Evaluation of a Single Dose of Ferric Carboxymaltose in Fatigued,Iron-Deficient Women – PREFER a Randomized,Placebo-Controlled Study

Background

Unexplained fatigue is often left untreated or treated with antidepressants. This randomized, placebo-controlled, single-blinded study evaluated the efficacy and tolerability of single-dose intravenous ferric carboxymaltose (FCM) in iron-deficient, premenopausal women with symptomatic, unexplained fatigue.

Methods

Fatigued women (Piper Fatigue Scale [PFS] score ≥5) with iron deficiency (ferritin <50 µg/L and transferrin saturation <20%, or ferritin <15 µg/L) and normal or borderline hemoglobin (≥115 g/L) were enrolled in 21 sites in Austria, Germany, Sweden and Switzerland, blinded to the study drug and randomized (computer-generated randomization sequence) to a single FCM (1000 mg iron) or saline (placebo) infusion. Primary endpoint was the proportion of patients with reduced fatigue (≥1 point decrease in PFS score from baseline to Day 56).

Results

The full analysis included 290 women (FCM 144, placebo 146). Fatigue was reduced in 65.3% (FCM) and 52.7% (placebo) of patients (OR 1.68, 95%CI 1.05–2.70; p = 0.03). A 50% reduction of PFS score was achieved in 33.3% FCM- vs. 16.4% placebo-treated patients (p<0.001). At Day 56, all FCM-treated patients had hemoglobin levels ≥120 g/L (vs. 87% at baseline); with placebo, the proportion decreased from 86% to 81%. Mental quality-of-life (SF-12) and the cognitive function scores improved better with FCM. ‘Power of attention’ improved better in FCM-treated patients with ferritin <15 µg/L. Treatment-emergent adverse events (placebo 114, FCM 209; most frequently headache, nasopharyngitis, pyrexia and nausea) were mainly mild or moderate.

Conclusion

A single infusion of FCM improved fatigue, mental quality-of-life, cognitive function and erythropoiesis in iron-deficient women with normal or borderline hemoglobin. Although more side effects were reported compared to placebo, FCM can be an effective alternative in patients who cannot tolerate or use oral iron, the common treatment of iron deficiency. Overall, the results support the hypothesis that iron deficiency can affect women’s health, and a normal iron status should be maintained independent of hemoglobin levels.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01110356","term_id":"NCT01110356"}}NCT01110356     

A Taxonomic Study of the Genus Alebroides Mats, from China(Homoptera, Cicadellidae, Typhlocybinae)

The genus Alebroides was established by Matsumura in 1931. As far asthe present authors have learned there are 7 species reported from Chinain previous works. They are listod as follows:     

Biomarkers of Oxidative Stress Study II: Are oxidation products of lipids,proteins, and DNA markers of CCl4 poisoning?

Oxidation products of lipids, proteins, and DNA in the blood, plasma, and urine of rats were measured as part of a comprehensive, multilaboratory validation study searching for noninvasive biomarkers of oxidative stress. This article is the second report of the nationwide Biomarkers of Oxidative Stress Study using acute CCl4 poisoning as a rodent model for oxidative stress. The time-dependent (2, 7, and 16 h) and dose-dependent (120 and 1200 mg/kg i.p.) effects of CCl4 on concentrations of lipid hydroperoxides, TBARS, malondialdehyde (MDA), isoprostanes, protein carbonyls, methionine sulfoxidation, tyrosine products, 8-hydroxy-2'-deoxyguanosine (8-OHdG), leukocyte DNA-MDA adducts, and DNA-strand breaks were investigated to determine whether the oxidative effects of CCl4 would result in increased generation of these oxidation products. Plasma concentrations of MDA and isoprostanes (both measured by GC-MS) and urinary concentrations of isoprostanes (measured with an immunoassay or LC/MS/MS) were increased in both low-dose and high-dose CCl4-treated rats at more than one time point. The other urinary markers (MDA and 8-OHdG) showed significant elevations with treatment under three of the four conditions tested. It is concluded that measurements of MDA and isoprostanes in plasma and urine as well as 8-OHdG in urine are potential candidates for general biomarkers of oxidative stress. All other products were not changed by CCl4 or showed fewer significant effects.     

