (p < 0.001), 1000 (p = 0.002), 2000 (p = 0.003), and 3000 Hz (p = 0.02). Conclusions: Paper patch myringoplasty improves both air conduction and BC hearing from small perforations over the round window. The decrease in BC hearing is a result of middle ear mechanics and is not a true sensorineural hearing loss.
Prevalence of Multiple Sclerosis: Door-to-Door Survey in Three Rural Areas of Coastal Black Sea Regions of Turkey
Authors: Türk Börü Ülkü , Taşdemir Mustafa , Güler Neşe , Dilaver Ayık Elif , Kumaş Ayşegül , Yıldırım Serhan , Duman Arda , Sur Haydar , Kurtzke John F.
Published: December 2011

Background: Little information exists on multiple sclerosis (MS) in Turkey. With a door-to-door survey in an urban part of Istanbul, we recently reported a prevalence rate of 101/100,000 population. We therefore investigated three rural areas of Turkey at the same latitude. Methods: The same survey methods were used for total populations of two rural areas (Kandıra and Geyve) near Istanbul, and for half the population of Erbaa, all near 40° north latitude on the Black Sea coast. Results: In Kandıra, 5 of 8 suspects were diagnosed as having MS among 8,171 screened, resulting in a prevalence rate of 61/100,000. Geyve with 7 MS cases in 17,016 screened had a prevalence of 41/100,000, and Erbaa with 15 MS cases in 28,177 screened one of 53/100,000. Together they showed a prevalence of 51/100,000. Of the 27 patients, 20 were women; 25 had definite and 2 possible MS, the former all with abnormal laboratory findings. Average ages were 30.5 years at onset and 39.1 years at diagnosis. Clinical features and course were typical of European MS. Conclusion: These findings indicate that Turkey is a high-risk MS area, similar to most regions of Mediterranean Europe, where all recent increases are likely due to (undefined) environmental factors.
2001–2011: A Decade of the LADIS (Leukoaraiosis And DISability) Study: What Have We Learned about White Matter Changes and Small-Vessel Disease?
Authors:   The LADIS Study Group
Published: December 2011

Over the last 20 years, evidence about the clinical correlates of cerebral white matter changes (WMC; also called leukoaraiosis) has been accumulating. WMC are now listed among the neuroimaging expressions of cerebral small-vessel disease and are no longer considered an innocuous finding because they are associated, in cross-sectional surveys, with various disturbances and, in follow-up studies, with poor prognosis. The Leukoaraiosis And DISability (LADIS) study has contributed substantially to this body of knowledge. LADIS is a European multicenter collaboration that was started in 2001 with the aim of assessing the independent role of WMC in predicting disability in subjects aged 65–84. The main results of the LADIS study have been released in 2009 with the demonstration that severe WMC more than double the risk of transition from an autonomous to a dependent status after 3 years of follow-up. The LADIS study has also contributed more focused substudies assessing the possible role of WMC in the decline of cognitive and motor performances, depressive symptoms associated with aging and cerebrovascular diseases, urinary disturbances, and also the role of other brain lesions (lacunar infarcts, cerebral atrophy, and corpus callosum morphology). The LADIS study provides a good example of harmonization of instruments (MRI protocol, clinical, neuropsychological, and functional scales) within an international collaboration. Currently, the LADIS study is providing data about the natural history of WMC. In this paper, we review the background and the main results of the LADIS study. This review puts forward some considerations for future studies in the field.
Pulmonary Capillary Wedge Pressure Augments Right Ventricular Pulsatile Loading
Authors: Tedford Ryan J. , Hassoun Paul M. , Mathai Stephen C. , Girgis Reda E. , Russell Stuart D. , Thiemann David R. , Cingolani Oscar H. , Mudd James O. , Borlaug Barry A. , Redfield Margaret M. , Lederer David J. , Kass David A.
Published: December 2011

Background—

Right ventricular failure from increased pulmonary vascular loading is a major cause of morbidity and mortality, yet its modulation by disease remains poorly understood. We tested the hypotheses that, unlike the systemic circulation, pulmonary vascular resistance (R
PA
) and compliance (C
PA
) are consistently and inversely related regardless of age, pulmonary hypertension, or interstitial fibrosis and that this relation may be changed by elevated pulmonary capillary wedge pressure, augmenting right ventricular pulsatile load.

