bluuebunny/crossref_metadata_2025 huggingface dataset:
Revised International Prognostic Scoring System for Myelodysplastic Syndromes
Authors: Greenberg Peter L. , Tuechler Heinz , Schanz Julie , Sanz Guillermo , Garcia-Manero Guillermo , Solé Francesc , Bennett John M. , Bowen David , Fenaux Pierre , Dreyfus Francois , Kantarjian Hagop , Kuendgen Andrea , Levis Alessandro , Malcovati Luca , Cazzola Mario , Cermak Jaroslav , Fonatsch Christa , Le Beau Michelle M. , Slovak Marilyn L. , Krieger Otto , Luebbert Michael , Maciejewski Jaroslaw , Magalhaes Silvia M. M. , Miyazaki Yasushi , Pfeilstöcker Michael , Sekeres Mikkael , Sperr Wolfgang R. , Stauder Reinhard , Tauro Sudhir , Valent Peter , Vallespi Teresa , van de Loosdrecht Arjan A. , Germing Ulrich , Haase Detlef
Published: June 2012

The International Prognostic Scoring Sytem (IPSS) is an important standard for ssessing prognosis of primary untreated adult patients with myelodysplastic syndromes (MDS). To refine the IPSS, MDS patient databases from international institutions were coalesced to assemble a much larger combined database (Revised-IPSS [IPSS-R], n = 7012, IPSS, n = 816) for analysis. Multiple statistically weighted clinical features were used to generate a prognostic categorization model. Bone marrow cytogenetics, marrow blast percentage, and cytopenias remained the basis of the new system. Novel components of the current analysis included: 5 rather than 3 cytogenetic prognostic subgroups with specific and new classifications of a number of less common cytogenetic subsets, splitting the low marrow blast percentage value, and depth of cytopenias. This model defined 5 rather than the 4 major prognostic categories that are present in the IPSS. Patient age, performance status, serum ferritin, and lactate dehydrogenase were significant additive features for survival but not for acute myeloid leukemia transformation. This system comprehensively integrated the numerous known clinical features into a method analyzing MDS patient prognosis more precisely than the initial IPSS. As such, this IPSS-R should prove beneficial for predicting the clinical outcomes of untreated MDS patients and aiding design and analysis of clinical trials in this disease.
Evolution of coding and non-coding genes in HOX clusters of a marsupial
Authors: Yu Hongshi , Lindsay James , Feng Zhi-Ping , Frankenberg Stephen , Hu Yanqiu , Carone Dawn , Shaw Geoff , Pask Andrew J , O’Neill Rachel , Papenfuss Anthony T , Renfree Marilyn B
Published: June 2012

Background

The HOX gene clusters are thought to be highly conserved amongst mammals and other vertebrates, but the long non-coding RNAs have only been studied in detail in human and mouse. The sequencing of the kangaroo genome provides an opportunity to use comparative analyses to compare the HOX clusters of a mammal with a distinct body plan to those of other mammals.

Results

Here we report a comparative analysis ofHOXgene clusters between an Australian marsupial of the kangaroo family and the eutherians. There was a strikingly high level of conservation ofHOXgene sequence and structure and non-protein coding genes including the microRNAsmiR-196a,miR-196b,miR-10aandmiR-10band the long non-coding RNAsHOTAIR,HOTAIRM1andHOXA11AS that play critical roles in regulating gene expression and controlling development. By microRNA deep sequencing and comparative genomic analyses, two conserved microRNAs (miR-10aandmiR-10b) were identified and one new candidate microRNA with typical hairpin precursor structure that is expressed in both fibroblasts and testes was found. The prediction of microRNA target analysis showed that several known microRNA targets, such asmiR-10,miR-414andmiR-464, were found in the tammarHOXclusters. In addition, several novel and putative miRNAs were identified that originated from elsewhere in the tammar genome and that target the tammarHOXBandHOXDclusters.

