A single high dose of oral Vitamin D3 is not enough to correct insufficiency and deficiency in a rheumatologic population

Introduction: Vitamin D plays a major role in bone metabolism and neuromuscular function. Supplementation with vitamin D is effective to reduce the risk of fall and of fracture. However adherence to oral daily vitamin D supplementation is low. Screening and correcting vitamin D insufficiency in a general rheumatologic population could improve both morbidity and quality of life in these patients with chronic painful disorders and at high risk of osteoporosis. After determining the prevalence of vitamin D deficiency in this population, we evaluated if supplementation with a single high dose of oral 25-OH vitamin D3 was sufficient to correct this abnormality. Methods: During one month (November 2009), levels of 25-OH vitamin D were systematically determined in our rheumatology outpatient clinic and classified into three groups: vitamin D deficiency (<10 µg/l), vitamin D insufficiency (10 to 30µg/l) or normal vitamin D (>30 µg/l). Patients with insufficiency or deficiency received respectively a single high dose of 300'000 IU or 600'000 IU oral vitamin D3. In addition, all patients with osteoporosis were prescribed daily supplement of calcium (1g) and vitamin D (800 IU). 25-OH vitamin D levels were reevaluated after 3 months. Results: Vitamin D levels were initially determined in 292 patients (mean age 53, 211 women, 87% Caucasian). 77% had inflammatory rheumatologic disease (IRD), 20% osteoporosis (OP) and 12% degenerative disease (DD). Vitamin D deficiency was present in 20 (6.8%), while 225 (77.1%) had insufficiency. Of the 245 patients with levels <30µg/l, a new determination of vitamin D level was available in 173 (71%) at 3 months (table 1). Conclusion: Vitamin D insufficiency is highly prevalent in our rheumatologic population (84%), and is not adequately corrected by a single high dose of oral vitamin D3 in more than half of the patients with IRD and DD. In patients with OP, despite association of a single high dose with daily oral vitamin D supplementation, 40% of patients are still deficient when reevaluated at 3 months.

State of Iowa’s Single Audit Report for the year ended June 30, 2005

State of Iowa’s Single Audit Report for the year ended June 30, 2005

A multicenter phase II study (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma

Introduction: Mantle cell lymphoma (MCL) accounts for 6% of all B-cell lymphomas and is in most cases an incurable disease. It is characterized by the translocation t(11;14) leading to Cyclin D1 over-expression. Cyclin D1 is downstream of the mammalian target of rapamycin (mTOR) threonine kinase and can be effectively blocked by mTOR inhibitors. We set out to define the single agent activity of the orally available mTOR inhibitor everolimus in a prospective, multicentre trial in patients with relapsed or refractory MCL (NCT00516412).Methods: Eligible patients with confirmed relapsed or refractory MCL received everolimus 10 mg for 28 days (one cycle) for a total of 6 cycles or until disease progression. The primary endpoint was the best objective response (OR) with adverse reactions, time to progression (TTP), time to treatment failure, response duration and molecular response as secondary endpoints.Results: A total of 36 patients with 35 evaluable patients at a median age of 69 years (range 40 to 85 years) from 19 centers were enrolled between August 2007 and January 2010. Treatment was generally well tolerated with anemia (11%), thrombocytopenia (11%), neutropenia (8%), diarrhea (3%) and fatigue (3%) being the most frequent complications of CTC grade 3 or higher. The OR rate was 20% (95% CI: 8-37%) with 2 complete remissions (CR) and 5 partial response (PR), stable disease (SD) 48% and progression disease (PD) 28%. At a median follow-up of 6 months, TTP was 5.45 months (95% CI: 2.8-8.2 months) for the entire population and 10.6 months for the 18 patients receiving 6 or more cycles of treatment. Three patients achieved a lasting complete molecular response when assessed in the peripheral blood.Conclusion: This study demonstrates that single agent everolimus is well tolerated and has anti-lymphoma activity including lasting molecular responses. Further studies of everolimus either in combination with chemotherapy or as single agent for maintenance treatment are warranted in MCL.

Genomewide association study using a high-density single nucleotide polymorphism array and case-control design identifies a novel essential hypertension susceptibility locus in the promoter region of endothelial NO synthase.

Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P=2.58 · 10(-13)). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; P=1.032 · 10(-14)). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16-3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.

The determinants of the prevalence of single mothers: A cross-country analysis

This paper examines the effect of public assistance, labor market and marriage marketconditions on the prevalence of single mother families across countries and over time. Amultinomial logit derived from a random utility approach is estimated using individualleveldata for 14 countries. I find evidence that increases in the level of public support are significantly and positively associated with a higher incidence of both never marriedand divorced mothers. The results also suggest that single mothers are more prevalentwhen female wages are lower. Higher male earnings and employment opportunities in awoman s marriage market appear to lead to fewer never married mothers, but more divorced mothers. Higher child support or alimony payments are associated with a higher prevalence of divorced mothers.