Methods and Results—

Several large clinical databases with right heart/pulmonary catheterization data were analyzed to determine the R
PA
-C
PA
relationship with pulmonary hypertension, pulmonary fibrosis, patient age, and varying pulmonary capillary wedge pressure. Patients with suspected or documented pulmonary hypertension (n=1009) and normal pulmonary capillary wedge pressure displayed a consistent R
PA
-C
PA
hyperbolic (inverse) dependence, C
PA
=0.564/(0.047+R
PA
), with a near-constant resistance-compliance product (0.48±0.17 seconds). In the same patients, the systemic resistance-compliance product was highly variable. Severe pulmonary fibrosis (n=89) did not change the R
PA
-C
PA
relation. Increasing patient age led to a very small but statistically significant change in the relation. However, elevation of the pulmonary capillary wedge pressure (n=8142) had a larger impact, significantly lowering C
PA
for any R
PA
and negatively correlating with the resistance-compliance product (
P
<0.0001).

Conclusions—

Pulmonary hypertension and pulmonary fibrosis do not significantly change the hyperbolic dependence between R
PA
and C
PA
, and patient age has only minimal effects. This fixed relationship helps explain the difficulty of reducing total right ventricular afterload by therapies that have a modest impact on mean R
PA
. Higher pulmonary capillary wedge pressure appears to enhance net right ventricular afterload by elevating pulsatile, relative to resistive, load and may contribute to right ventricular dysfunction.
Meteorological Education and Training Using A-Train Profilers
Authors: Lee Thomas F. , Bankert Richard L. , Mitrescu Cristian
Published: December 2011

NASA A-Train vertical profilers provide detailed observations of atmospheric features not seen in traditional imagery from other weather satellite data. CloudSat and Cloud–Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO) profiles vividly depict the vertical dimension of otherwise two-dimensional features shown in mapped products. However, most forecasters have never seen these profiles and do not appreciate their capacity to convey fundamental information about cloud and precipitation systems. Here, these profiles are accompanied by weather satellite images and explained in the context of various meteorological regimes. Profile examples are shown over frontal systems, marine stratocumulus, orographic barriers, tropical cyclones, and a severe thunderstorm.
Historical Developments of Political Islam with Reference to Bangladesh
Authors: Hasan Mubashar
Published: December 2011

This paper looks into the historic development of political Islam in Bangladesh, the third largest Muslim country of the world. Identifying origins and sociology of Bengali Muslims, this paper finds that development of political Islam took place in Bangladesh mainly in four phases: the Turkish war and the founding of the Khilafat movement during the First World War; the Oil crisis in the 1970s and the boost of Islamic institutions and practices in Bangladesh’s political discourse, mainly supported by the Middle Eastern countries; the Soviet–Afghanistan war and its linkage with Bangladeshi radicals in the 1990s; and by the globalization of war between Al-Qayeda and West and its implication on Bangladesh through the rise of extreme groups.
Numerically derived evidence for late-Holocene climate change and its impact on human presence in the southwest Taurus Mountains, Turkey
Authors: Bakker J , Kaniewski D , Verstraeten G , De Laet V , Waelkens M
Published: December 2011

A well-dated pollen diagram from Gravgaz marsh, near the archaeological site of Sagalassos (western Taurus Mountains, Turkey), provides the first detailed record of vegetation change in southwest Turkey during the last two millennia. A newly developed numerical analysis disentangles the climatic and anthropogenic influences on vegetation and reveals for the first time for southwest Turkey the timing and influence of late-Holocene climate change. Results show that sudden vegetation changes, driven by changes in moisture availability, co-occurred with well-defined European climate shifts. A trend towards dry conditions, from c. ad 640 to 940, coincides with the cold early Middle Ages in Europe. During this period, human presence in the region diminished and agricultural activity switched focus from crop cultivation to pastoralism while signs of cereal cultivation temporarily ceased. This period was followed by a return to moister conditions from ad 940 to 1280, coinciding with the ‘Medieval Climate Anomaly’. During this period there was a resurgence of human activity in the basin. Another trend towards dry conditions occurred at c. ad 1280, corresponding with the start of the ‘Little Ice Age’ in Europe and another disappearance of cereal pollen until the present day. The numerical analyses suggest that human impact around Gravgaz during the last two millennia is primarily driven by climatic changes.
The economic value of a meeting: Evidence from an investment game experiment
Authors: Becchetti Leonardo , Antoni Giacomo Degli , Faillo Marco , Mittone Luigi
Published: December 2011