Conclusions

This study confirms that the emergence of known long non-coding RNAs in the HOX clusters clearly predate the marsupial-eutherian divergence 160 Ma ago. It also identified a new potentially functional microRNA as well as conserved miRNAs. These non-coding RNAs may participate in the regulation ofHOXgenes to influence the body plan of this marsupial.
Transcriptome characterization via 454 pyrosequencing of the annelid Pristina leidyi, an emerging model for studying the evolution of regeneration
Authors: Nyberg Kevin G , Conte Matthew A , Kostyun Jamie L , Forde Alison , Bely Alexandra E
Published: June 2012

Background

The naid annelids contain a number of species that vary in their ability to regenerate lost body parts, making them excellent candidates for evolution of regeneration studies. However, scant sequence data exists to facilitate such studies. We constructed a cDNA library from the naid Pristina leidyi, a species that is highly regenerative and also reproduces asexually by fission, using material from a range of regeneration and fission stages for our library. We then sequenced the transcriptome of P. leidyi using 454 technology.

Results

454 sequencing produced 1,550,174 reads with an average read length of 376 nucleotides. Assembly of 454 sequence reads resulted in 64,522 isogroups and 46,679 singletons for a total of 111,201 unigenes in this transcriptome. We estimate that over 95% of the transcripts in our library are present in our transcriptome. 17.7% of isogroups had significant BLAST hits to the UniProt database and these include putative homologs of a number of genes relevant to regeneration research. Although many sequences are incomplete, the mean sequence length of transcripts (isotigs) is 707 nucleotides. Thus, many sequences are large enough to be immediately useful for downstream applications such as gene expression analyses. Using in situ hybridization, we show that two Wnt/β-catenin pathway genes (homologs of frizzled and β-catenin) present in our transcriptome are expressed in the regeneration blastema of P. leidyi, demonstrating the usefulness of this resource for regeneration research.

Conclusions

454 sequencing is a rapid and efficient approach for identifying large numbers of genes in an organism that lacks a sequenced genome. This transcriptome dataset will be a valuable resource for molecular analyses of regeneration in P. leidyi and will serve as a starting point for comparisons to non-regenerating naids. It also contributes significantly to the still limited genomic resources available for annelids and lophotrochozoans more generally.
Predicting cancer-associated germline variations in proteins
Authors: Martelli Pier Luigi , Fariselli Piero , Balzani Eva , Casadio Rita
Published: June 2012

Background

Various computational methods are presently available to classify whether a protein variation is disease-associated or not. However data derived from recent technological advancements make it feasible to extend the annotation of disease-associated variations in order to include specific phenotypes. Here we tackle the problem of distinguishing between genetic variations associated to cancer and variations associated to other genetic diseases.

Results

We implement a new method based on Support Vector Machines that takes as input the protein variant and the protein function, as described by its associated Gene Ontology terms. Our approach succeeds in discriminating between germline variants that are likely to be cancer-associated from those that are related to other genetic disorders. The method performs with values of 90% accuracy and 0.61 Matthews correlation coefficient on a set comprising 6478 germline variations (16% are cancer-associated) in 592 proteins. The sensitivity and the specificity on the cancer class are 69% and 66%, respectively. Furthermore the method is capable of correctly excluding some 96% of 3392 somatic cancer-associated variations in 1983 proteins not included in the training/testing set.

Conclusions

Here we prove feasible that a large set of cancer associated germline protein variations can be successfully discriminated from those associated to other genetic disorders. This is a step further in the process of protein variant annotation. Scoring largely improves when protein function as encoded by Gene Ontology terms is considered, corroborating the role of protein function as a key feature for a correct annotation of its variations.
Variation of chemosensory receptor content of Campylobacter jejuni strains and modulation of receptor gene expression under different in vivo and in vitro growth conditions
Authors: Day Christopher J , Hartley-Tassell Lauren E , Shewell Lucy K , King Rebecca M , Tram Greg , Day Serena K , Semchenko Evgeny A , Korolik Victoria
Published: June 2012

Background

Chemotaxis is crucial for the colonisation/infection of hosts with Campylobacter jejuni. Central to chemotaxis are the group A chemotaxis genes that are responsible for sensing the external environment. The distribution of group A chemoreceptor genes, as found in the C. jejuni sequenced strains, tlp1-4, 7, 10 and 11 were determined in 33 clinical human and avian isolates.