Infestation and natural parasitism of aphids in single and mixed pastures of black oats and ryegrass

Some species of aphids are major pests on cereal crops and grass pastures. Usually these pests are not adequately controlled in pasture lands that become sources of aphid infestations to cereal crops. The dynamics of aphids and the incidence of natural enemies are less known in pasture systems than in cereal fields. The objective of this work was to assess the aphid infestation and natural aphid parasitism in different pasture composition. Three hypotheses were tested: 1- the aphid species composition in pastures may vary according to the cereal species in the field; 2- the mixture of two plant species can modify the amount and diversity of aphids; 3- the plant species composition of pasture fields influences the parasitism of aphids. Empirical data were obtained from three Poaceae fields: black oats (Avena strigosa L.), ryegrass (Lolium multiflorum L.), and a mixed field of black oats and ryegrass. The most abundant aphid species was Rhopalosiphum padi followed by Sitobion avenae. Plant species composition increases the amount and the parasitism rates of aphids. The mixture of heavily infested black oats with a poorly infested ryegrass resulted in reduction of aphid infestation in comparison with heavily-infested single plant species field. This is possible because the conditions are favorable for the development of parasitoid populations. Aphidius colemani was the main parasitoid found in these areas.

Single mothers and incentives to work: The French experience

This paper analyzes the effect of the 1998 reform of the French single parents allowanceon the labor supply of single mothers with very young children. The reform aimed atencouraging participation by allowing eligible single parents to accumulate benefits andlabor earnings for a limited period of time. Using data from the French EmploymentSurvey, the analysis shows that single mothers affected by the reform had experienced asignificant increase in their employment rate four years after the reform wasimplemented. During the same period, the employment rate of married mothers withyoung children did not experience a significant change, suggesting that at least part ofthe increase was a consequence of the reform. These results provide some evidence thatbenefit schedules that provide financial incentives to work can have significant effectsin getting single moms back to work, even in the presence of very young children.

State of Iowa’s Single Audit Report for the year ended June 30, 2008

State of Iowa’s Single Audit Report for the year ended June 30, 2008

Death and resurrection of the human IRGM gene

Immunity-related GTPases (IRG) play an important role in defense against intracellular pathogens. One member of this gene family in humans, IRGM, has been recently implicated as a risk factor for Crohn's disease. We analyzed the detailed structure of this gene family among primates and showed that most of the IRG gene cluster was deleted early in primate evolution, after the divergence of the anthropoids from prosimians ( about 50 million years ago). Comparative sequence analysis of New World and Old World monkey species shows that the single-copy IRGM gene became pseudogenized as a result of an Alu retrotransposition event in the anthropoid common ancestor that disrupted the open reading frame (ORF). We find that the ORF was reestablished as a part of a polymorphic stop codon in the common ancestor of humans and great apes. Expression analysis suggests that this change occurred in conjunction with the insertion of an endogenous retrovirus, which altered the transcription initiation, splicing, and expression profile of IRGM. These data argue that the gene became pseudogenized and was then resurrected through a series of complex structural events and suggest remarkable functional plasticity where alleles experience diverse evolutionary pressures over time. Such dynamism in structure and evolution may be critical for a gene family locked in an arms race with an ever-changing repertoire of intracellular parasites.

Un projet multicentrique suisse pour améliorer la prévention et la récidive après un syndrome coronarien aigu [A Swiss multicentric project to improve the prevention of cardiovascular event recurrence after acute coronary syndromes].

Recurrence of cardiovascular events and mortality remain high after acute coronary syndromes. A Swiss multicentric study, "Inflammation and acute coronary syndromes (ACS)--Novel strategies for prevention and clinical managements", is currently underway with the support of the Swiss National Science Foundation. The study includes a clinical research subproject of which the aim is to assess the impact of the ELIPS program (multi-dimEnsionaL prevention Program after acute coronary Syndrome) on the recurrence of cardiovascular events after an ACS. The basic research sub-projects aim to investigate novel cardiovascular risk biomarkers and genetic determinants of recurrence and to study the role of stem cells after an ACS. Another sub-project will evaluate intracoronary imaging techniques and the efficacy of different types of stents.

Virtual autopsy with multiphase postmortem computed tomographic angiography versus traditional medical autopsy to investigate unexpected deaths of hospitalized patients: a cohort study.