The decrease of social distance between subjects and between subjects and experimenters facilitates the deviation from purely selfish behavior in different experimental contexts. Even though the effects of social distance reduction are widely documented, little is known about subjects’ preferences for anonymity, and in particular about the willingness to remove it if they are given the opportunity. In a variant of the investment game we give players the opportunity to decrease the social distance and investigate three main issues: a) how many subjects decide to remove anonymity when this is allowed; b) how this choice is associated with their behavior in the game; c) why should rational subjects opt for removing anonymity. Evidence shows that a significant number of subjects (43.5%) expects to obtain a positive utility by meeting their counterpart and they are ready to risk and/or lose money to get this utility.
How rational are justices on the Supreme Court of the United States? Doctrinal considerations during agenda setting
Authors: Sommer Udi
Published: December 2011

Justices on the US Supreme Court are rational and therefore strategic policymakers. Yet, how rational are they? How far into the future would their strategic considerations reach? Due to potential influence on both policy and doctrine, ceteris paribus they find opinion authorship desirable; when selecting cases, in addition to thinking about legal issues and the final disposition, justices strategically consider opinion crafting. To overcome the measurement error inherent to the estimation of rational behavior of the type proposed here, the Simulation Extrapolation protocol is introduced. There is strong support for the notion of doctrine-minded justices at cert. The social implications of such rational behavior are far-reaching; employing this strategy, over the course of her time in office, a justice would be able to considerably influence several policy and legal issues. In closing, implications of strategic behavior on the individual-justice level for the constitutional position of the Court within American society are discussed.
Exercise and disease progression in multiple sclerosis: can exercise slow down the progression of multiple sclerosis?
Authors: Dalgas Ulrik , Stenager Egon
Published: December 2011

It has been suggested that exercise (or physical activity) might have the potential to have an impact on multiple sclerosis (MS) pathology and thereby slow down the disease process in MS patients. The objective of this literature review was to identify the literature linking physical exercise (or activity) and MS disease progression. A systematic literature search was conducted in the following databases: PubMed, SweMed+, Embase, Cochrane Library, PEDro, SPORTDiscus and ISI Web of Science. Different methodological approaches to the problem have been applied including (1) longitudinal exercise studies evaluating the effects on clinical outcome measures, (2) cross-sectional studies evaluating the relationship between fitness status and MRI findings, (3) cross-sectional and longitudinal studies evaluating the relationship between exercise/physical activity and disability/relapse rate and, finally, (4) longitudinal exercise studies applying the experimental autoimmune encephalomyelitis (EAE) animal model of MS. Data from intervention studies evaluating disease progression by clinical measures (1) do not support a disease-modifying effect of exercise; however, MRI data (2), patient-reported data (3) and data from the EAE model (4) indicate a possible disease-modifying effect of exercise, but the strength of the evidence limits definite conclusions. It was concluded that some evidence supports the possibility of a disease-modifying potential of exercise (or physical activity) in MS patients, but future studies using better methodologies are needed to confirm this.
Long-term antipsychotic polypharmacy: how does it start, why does it continue?
Authors: Grech Patrice , Taylor David
Published: December 2011

Background: Antipsychotic polypharmacy remains a widespread and persistent practice, despite a lack of empirical evidence to support its safety and efficacy. This study aimed to assess antipsychotic treatment prior to the initiation of polypharmacy and ascertained clinicians’ reasons for coprescribing long term. We also aimed to determine patterns of antipsychotic coprescription and associated outcome.

Method: Prescription charts across a large mental health trust were reviewed to identify all patients coprescribed two or more antipsychotics excluding clozapine. For those receiving antipsychotic polypharmacy for at least 6 months, electronic patient records were examined to obtain demographic data, documented reasons for initiating polypharmacy and prior prescribing information. Sequence of prescribing, clinical outcome, adverse effects and prescriber considerations to revert to monotherapy were determined.

