Treatment outcome of intravenous artesunate in patients with severe malaria in the Netherlands and Belgium

<p>Abstract</p> <p>Background</p> <p>Intravenous (IV) artesunate is the treatment of choice for severe malaria. In Europe, however, no GMP-manufactured product is available and treatment data in European travellers are scarce. Fortunately, artesunate became available in the Netherlands and Belgium through a named patient programme. This is the largest case series of artesunate treated patients with severe malaria in Europe.</p> <p>Methods</p> <p>Hospitalized patients treated with IV artesunate between November 2007 and December 2010 in the Netherlands and Belgium were retrospectively evaluated. Patient characteristics, treatment and clinical outcome were recorded on a standardized form and mortality, parasite clearance times and the occurrence of adverse events were evaluated.</p> <p>Results</p> <p>Of the 68 treated patients, including 55 with severe malaria, two patients died (2/55 = 3.6%). The mean time to 50% parasite clearance (PCT50), 90% and 99% were 4.4 hours (3.9 - 5.2), 14.8 hours (13.0 - 17.2), and 29.5 hours (25.9 - 34.4) respectively. Artesunate was well tolerated. However, an unusual form of haemolytic anaemia was observed in seven patients. The relationship with artesunate remains uncertain.</p> <p>Conclusions</p> <p>Data from the named patient programme demonstrate that IV artesunate is effective and well-tolerated in European travellers lacking immunity. However, increased attention needs to be paid to the possible development of haemolytic anaemia 2-3 weeks after start of treatment.</p> <p>Treatment of IV artesunate should be limited to the period that IV treatment is required and should be followed by a full oral course of an appropriate anti-malarial drug.</p

Kinetics and 28-day test-retest repeatability and reproducibility of [C-11]UCB-J PET brain imaging

[C-11]UCB-J is a novel radioligand that binds to synaptic vesicle glycoprotein 2A (SV2A). The main objective of this study was to determine the 28-day test-retest repeatability (TRT) of quantitative [C-11]UCB-J brain positron emission tomography (PET) imaging in Alzheimer's disease (AD) patients and healthy controls (HCs). Nine HCs and eight AD patients underwent two 60 min dynamic [C-11]UCB-J PET scans with arterial sampling with an interval of 28 days. The optimal tracer kinetic model was assessed using the Akaike criteria (AIC). Micro-/macro-parameters such as tracer delivery (K-1) and volume of distribution (V-T) were estimated using the optimal model. Data were also analysed for simplified reference tissue model (SRTM) with centrum semi-ovale (white matter) as reference region. Based on AIC, both 1T2k_V-B and 2T4k_V-B described the [C-11]UCB-J kinetics equally well. Analysis showed that whole-brain grey matter TRT for V-T, DVR and SRTM BPND were -2.2% +/- 8.5, 0.4% +/- 12.0 and -8.0% +/- 10.2, averaged over all subjects. [C-11]UCB-J kinetics can be well described by a 1T2k_V-B model, and a 60 min scan duration was sufficient to obtain reliable estimates for both plasma input and reference tissue models. TRT for V-T, DVR and BPND wa

Long-term culture of genome-stable bipotent stem cells from adult human liver.

Despite the enormous replication potential of the human liver, there are currently no culture systems available that sustain hepatocyte replication and/or function in vitro. We have shown previously that single mouse Lgr5+ liver stem cells can be expanded as epithelial organoids in vitro and can be differentiated into functional hepatocytes in vitro and in vivo. We now describe conditions allowing long-term expansion of adult bile duct-derived bipotent progenitor cells from human liver. The expanded cells are highly stable at the chromosome and structural level, while single base changes occur at very low rates. The cells can readily be converted into functional hepatocytes in vitro and upon transplantation in vivo. Organoids from α1-antitrypsin deficiency and Alagille syndrome patients mirror the in vivo pathology. Clonal long-term expansion of primary adult liver stem cells opens up experimental avenues for disease modeling, toxicology studies, regenerative medicine, and gene therapy.This work was supported by grants to MH (EU/236954) and to HC (The United European Gastroenterology Federation (UEGF) Research Prize 2010, EU/232814-StemCellMark and NWO/116002008). MH is supported by The Wellcome Trust Sir Henry Dale fellowship. The Rspo cell line was kindly provided by Dr. Calvin Kuo.This is the final published version. It first appeared at http://www.cell.com/abstract/S0092-8674%2814%2901566-9