BACKGROUND: "Virtual" autopsy by postmortem computed tomography (PMCT) can replace medical autopsy to a certain extent but has limitations for cardiovascular diseases. These limitations might be overcome by adding multiphase PMCT angiography. OBJECTIVE: To compare virtual autopsy by multiphase PMCT angiography with medical autopsy. DESIGN: Prospective cohort study. (ClinicalTrials.gov: NCT01541995) SETTING: Single-center study at the University Medical Center Hamburg-Eppendorf, Hamburg, Germany, between 1 April 2012 and 31 March 2013. PATIENTS: Hospitalized patients who died unexpectedly or within 48 hours of an event necessitating cardiopulmonary resuscitation. MEASUREMENTS: Diagnoses from clinical records were compared with findings from both types of autopsy. New diagnoses identified by autopsy were classified as major or minor, depending on whether they would have altered clinical management. RESULTS: Of 143 eligible patients, 50 (35%) had virtual and medical autopsy. Virtual autopsy confirmed 93% of all 336 diagnoses identified from antemortem medical records, and medical autopsy confirmed 80%. In addition, virtual and medical autopsy identified 16 new major and 238 new minor diagnoses. Seventy-three of the virtual autopsy diagnoses, including 32 cases of coronary artery stenosis, were identified solely by multiphase PMCT angiography. Of the 114 clinical diagnoses classified as cardiovascular, 110 were confirmed by virtual autopsy and 107 by medical autopsy. In 11 cases, multiphase PMCT angiography showed "unspecific filling defects," which were not reported by medical autopsy. LIMITATION: These results come from a single center with concerted interest and expertise in postmortem imaging; further studies are thus needed for generalization. CONCLUSION: In cases of unexpected death, the addition of multiphase PMCT angiography increases the value of virtual autopsy, making it a feasible alternative for quality control and identification of diagnoses traditionally made by medical autopsy. PRIMARY FUNDING SOURCE: University Medical Center Hamburg-Eppendorf.

Photodamage to Oxygen Evolving Complex - An Initial Event in Photoinhibition of Photosystem II.

Photosystem II (PSII) of oxygenic photosynthesis is susceptible to photoinhibition. Photoinhibition is defined as light induced damage resulting in turnover of the D1 protein subunit of the reaction center of PSII. Both visible and ultraviolet (UV) light cause photoinhibition. Photoinhibition induced by UV light damages the oxygen evolving complex (OEC) via absorption of UV photons by the Mn ion(s) of OEC. Under visible light, most of the earlier hypotheses assume that photoinhibition occurs when the rate of photon absorption by PSII antenna exceeds the use of the absorbed energy in photosynthesis. However, photoinhibition occurs at all light intensities with the same efficiency per photon. The aim of my thesis work was to build a model of photoinhibition that fits the experimental features of photoinhibition. I studied the role of electron transfer reactions of PSII in photoinhibition and found that changing the electron transfer rate had only minor influence on photoinhibition if light intensity was kept constant. Furthermore, quenching of antenna excitations protected less efficiently than it would protect if antenna chlorophylls were the only photoreceptors of photoinhibition. To identify photoreceptors of photoinhibition, I measured the action spectrum of photoinhibition. The action spectrum showed resemblance to the absorption spectra of Mn model compounds suggesting that the Mn cluster of OEC acts as a photoreceptor of photoinhibition under visible light, too. The role of Mn in photoinhibition was further supported by experiments showing that during photoinhibition OEC is damaged before electron transfer activity at the acceptor side of PSII is lost. Mn enzymes were found to be photosensitive under visible and UV light indicating that Mn-containing compounds, including OEC, are capable of functioning as photosensitizers both in visible and UV light. The experimental results above led to the Mn hypothesis of the mechanism of continuous-light-induced photoinhibition. According to the Mn hypothesis, excitation of Mn of OEC results in inhibition of electron donation from OEC to the oxidized primary donor P680+ both under UV and visible light. P680 is oxidized by photons absorbed by chlorophyll, and if not reduced by OEC, P680+ may cause harmful oxidation of other PSII components. Photoinhibition was also induced with intense laser pulses and it was found that the photoinhibitory efficiency increased in proportion to the square of pulse intensity suggesting that laser-pulse-induced photoinhibition is a two-photon reaction. I further developed the Mn hypothesis suggesting that the initial event in photoinhibition under both continuous and pulsed light is the same: Mn excitation that leads to the inhibition of electron donation from OEC to P680+. Under laser-pulse-illumination, another Mn-mediated inhibitory photoreaction occurs within the duration of the same pulse, whereas under continuous light, secondary damage is chlorophyll mediated. A mathematical model based on the Mn hypothesis was found to explain photoinhibition under continuous light, under flash illumination and under the combination of these two.