Results: In all, 38 patients had been receiving two antipsychotics excluding clozapine for longer than 6 months. In 39% of cases patients had been prescribed no or only one antipsychotic before initiation of polypharmacy while 48% had been trialled on clozapine. The most frequently documented reason for coprescribing was that residual psychotic symptoms remained with monotherapy. An improvement in psychotic symptoms was documented in 26% of patients receiving polypharmacy. Prescribers considered stopping polypharmacy in 23 patients.

Conclusion: Antipsychotics were coprescribed largely to improve symptoms and clinical outcome in patients with inadequate response to monotherapy. Polypharmacy was not solely reserved for patients in whom all other therapeutic options had failed. There was some evidence to suggest that patients did benefit from coprescription, albeit at the expense of an increased adverse effect burden. Prospective randomized trials of specific antipsychotic combinations are required to assess the therapeutic utility of this under-researched practice.
Rehabilitation, weaning and physical therapy strategies in chronic critically ill patients
Authors: Ambrosino N. , Venturelli E. , Vagheggini G. , Clini E.
Published: December 2011

In critically ill patients, a prolonged hospital stay, due to the initial acute insult and adverse side-effects of drug therapy, may cause severe late complications, such as muscle weakness, prolonged symptoms, mood alterations and poor health-related quality of life.

The clinical aims of physical rehabilitation in both medical and surgical intensive care units (ICUs) are focussed on the patient to improve their short- and even long-term care.

The purpose of this article is to review the currently available evidence on comprehensive rehabilitation programmes in critically ill patients, and describe the key components and techniques used, particularly in specialised ICUs.

Despite the literature suggesting that several techniques have led to beneficial effects and that muscle training is associated with weaning success, scientific evidence is limited. Due to limitations in undertaking comparative studies in ICUs, further studies with solid clinical short- and long-term outcome measures are now welcomed.
Acute exacerbations and pulmonary hypertension in advanced idiopathic pulmonary fibrosis
Authors: Judge Eoin P. , Fabre Aurelie , Adamali Huzaifa I. , Egan Jim J.
Published: December 2011

The aim of this study was to evaluate the risk factors for and outcomes of acute exacerbations in patients with advanced idiopathic pulmonary fibrosis (IPF), and to examine the relationship between disease severity and neovascularisation in explanted IPF lung tissue.

55 IPF patients assessed for lung transplantation were divided into acute (n=27) and non-acute exacerbation (n=28) groups. Haemodynamic data was collected at baseline, at the time of acute exacerbation and at lung transplantation. Histological analysis and CD31 immunostaining to quantify microvessel density (MVD) was performed on the explanted lung tissue of 13 transplanted patients.

Acute exacerbations were associated with increased mortality (p=0.0015). Pulmonary hypertension (PH) at baseline and acute exacerbations were associated with poor survival (p<0.01). PH at baseline was associated with a significant risk of acute exacerbations (HR 2.217, p=0.041). Neovascularisation (MVD) was significantly increased in areas of cellular fibrosis and significantly decreased in areas of honeycombing. There was a significant inverse correlation between mean pulmonary artery pressure and MVD in areas of honeycombing.

Acute exacerbations were associated with significantly increased mortality in patients with advanced IPF. PH was associated with the subsequent development of an acute exacerbation and with poor survival. Neovascularisation was significantly decreased in areas of honeycombing, and was significantly inversely correlated with mean pulmonary arterial pressure in areas of honeycombing.
Pulmonary hypertension in systemic sclerosis and systemic lupus erythematosus
Authors: Johnson S.R. , Granton J.T.
Published: December 2011

Pulmonary arterial hypertension (PAH) is a severe manifestation of systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). Due to improvements in the understanding of the pathogenesis of these diseases, improved methodological rigour in the conduct of epidemiological studies and the advent of successful therapies, our understanding of SSc-PAH and SLE-PAH has evolved considerably. In this review we will review the current evidence regarding the prevalence, prognostic factors and survival estimates for SSc-PAH and SLE-PAH. In doing so, we will compare and contrast these two diseases, highlight clinically useful features, discuss methodological limitations of existing data, and draw attention to areas where research is needed.
Asthma and suicide-related adverse events: a review of observational studies
Authors: Iessa N. , Murray M.L. , Curran S. , Wong I.C.K.
Published: December 2011

Suicide is a major public health concern. There are several risk factors associated with suicide. Chronic illnesses, such as asthma, have been linked to an increased risk of suicide-related events. This study reviews the evidence of an association between asthma and suicide using published epidemiological observational studies.