Multidrug Resistant 2009 A/H1N1 Influenza Clinical Isolate with a Neuraminidase I223R Mutation Retains Its Virulence and Transmissibility in Ferrets

Only two classes of antiviral drugs, neuraminidase inhibitors and adamantanes, are approved for prophylaxis and therapy against influenza virus infections. A major concern is that influenza virus becomes resistant to these antiviral drugs and spreads in the human population. The 2009 pandemic A/H1N1 influenza virus is naturally resistant to adamantanes. Recently a novel neuraminidase I223R mutation was identified in an A/H1N1 virus showing cross-resistance to the neuraminidase inhibitors oseltamivir, zanamivir and peramivir. However, the ability of this virus to cause disease and spread in the human population is unknown. Therefore, this clinical isolate (NL/2631-R223) was compared with a well-characterized reference virus (NL/602). In vitro experiments showed that NL/2631-I223R replicated as well as NL/602 in MDCK cells. In a ferret pathogenesis model, body weight loss was similar in animals inoculated with NL/2631-R223 or NL/602. In addition, pulmonary lesions were similar at day 4 post inoculation. However, at day 7 post inoculation, NL/2631-R223 caused milder pulmonary lesions and degree of alveolitis than NL/602. This indicated that the mutant virus was less pathogenic. Both NL/2631-R223 and a recombinant virus with a single I223R change (recNL/602-I223R), transmitted among ferrets by aerosols, despite observed attenuation of recNL/602-I223R in vitro. In conclusion, the I223R mutated virus isolate has comparable replicative ability and transmissibility, but lower pathogenicity than the reference virus based on these in vivo studies. This implies that the 2009 pandemic influenza A/H1N1 virus subtype with an isoleucine to arginine change at position 223 in the neuraminidase has the potential to spread in the human population. It is important to be vigilant for this mutation in influenza surveillance and to continue efforts to increase the arsenal of antiviral drugs to combat influenza

Postpartum behaviour as predictor of weight change from before pregnancy to one year postpartum

<p>Abstract</p> <p>Background</p> <p>Postpartum weight retention affects many women and increases the risk of becoming overweight. The research objective was to study modifiable factors contributing to weight change at one year postpartum.</p> <p>Methods</p> <p>In this prospective cohort, postpartum behavior, such as physical activity, sedentary behavior, sleep, and intake of total energy, total fat and saturated fatty acids of 118 Dutch women were assessed in 2003/2004 by self-report at 6 weeks, 6 and 12 months postpartum. Mean postpartum scores were computed for the behavioral measures. In linear regression models it was determined which factors were associated with average weight change from before pregnancy to one year postpartum. Furthermore, factors associated with substantial postpartum weight retention (≥ 5 kg) were also studied in logistic regression models.</p> <p>Results</p> <p>At one year postpartum, the average weight of participants had increased by 0.9 kg (SD 4.4). Moreover, 20% of the women retained ≥ 5 kg. Women who perceived themselves more physically active than others were almost ten times less likely to retain ≥ 5 kg than women who perceived themselves equally active (OR = 0.11, 95%CI: 0.02 - 0.66). Exceeding the guideline for saturated fatty acid intake (OR = 3.40, 95%CI: 1.04 - 11.11), total gestational weight gain (OR = 1.14/kg, 95%CI: 1.01 - 1.27), and not having completed post high school education (OR = 5.13, 95%CI: 1.66 - 15.90) increased the odds of retaining ≥ 5 kg.</p> <p>Conclusions</p> <p>Since one in five women had substantial weight retention postpartum, effective interventions for the prevention of weight retention are much needed. Future studies should evaluate whether interventions focusing on the identified modifiable postpartum factors are successful in reducing weight retention after childbirth.</p

Prevention of fall incidents in patients with a high risk of falling: design of a randomised controlled trial with an economic evaluation of the effect of multidisciplinary transmural care