Results

Group A tlp gene content varied among the strains with genes encoding tlp1 (aspartate receptor, ccaA) and tlp7 present in all strains tested, where as tlp11 was present in only one of our international collection clinical isolates, C. jejuni 520, but was more prevalent (9/13) in the freshly isolated clinical stains from patients who required hospitalisation due to C. jejuni infection (GCH1-17). Relative expression levels of the group A tlp genes were also determined in C. jejuni reference strains NCTC 11168-GS, 11168-O and 81116 using cells grown in vitro at 37°C, 42°C and maintained at room temperature and with cells isolated directly from murine and avian hosts by immune magnetic separation without subsequent culture. Gene expression of tlp genes was varied based on strain, growth conditions and in vivo isolation source. Tlp1, although the most conserved, showed the lowest and most varied mRNA expression and protein production under laboratory conditions. Tlp7 was highly expressed at most conditions tested, and gene expression was not influenced by the tlp7 gene encoding a full length protein or one expressed as separate periplasmic and cytoplasmic domains.

Conclusion

We have shown that chemosensory receptor set variation exists among C. jejuni strains, but is not dependent on the isolation source.
Mediators between bereavement and somatic symptoms
Authors: Konkolÿ Thege Barna , Pilling János , Cserháti Zoltán , Koppˆ Maria S
Published: June 2012

Background

In our research we examined the frequency of somatic symptoms among bereaved (N = 185) and non-bereaved men and women in a national representative sample (N = 4041) and investigated the possible mediating factors between bereavement status and somatic symptoms.

Methods

Somatic symptoms were measured by the Patient Health Questionnaire (PHQ-15), anxiety with a four-point anxiety rating scale, and depression with a nine-item shortened version of the Beck Depression Inventory.

Results

Among the bereaved, somatic symptoms proved to be significantly more frequent in both genders when compared to the non-bereaved, as did anxiety and depression. On the multivariate level, the results show that both anxiety and depression proved to be a mediator between somatic symptoms and bereavement. The effect sizes indicated that for both genders, anxiety was a stronger predictor of somatic symptoms than depression.

Conclusions

The results of our research indicate that somatic symptoms accompanying bereavement are not direct consequences of this state but they can be traced back to the associated anxiety and depression. These results draw attention to the need to recognize anxiety and depression looming in the background of somatic complaints in bereavement and to the importance of the dissemination of related information.
The association between general practitioners’ attitudes towards breast cancer screening and women’s screening participation
Authors: Jensen Line Flytkjær , Mukai Thomas Ostersen , Andersen Berit , Vedsted Peter
Published: June 2012

Background

Breast cancer screening in Denmark is organised by the health services in the five regions. Although general practitioners (GPs) are not directly involved in the screening process, they are often the first point of contact to the health care system and thus play an important advisory role. No previous studies, in a health care setting like the Danish system, have investigated the association between GPs’ attitudes towards breast cancer screening and women’s participation in the screening programme.

Methods

Data on women’s screening participation was obtained from the regional screening authorities. Data on GPs’ attitudes towards breast cancer screening was taken from a previous survey among GPs in the Central Denmark Region. This study included women aged 50-69 years who were registered with a singlehanded GP who had participated in the survey.

Results

The survey involved 67 singlehanded GPs with a total of 13,288 women on their lists. Five GPs (7%) had a negative attitude towards breast cancer screening. Among registered women, 81% participated in the first screening round. Multivariate analyses revealed that women registered with a GP with a negative attitude towards breast cancer screening were 17% (95% CI: 2-34%) more likely to be non-participants compared with women registered with a GP with a positive attitude towards breast cancer screening.