An electronic search using PubMed and EMBASE was performed. Studies that investigated the association of asthma with suicide-related behaviour were selected. Studies were examined to form a descriptive analysis.

Six observational studies met the selection criteria, of which at least one suicide-related adverse event was studied. Three studies investigated completed suicide, two suicide attempts and four suicide ideation. Two of the studies focused on individuals aged <18 yrs.

Evidence from observational data support the hypothesis of an association between asthma and suicide-related behaviour (ideation, attempts and completion); however, epidemiological studies, with more objective measures and larger sample sizes, adjusting for a wider scope of suicide-related confounding factors (e.g.comorbidities), and with a longitudinal design, are needed for a more conclusive answer.
The role of the right ventricle in pulmonary arterial hypertension
Authors: Vonk Noordegraaf A. , Galiè N.
Published: December 2011

Although changes in the pulmonary vasculature are the primary cause of pulmonary arterial hypertension (PAH), severity of symptoms and survival are strongly associated with right ventricular function, and right heart failure is the main cause of death in patients with PAH. Echocardiography and cardiac magnetic resonance imaging allow noninvasive evaluation of right ventricular function and structure, and a number of indices have been shown to have potential prognostic value in PAH. Given the importance of the right ventricle in PAH, preservation and improvement of its function should be important aspects of therapy; however, there are currently few data specifically related to this aspect of treatment response. Simple, reproducible, noninvasive measures of right ventricular function would help to improve the management of patients with PAH, and to provide tools with which to help establish the optimal therapeutic approach to manage not only the effects of the disease on the pulmonary vasculature, but also to support and improve right ventricular function.
Optimal management of severe pulmonary arterial hypertension
Authors: Sitbon O. , Simonneau G.
Published: December 2011

Over the past decade, awareness among the medical profession of pulmonary arterial hypertension (PAH) being a treatable disease has increased. Despite this, approximately one-fifth of newly diagnosed patients are classified as being in the most severely compromised functional class (i.e.New York Health Association/World Health Organization functional class (NYHA/WHO FC) IV). The prognosis for patients in NYHA/WHO FC IV is poor, with 3-yr survival being around 40%, even with treatment. Poor prognosis coupled with severe functional impairment means it is vital that these patients receive optimal treatment. There are also subgroups of patients, who, although classified as NYHA/WHO FC III, may actually be severely haemodynamically compromised and at risk of rapid deterioration. Such subgroups include patients with PAH associated with systemic sclerosis or certain heritable mutations. These patients should be considered as being at the more severe end of the disease spectrum. In this article we will discuss the optimal management of patients with severe PAH. This includes newly emerging evidence from small-scale, open-label studies that use upfront combination therapy with intravenous epoprostenol plus oral PAH-specific drugs. We also review treatment strategies that may offer clinical benefits to patients with more severe PAH.
Cell cycle phase classification in 3D in vivo microscopy of Drosophila embryogenesis
Authors: Du Tie Hua , Puah Wee Choo , Wasser Martin
Published: December 2011

Background

Cell divisions play critical roles in disease and development. The analysis of cell division phenotypes in high content image-based screening and time-lapse microscopy relies on automated nuclear segmentation and classification of cell cycle phases. Automated identification of the cell cycle phase helps biologists quantify the effect of genetic perturbations and drug treatments. Most existing studies have dealt with 2D images of cultured cells. Few, if any, studies have addressed the problem of cell cycle classification in 3D image stacks of intact tissues.

Results

We developed a workflow for the automated cell cycle phase classification in 3D time-series image datasets of live Drosophila embryos expressing the chromatin marker histone-GFP. Upon image acquisition by laser scanning confocal microscopy and 3D nuclear segmentation, we extracted 3D intensity, shape and texture features from interphase nuclei and mitotic chromosomes. We trained different classifiers, including support vector machines (SVM) and neural networks, to distinguish between 5 cell cycles phases (Interphase and 4 mitotic phases) and achieved over 90% accuracy. As the different phases occur at different frequencies (58% of samples correspond to interphase), we devised a strategy to improve the identification of classes with low representation. To investigate which features are required for accurate classification, we performed feature reduction and selection. We were able to reduce the feature set from 42 to 9 without affecting classifier performance. We observed a dramatic decrease of classification performance when the training and testing samples were derived from two different developmental stages, the nuclear divisions of the syncytial blastoderm and the cell divisions during gastrulation. Combining samples from both developmental stages produced a more robust and accurate classifier.