Background. Annually, about 30% of the persons of 65 years and older falls at least once and 15% falls at least twice. Falls often result in serious injuries, such as fractures. Therefore, the prevention of accidental falls is necessary. The aim is to describe the design of a study that evaluates the efficacy and cost-effectiveness of a multidisciplinary assessment and treatment of multiple fall risk factors in independently living older persons with a high risk of falling. Methods/Design. The study is designed as a randomised controlled trial (RCT) with an economic evaluation. Independently living persons of 65 years and older who recently experienced a fall are interviewed in their homes and screened for risk of recurrent falling using a validated fall risk profile. Persons at low risk of recurrent falling are excluded from the RCT. Persons who have a high risk of recurrent falling are blindly randomised into an intervention (n = 100) or usual care (n = 100) group. The intervention consists of a multidisciplinary assessment and treatment of multifactorial fall risk factors. The transmural multidisciplinary appraoch entails close cooperation between geriatrician, primary care phys

Common variants in the regulative regions of GRIA1 and GRIA3 receptor genes are associated with migraine susceptibility

<p>Abstract</p> <p>Background</p> <p>Glutamate is the principal excitatory neurotransmitter in the central nervous system which acts by the activation of either ionotropic (AMPA, NMDA and kainate receptors) or G-protein coupled metabotropic receptors. Glutamate is widely accepted to play a major role in the path physiology of migraine as implicated by data from animal and human studies. Genes involved in synthesis, metabolism and regulation of both glutamate and its receptors could be, therefore, considered as potential candidates for causing/predisposing to migraine when mutated.</p> <p>Methods</p> <p>The association of polymorphic variants of <it>GRIA1</it>-<it>GRIA4 </it>genes which encode for the four subunits (GluR1-GluR4) of the alpha-amino-3- hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor for glutamate was tested in migraineurs with and without aura (MA and MO) and healthy controls.</p> <p>Results</p> <p>Two variants in the regulative regions of <it>GRIA1 </it>(rs2195450) and <it>GRIA3 </it>(rs3761555) genes resulted strongly associated with MA (P = 0.00002 and P = 0.0001, respectively), but not associated with MO, suggesting their role in cortical spreading depression. Whereas the rs548294 variant in <it>GRIA1 </it>gene showed association primarily with MO phenotype, supporting the hypothesis that MA and MO phenotypes could be genetically related. These variants modify binding sites for transcription factors altering the expression of <it>GRIA1 </it>and <it>GRIA3 </it>genes in different conditions.</p> <p>Conclusions</p> <p>This study represents the first genetic evidence of a link between glutamate receptors and migraine.</p

Design of the New Life(style) study: a randomised controlled trial to optimise maternal weight development during pregnancy. [ISRCTN85313483]

BACKGROUND: Preventing excessive weight gain during pregnancy is potentially important in the prevention of overweight and obesity among women of childbearing age. However, few intervention studies aiming at weight management during pregnancy have been performed and most of these interventions were not as successful as expected. In this paper the design of the New Life(style) study is described as well as the content of the individually tailored intervention program, which focuses on controlling weight development during pregnancy. METHODS: The effectiveness of the New Life(style) intervention program versus usual care by midwives is evaluated in a randomised controlled trial. Women who expect their first child and visit one of the participating midwifery practices are included. The intervention is standardised in a protocol and executed by trained counsellors with the women who are randomised in the intervention group. During 5 sessions – at 18, 22, 30 and 36 weeks of pregnancy and at 8 weeks postpartum – individual weight gain is discussed in relation to weight gain guidelines for pregnant women of the American Institute of Medicine. Counsellors coach the women to maintain or optimise a healthy lifestyle, in a period of drastic physical and mental changes. Data is collected at 15, 25, 35 weeks of pregnancy and at 6, 26, and 52 weeks after delivery. Primary outcome measures are body weight, BMI, and skinfold thickness. Secondary outcome measures include physical activity, nutrition and blood levels of factors that are associated with energy homeostasis. DISCUSSION: Results of the current RCT will improve the knowledge of determinants of weight gain during pregnancy, weight retention after childbirth and of the effectiveness of the intervention program that is described. Caregivers and researchers in the field of health promotion are offered more insight in specific elements of the New Life(style) intervention program