Conclusion

The GPs' attitudes may influence the participation rate even in a system where GPs are not directly involved in the screening process. However, further studies are needed to investigate this association.
Change of water consumption and its potential influential factors in Shanghai: A cross-sectional study
Authors: Chen Hanyi , Zhang Yaying , Ma Linlin , Liu Fangmin , Zheng Weiwei , Shen Qinfeng , Zhang Hongmei , Wei Xiao , Tian Dajun , He Gengsheng , Qu Weidong
Published: June 2012

Background

Different water choices affect access to drinking water with different quality. Previous studies suggested social-economic status may affect the choice of domestic drinking water. The aim of this study is to investigate whether recent social economic changes in China affect residents’ drinking water choices.

Methods

We conducted a cross-sectional survey to investigate residents’ water consumption behaviour in 2011. Gender, age, education, personal income, housing condition, risk perception and personal preference of a certain type of water were selected as potential influential factors. Univariate and backward stepwise logistic regression analyses were performed to analyse the relation between these factors and different drinking water choices. Basic information was compared with that of a historical survey in the same place in 2001. Self-reported drinking-water-related diarrhoea was found correlated with different water choices and water hygiene treatment using chi-square test.

Results

The percentage of tap water consumption remained relatively stable and a preferred choice, with 58.99% in 2001 and 58.25% in 2011. The percentage of bottled/barrelled water consumption was 36.86% in 2001 and decreased to 25.75% in 2011. That of household filtrated water was 4.15% in 2001 and increased to 16.00% in 2011. Logistic regression model showed strong correlation between one’s health belief and drinking water choices (P < 0.001). Age, personal income, education, housing condition, risk perception also played important roles (P < 0.05) in the models. Drinking-water-related diarrhoea was found in all types of water and improper water hygiene behaviours still existed among residents.

Conclusions

Personal health belief, housing condition, age, personal income, education, taste and if worm ever founded in tap water affected domestic drinking water choices in Shanghai.
Parental reports of the oral health-related quality of life of children with cerebral palsy
Authors: Abanto Jenny , Carvalho Thiago S , Bönecker Marcelo , Ortega Adriana OL , Ciamponi Ana L , Raggio Daniela P
Published: June 2012

Background

The severity of physical and mental impairments and oral problems, as well as socioeconomic factors, may have an impact on quality of life of children with cerebral palsy (CP). The aim of this research was to assess the impact of impairments and oral health conditions, adjusted by socioeconomic factors, on the Oral Health-Related Quality of Life (OHRQoL) of children with CP using their parents as proxies.

Methods

Sixty children, between 6-14 years of age were selected. Their parents answered a children’s OHRQoL instrument (5 domains) which combines the Parental-Caregivers Perception Questionnaire (P-CPQ) and Family Impact Scale (FIS). The severity of dental caries, type of CP, communication ability, gross motor function, seizures and socioeconomic conditions were assessed.

Results

Considering the total score of the OHRQoL instrument, only the reduction of communication ability and dental caries severity had a negative impact on the OHRQoL (p < 0.05). Considering each domain of the instrument, the severity of the type of CP and its reduction of communication ability showed a negative impact on oral symptoms and functional limitations domains (p < 0.05). Seizures have a negative impact on oral symptoms domain (p = 0.006). The multivariate fitted model showed that the severity of dental caries, communication ability and low family income were negatively associated with the impact on OHRQoL (p = 0.001).

Conclusions

The severity of dental caries, communication ability, and family income are conditions strongly associated with a negative impact on OHRQoL of children with CP.
A randomized, double-blind comparison of OROS®hydromorphone and controlled-release morphine for the control of chronic cancer pain
Authors: Hanna Magdi , Thipphawong John ,   the 118 study group
Published: June 2012

Background

Long-acting opioid formulations are advocated for maintaining pain control in chronic cancer pain. OROS® hydromorphone is a sustained-release formulation of hydromorphone that requires dosing once daily to maintain therapeutic concentrations. The objective of this study was to demonstrate the clinical equivalence of immediate-release and sustained-release formulations of hydromorphone and morphine for chronic cancer pain.