Conclusions

Our study demonstrates that automated cell cycle phase classification, besides 2D images of cultured cells, can also be applied to 3D images of live tissues. We could reduce the initial 3D feature set from 42 to 9 without compromising performance. Robust classifiers of intact animals need to be trained with samples from different developmental stages and cell types. Cell cycle classification in live animals can be used for automated phenotyping and to improve the performance of automated cell tracking.
A comparative structural bioinformatics analysis of inherited mutations in β-D-Mannosidase across multiple species reveals a genotype-phenotype correlation
Authors: Huynh Thi , Khan Javed Mohammed , Ranganathan Shoba
Published: December 2011

Background

Lysosomal β-D-mannosidase is a glycosyl hydrolase that breaks down the glycosidic bonds at the non-reducing end of N-linked glycoproteins. Hence, it is a crucial enzyme in polysaccharide degradation pathway. Mutations in the MANBA gene that codes for lysosomal β-mannosidase, result in improper coding and malfunctioning of protein, leading to β-mannosidosis. Studying the location of mutations on the enzyme structure is a rational approach in order to understand the functional consequences of these mutations. Accordingly, the pathology and clinical manifestations of the disease could be correlated to the genotypic modifications.

Results

The wild-type and inherited mutations of β-mannosidase were studied across four different species, human, cow, goat and mouse employing a previously demonstrated comprehensive homology modeling and mutational mapping technique, which reveals a correlation between the variation of genotype and the severity of phenotype in β-mannosidosis. X-ray crystallographic structure of β-mannosidase from Bacteroides thetaiotaomicron was used as template for 3D structural modeling of the wild-type enzymes containing all the associated ligands. These wild-type models subsequently served as templates for building mutational structures. Truncations account for approximately 70% of the mutational cases. In general, the proximity of mutations to the active site determines the severity of phenotypic expressions. Mapping mutations to the MANBA gene sequence has identified five mutational hot-spots.

Conclusion

Although restrained by a limited dataset, our comprehensive study suggests a genotype-phenotype correlation in β-mannosidosis. A predictive approach for detecting likely β-mannosidosis is also demonstrated where we have extrapolated observed mutations from one species to homologous positions in other organisms based on the proximity of the mutations to the enzyme active site and their co-location from different organisms. Apart from aiding the detection of mutational hotspots in the gene, where novel mutations could be disease-implicated, this approach also provides a way to predict new disease mutations. Higher expression of the exoglycosidase chitobiase is said to play a vital role in determining disease phenotypes in human and mouse. A bigger dataset of inherited mutations as well as a parallel study of β-mannosidase and chitobiase activities in prospective patients would be interesting to better understand the underlying reasons for β-mannosidosis.
Prioritizing disease candidate genes by a gene interconnectedness-based approach
Authors: Hsu Chia-Lang , Huang Yen-Hua , Hsu Chien-Ting , Yang Ueng-Cheng
Published: December 2011

Background

Genome-wide disease-gene finding approaches may sometimes provide us with a long list of candidate genes. Since using pure experimental approaches to verify all candidates could be expensive, a number of network-based methods have been developed to prioritize candidates. Such tools usually have a set of parameters pre-trained using available network data. This means that re-training network-based tools may be required when existing biological networks are updated or when networks from different sources are to be tried.

Results

We developed a parameter-free method, interconnectedness (ICN), to rank candidate genes by assessing the closeness of them to known disease genes in a network. ICN was tested using 1,993 known disease-gene associations and achieved a success rate of ~44% using a protein-protein interaction network under a test scenario of simulated linkage analysis. This performance is comparable with those of other well-known methods and ICN outperforms other methods when a candidate disease gene is not directly linked to known disease genes in a network. Interestingly, we show that a combined scoring strategy could enable ICN to achieve an even better performance (~50%) than other methods used alone.

Conclusions

ICN, a user-friendly method, can well complement other network-based methods in the context of prioritizing candidate disease genes.