Synthesis,Antifungal Activity,and Molecular Simulation Study of L–Carvone-Derived 1,3,4-Oxadiazole-Thioether Compounds

To discover potent antifungal molecules with new and distinctive structures, 20 novel L-carvone-derived 1,3,4-oxadiazole-thioether compounds 5 a – 5 t were synthesized through multi-step reaction of L-carvone, and their structures were confirmed by FT-IR, ¹H-NMR, ¹³C-NMR, and HR-MS. The antifungal activities of compounds 5 a – 5 t were preliminarily tested by in vitro method, and the results indicated that all of the title compounds displayed certain antifungal activities against the eight tested plant fungi, especially for P. piricola. Among them, compound 5 i (R=p-F) with the most significant antifungal activity deserved further study for discovering and developing novel natural product-based antifungal agents. Moreover, two molecular simulation technologies were employed for the investigation of their structure–activity relationships (SARs). Firstly, a reasonable and effective 3D-QSAR model was established by the comparative molecular field (CoMFA) method, and the relationship of the substituents linked with the benzene rings and the inhibitory activities of the title compounds against P. piricola was elucidated. Then, the binding mode of compound 5 i (R=p-F) and its potential biological target (CYP51) was simulated by molecular docking, and it was found that compound 5 i could readily bind with CYP51 in the active site, and the ligand-receptor interactions involved three hydrogen bonds and several hydrophobic effects.     

Study on Attenuation Characteristics of Biocontrol Strain Anti-8098A, Bacillus cereus, against Ralstoniasolanacearum

The present study dealt with the attenuation characteristics of bacterial-wilt-disease biocontrol strain Anti-8098A, Bacillus cereus, againstpathogeny Ralstonia solanacearum (RS). In order to distinguish the pathogenicity of RS, the attenuation index (radius of the center red ring/radius of the whole mycelium ring, on TTC culture medium) was established (Hayward, 1976), companying with the mortality of tomato     

The making of ethology: The association for the Study of Animal Behaviour, 1936–1986

The paper reviews the history of the Association for the Study of Animal Behaviour in its 50th anniversary year. Having discussed the founding of the Institute for the Study of Animal Behaviour in 1936, the paper establishes its principal aims, follows its fortunes before and during the war, traces its role in the expansion and institutionalization of ethology in Britainbetween 1945 and 1950, and summarizes its transformation into a flourishing scientific society in the 1950s and 1960s. It is concluded that the history of the Association is, to a striking extent, a microcosm of the making of ethology as a successful scientific discipline.     

Methodology and Problems of Protein‐Ligand Docking: Case Study of Dihydroorotate Dehydrogenase,Thymidine Kinase,and Phosphodiesterase 4

Abstract

The docking methodology was applied to three different therapeutically interesting enzymes: human dihydroorotate dehydrogenase (DHODH), Herpes simplex virus type I thymidine kinase (HSV1 TK) and human phosphodiesterase 4 (PDE4). Programs FlexX, AutoDock and DOCK where used. The three targets represent three distinct cases. For DHODH and HSV1 TK, the binding modes of substrate and inhibitors within the active site are known, while the binding orientation of cAMP within PDE4 has been solely hypothesized. Active site of DHODH is mainly hydrophobic and the binding mode of the inhibitor brequinar was used as a template for evaluating the docking strategies. The presence of cofactors revealed to be crucial for the definition of the docking site. The HSV1 TK active site is small and polar and contains crystal water molecules and ATP. Docking of thymidine and aciclovir (ACV) within the active site was analyzed by keeping or removing water molecules. It showed the crucial role of water in predicting the binding of pyrimidines and purines. The crystal structure of PDE4 contains magnesium and zinc cations as well as catalytic water molecule but no ligand. Several docking experiments of cAMP and rolipram were performed and the results showed clear‐cut dependence between the ligand orientation and the presence of metals in the active site. All three cases show specific problems of the docking methodology, depending on the character of the active site.     