Methods

200 patients with cancer pain (requiring ≤ 540 mg/d of oral morphine) participated in this double-blind, parallel-group trial. Patients were randomized to receive hydromorphone or morphine (immediate-release for 2–9 days, sustained-release for 10–15 days). Efficacy was assessed with the Brief Pain Inventory (BPI), investigator and patient global evaluations, Eastern Cooperative Oncology Group performance status, and the Mini-Mental State Examination. The primary endpoint was the 'worst pain in the past 24 hours' item of the BPI, in both the immediate-release and sustained-release study phases, with treatments deemed equivalent if the 95% confidence intervals (CI) of the between-group differences at endpoint were between -1.5 and 1.5. No equivalence limits were defined for secondary endpoints.

Results

Least-squares mean differences (95% CI) between groups were 0.2 (-0.4, 0.9) in the immediate-release phase and -0.8 (-1.6, -0.01) in the sustained-release phase (intent-to-treat population), indicating that the immediate-release formulations met the pre-specified equivalence criteria, but that the lower limit of the 95% CI (-1.6) was outside the boundary (-1.5) for the sustained-release formulations. BPI 'pain now PM' was significantly lower with OROS® hydromorphone compared with controlled-release morphine (least-squares mean difference [95% CI], -0.77 [-1.49, -0.05]; p = 0.0372). Scores for other secondary efficacy variables were similar between the two sustained-release treatments. At endpoint, > 70% of investigators and patients rated both treatments as good to excellent. The safety profiles of hydromorphone and morphine were similar and typical of opioid analgesics.

Conclusion

Equivalence was demonstrated for immediate-release formulations of hydromorphone and morphine, but not for the sustained-release formulations of OROS® hydromorphone and controlled-release morphine. The direction of the mean difference between the treatments (-0.8) and the out-of-range lower limit of the 95% CI (-1.6) were in favor of OROS® hydromorphone.

Trial registration

ClinicalTrials.gov: NCT0041054
Health economic evaluation of acupuncture along meridians for treating migraine in China: results from a randomized controlled trial
Authors: Deng Zhu-qing , Zheng Hui , Zhao Ling , Zhou Si-yuan , Li Ying , Liang Fan-rong
Published: June 2012

Background

To evaluate different types of acupuncture treatment for migraine in China from the perspective of health economics, particularly the comparison between treatment of specific acupoints in Shaoyang meridians and penetrating sham acupoints treatment.

Methods

Data were obtained from a multicenter, randomized controlled trial of acupuncture treatment in patients with migraine. Four-hundred eighty migraineurs were randomly assigned to 3 arms of treatment with genuine acupoints and 1 arm of penetrating sham acupoints. The primary outcome measurement was the cost-effectiveness ratio (C/E), expressed as cost per 1 day reduction of headache days from baseline to week 16. Cost-comparison analyses, differences in the migraine-specific quality of life questionnaire (MSQ), and the incremental cost-effectiveness ratio were taken as secondary outcome measurements. In addition, a sensitivity analysis was conducted.

Results

The total cost per patient was ¥1273.2 (95% CI 1171.3-1375.1) in the Shaoyang specific group, ¥1427.7 (95% CI 1311.8-1543.6) in the Shaoyang non-specific group, ¥1490.8 (95% CI 1327.1-1654.6) in the Yangming specific group, and ¥1470.1 (95% CI 1358.8-1581.3) in the sham acupuncture group. The reduced days with migraine were 3.972 ± 2.7, 3.555 ± 2.8, 3.793 ± 3.6, and 2.155 ± 3.7 in these 4 groups (P < 0.05 for each genuine acupoints group vs the sham group), respectively, at week 16. The C/Es of the 4 groups were 320.5, 401.6, 393.1, and 682.2, respectively. Results of the sensitivity analysis were consistent with that of the cost-effectiveness analysis. The Shaoyang specific group significantly improved in all 3 MSQ domains compared with the sham acupuncture group.