Study of β-lactam-based drug interaction with albumin protein using optical,sensing, and docking methods

Journal of Biological Physics - The quality and strength of drug and albumin interaction affecting the drug-free concentration and physiological activity are important issues in pharmacokinetic...     

Vibrational Study of a Nucleoside Analogue with Antiviral Activity, 5-Chloro-2′-deoxyuridine,CDU

Abstract

The experimental FTIR and FT-Raman spectra of 5-chloro-2′-deoxyuridine have been assigned on the basis of normal coordinate analyses, in the light of observed and calculated wavenumbers and isotopic shifts. The results indicate that virtually all normal modes of IDU involve some degree of vibrational coupling between the chlorouracil base and the deoxyribose moiety.     

Non-dermatophytic Molds as Agents of Onychomycosis in Izmir,Turkey – A Prospective Study

The purpose of this study was to determine the prevalence of causative non-dermatophytic filamentous fungi in onychomycosis. Totally 1,222 (1,222 × 3 = 3,666) samples of nail scrapings from 1,146 patients (from 76 patients two specimens: both from finger- and toe-nails) with prediagnosis of onychomycosis sent to the Mycology Laboratory from the Clinic of Dermatology, Ege University Hospital, Izmir, Turkey, July 2001–December 2003, were prospectively studied with conventional mycological procedures. The set criteria for the diagnosis of onychomycosis due to non-dermatophytic molds were: (1) Observation of fungal elements in 15% KOH-preparations made from nail scrapings, (2) growth of the same mold in all three consecutive cultures of the specimens taken three times from the same patient with one-week intervals, (3) no growth of a dermatophyte or yeast in three consecutive cultures. As agents of onychomycosis molds were detected in 33 (9%), dermatophytes in 175 (48%), yeasts in 150 (41%), and mixed (two different fungi) in 8 (2%) patients. In cases of mold onychomycosis, 11 (33%) had finger-nail and 22 (67%) toe-nail infection; 25 (76%) were female and 8 (24%) male; and 27 (82%) were above 40 years of age. The agents of mold onychomycosis, in order of frequency, were Aspergillus niger (7), Acremonium spp. (6), Fusarium spp. (6), Ulocladium spp. (4), sterile mycelia (2), Alternaria sp. (1), Aspergillus flavus (1), Aspergillus fumigatus (1), Aspergillus terreus (1), Cladosporium sp. (1), Paecilomyces spp. (1), Scopulariopsis sp. (1) and Trichoderma sp. (1). In conclusion, this study showed that non-dermatophytic molds were responsible for nearly 10% of onychomycoses cases attending the dermatology outpatient clinic of a university hospital in Izmir, Turkey. Since molds are common contaminants in the laboratory, cultures from consecutively taken nail scrapings should be made and carefully evaluated in order to diagnose a “mold onychomycosis”.     

The Burden of Acute Disease in Mahajanga,Madagascar – A 21 Month Study

Background

Efforts to develop effective and regionally-appropriate emergency care systems in sub-Saharan Africa are hindered by a lack of data on both the burden of disease in the region and on the state of existing care delivery mechanisms. This study describes the burden of acute disease presenting to an emergency unit in Mahajanga, Madagascar.

Methods and Findings

Handwritten patient registries on all emergency department patients presenting between 1 January 2011 and 30 September 2012 were reviewed and data entered into a database. Data included age, sex, diagnosis, and disposition. We classified diagnoses into Clinical Classifications Software (CCS) multi-level categories. The population was 53.5% male, with a median age of 31 years. The five most common presenting conditions were 1) Superficial injury; contusion, 2) Open wounds of head; neck; and trunk, 3) Open wounds of extremities, 4) Intracranial injury, and 5) Unspecified injury and poisoning. Trauma accounted for 48%, Infectious Disease for 15%, Mental Health 6.1%, Noncommunicable 29%, and Neoplasms 1.2%. The acuity seen was high, with an admission rate of 43%. Trauma was the most common reason for admission, representing 19% of admitted patients.

Conclusions

This study describes the burden of acute disease at a large referral center in northern Madagascar. The Centre Hôpitalier Universitaire de Mahajanga sees a high volume of acutely ill and injured patients. Similar to other reports from the region, trauma is the most common pathology observed, though infectious disease was responsible for the majority of adult mortality. Typhoid fever other intestinal infections were the most lethal CCS-coded pathologies. By utilizing a widely understood classification system, we are able to highlight contrasts between Mahajanga’s acute and overall disease burden as well as make comparisons between this region and the rest of the globe. We hope this study will serve to guide the development of context-appropriate emergency medicine systems in the region.     

Comparative Study of the Absorption,Plasma Levels,and Urinary Excretion of the “New” and the “Old” Lanoxin

A comparative study was performed of the absorption, the plasma level at equilibrium, and the urinary excretion of digoxin using two types of Lanoxin tablets, those produced before and after the 1972 alteration of the tablet manufacture.After a single dose the absorption rate of the new tablets was about twice as great as the old, both in young subjects and in the elderly patients. There were no significant differences in the plasma levels of digoxin for the two tablets 15 hours after the last administration in patients on an equal maintenance dose. The urinary excretion of digoxin increased about 40% when the “old” Lanoxin was replaced by the “new.” In elderly patients a daily dose of 0·125 mg twice daily of the new tablets should be sufficient to reach the therapeutic range. Young people need a higher dosage. If the kidney function is reduced by as much as 50% the dose should be reduced.     

A Metabolic Study of Huntington’s Disease

Background

Huntington’s disease patients have a number of peripheral manifestations suggestive of metabolic and endocrine abnormalities. We, therefore, investigated a number of metabolic factors in a 24-hour study of Huntington’s disease gene carriers (premanifest and moderate stage II/III) and controls.

Methods

Control (n = 15), premanifest (n = 14) and stage II/III (n = 13) participants were studied with blood sampling over a 24-hour period. A battery of clinical tests including neurological rating and function scales were performed. Visceral and subcutaneous adipose distribution was measured using magnetic resonance imaging. We quantified fasting baseline concentrations of glucose, insulin, cholesterol, triglycerides, lipoprotein (a), fatty acids, amino acids, lactate and osteokines. Leptin and ghrelin were quantified in fasting samples and after a standardised meal. We assessed glucose, insulin, growth hormone and cortisol concentrations during a prolonged oral glucose tolerance test.

Results

We found no highly significant differences in carbohydrate, protein or lipid metabolism markers between healthy controls, premanifest and stage II/III Huntington’s disease subjects. For some markers (osteoprotegerin, tyrosine, lysine, phenylalanine and arginine) there is a suggestion (p values between 0.02 and 0.05) that levels are higher in patients with premanifest HD, but not moderate HD. However, given the large number of statistical tests performed interpretation of these findings must be cautious.

Conclusions

Contrary to previous studies that showed altered levels of metabolic markers in patients with Huntington’s disease, our study did not demonstrate convincing evidence of abnormalities in any of the markers examined. Our analyses were restricted to Huntington’s disease patients not taking neuroleptics, anti-depressants or other medication affecting metabolic pathways. Even with the modest sample sizes studied, the lack of highly significant results, despite many being tested, suggests that the majority of these markers do not differ markedly by disease status.     

'Population laboratories' or 'laboratory populations'? Making sense of the Baltimore Longitudinal Study of Aging, 1965-1987

Interest among historians, philosophers and sociologists of science in population-based biomedical research has focused on the randomised controlled trial to the detriment of the longitudinal study, the temporally extended, serial observation of individuals residing in the same community. This is perhaps because the longitudinal study is regarded as having played a secondary role in the debates about the validity of populations-based approaches that helped to establish epidemiology as one of the constitutive disciplines of contemporary biomedicine. Drawing on archival data and publications relating to the Baltimore Longitudinal Study of Aging, we argue however that the historical development of the longitudinal study is richer and more significant than has been appreciated. We argue that this history is shaped by the tension between two sets of epistemic practices, devices and norms. On the one side there were those who emphasised randomisation and sampling to evidence claims about, and justify policies with respect to, the aetiology of disease. On the other side there were those who evoked the technical repertoire of physiological research, especially the notion of the ‘model organism’, to argue for a different integration of the individual in modern society.