Conclusions

Treatment of specific acupoints in Shaoyang meridians is more cost-effective than that of non-acupoints, representing a dramatic improvement in the quality of life of people with migraine and a significant reduction in cost. Compared with the other 3 groups, Shaoyang-specific acupuncture is a relatively cost-effective treatment for migraine prophylaxis in China.

Trial registration

Clinical Trials.gov NCT00599586
Population prevalence of high dose paracetamol in dispensed paracetamol/opioid prescription combinations: an observational study
Authors: Clark Roderick , Fisher Judith E , Sketris Ingrid S , Johnston Grace M
Published: June 2012

Background

Paracetamol (acetaminophen) is generally considered a safe medication, but is associated with hepatotoxicity at doses above doses of 4.0g/day, and even below this daily dose in certain populations.

Methods

The Nova Scotia Prescription Monitoring Program (NSPMP) in the Canadian province of Nova Scotia is a legislated organization that collects dispensing information on all out-of-hospital prescription controlled drugs dispensed for all Nova Scotia residents. The NSPMP provided data to track all paracetamol/opioids redeemed by adults in Nova Scotia, from July 1, 2005 to June 30, 2010. Trends in the number of adults dispensed these prescriptions and the numbers of prescriptions and tablets dispensed over this period were determined. The numbers and proportions of adults who filled prescriptions exceeding 4.0g/day and 3.25g/day were determined for the one-year period July 1, 2009 to June 30, 2010. Data were stratified by sex and age (<65 versus 65+).

Results

Both the number of prescriptions filled and the number of tablets dispensed increased over the study period, although the proportion of the adult population who filled at least one paracetamol/opioid prescription was lower in each successive one-year period. From July 2009 to June 2010, one in 12 adults (n=59,197) filled prescriptions for over 13 million paracetamol/opioid tablets. Six percent (n=3,786) filled prescriptions that exceeded 4.0g/day and 18.6% (n=11,008) exceeded 3.25g/day of paracetamol at least once. These findings exclude non-prescription paracetamol and paracetamol–only prescribed medications.

Conclusions

A substantial number of individuals who redeem prescriptions for paracetamol/opioid combinations may be at risk of paracetamol-related hepatotoxicity. Healthcare professionals must be vigilant when prescribing and dispensing these medications in order to reduce the associated risks.
Prioritisation criteria for the selection of new diagnostic technologies for evaluation
Authors: Plüddemann Annette , Heneghan Carl , Thompson Matthew , Roberts Nia , Summerton Nicholas , Linden-Phillips Luan , Packer Claire , Price Christopher P
Published: June 2012

Background

Currently there is no framework for those involved in the identification, evaluation and prioritisation of new diagnostic technologies. Therefore we aimed to develop prioritisation criteria for the assessment of new diagnostic technologies, by gaining international consensus on not only which criteria should be used, but also their relative importance.

Methods

A two-round Delphi process was used to generate consensus amongst an international panel of twenty-six experts on priority criteria for diagnostic health technology assessment. Participants represented a range of health care and related professions, including government, industry, health services and academia.

Results

Based on the responses to the first questionnaire 18 criteria were placed into three categories: high, intermediate and moderate priority. For 16 of the 18 criteria, agreement with the categorisation of the criteria into the high, intermediate and moderate categories was high at ≥ 70% (10 had agreement ≥ 80%). A further questionnaire and panel discussion reduced the criteria to 16 and two categories; seven were classified as high priority and nine intermediate.

Conclusions

This study proposes an objective structure of prioritisation criteria to use when assessing new diagnostic technologies, based on an expert consensus process. The value of these criteria is that no one single component should be used as the decisive driver for prioritisation of new diagnostic technologies for adoption in healthcare settings. Future studies should be directed at establishing the value of these prioritisation criteria across a range of healthcare settings.
Genetic polymorphism and natural selection in the C-terminal 42 kDa region of merozoite surface protein-1 among Plasmodium vivax Korean isolates
Authors: Kang Jung-Mi , Ju Hye-Lim , Kang Yoo-Mi , Lee Dong-Hyun , Moon Sung-Ung , Sohn Woon-Mok , Park Jae-Won , Kim Tong-Soo , Na Byoung-Kuk
Published: June 2012

Background

The carboxy-terminal 42 kDa region ofPlasmodium vivaxmerozoite surface protein-1 (PvMSP-142) is a leading candidate antigen for blood stage vaccine development. However, this region has been observed to be highly polymorphic among filed isolates ofP. vivax. Therefore it is important to analyse the existing diversity of this antigen in the field isolates ofP. vivax. In this study, the genetic diversity and natural selection in PvMSP-142amongP. vivaxKorean isolates were analysed.

Methods

A total of 149P. vivax-infected blood samples collected from patients in Korea were used. The region flanking PvMSP-142was amplified by PCR, cloned intoEscherichia coli, and then sequenced. The polymorphic characteristic and natural selection of PvMSP-142were analysed using the DNASTAR, MEGA4 and DnaSP programs.

Results

A total of 11 distinct haplotypes of PvMSP-142with 40 amino acid changes, as compared to the reference Sal I sequence, were identified in the KoreanP. vivaxisolates. Most of the mutations were concentrated in the 33 kDa fragment (PvMSP-133), but a novel mutation was found in the 19 kDa fragment (PvMSP-119). PvMSP-142of Korean isolates appeared to be under balancing selection. Recombination may also play a role in the resulting genetic diversity of PvMSP-142.

Conclusions

PvMSP-142of KoreanP. vivaxisolates displayed allelic polymorphisms caused by mutation, recombination and balancing selection. These results will be useful for understanding the nature of theP. vivaxpopulation in Korea and for development of a PvMSP-142based vaccine againstP. vivax.
Clinical manifestations of new versus recrudescent malaria infections following anti-malarial drug treatment
Authors: Shaukat Ayesha M , Gilliams Elizabeth A , Kenefic Leo J , Laurens Matthew B , Dzinjalamala Fraction K , Nyirenda Osward M , Thesing Phillip C , Jacob Christopher G , Molyneux Malcolm E , Taylor Terrie E , Plowe Christopher V , Laufer Miriam K
Published: June 2012

Background

Distinguishing new from recrudescent infections in post-treatment episodes of malaria is standard in anti-malarial drug efficacy trials. New infections are not considered malaria treatment failures and as a result, the prevention of subsequent episodes of malaria infection is not reported as a study outcome. However, in moderate and high transmission settings, new infections are common and the ability of a short-acting medication to cure an initial infection may be outweighed by its inability to prevent the next imminent infection. The clinical benefit of preventing new infections has never been compared to that of curing the initial infection.

Methods

Children enrolled in a sulphadoxine-pyrimethamine efficacy study in Blantyre, Malawi from 1998–2004 were prospectively evaluated. Six neutral microsatellites were used to classify new and recrudescent infections in children aged less than 10 years with recurrent malaria infections. Children from the study who did not experience recurrent parasitaemia comprised the baseline group. The odds of fever and anaemia, the rate of haemoglobin recovery and time to recurrence were compared among the groups.

Results

Fever and anemia were more common among children with parasitaemia compared to those who remained infection-free throughout the study period. When comparing recrudescent vs. new infections, the incidence of fever was not statistically different. However, children with recrudescent infections had a less robust haematological recovery and also experienced recurrence sooner than those whose infection was classified as new.

Conclusions

The results of this study confirm the paramount importance of providing curative treatment for all malaria infections. Although new and recrudescent infections caused febrile illnesses at a similar rate, recurrence due to recrudescent infection did have a worsened haemological outcome than recurrence due to new infections. Local decision-makers should take into account the results of genotyping to distinguish new from recrudescent infections when determining treatment policy on a population level. It is appropriate to weigh recrudescent malaria more heavily than new infection in assessing treatment efficacy.
A novel approach to denoising ion trap tandem mass spectra
Authors: Ding Jiarui , Shi Jinhong , Poirier Guy G , Wu Fang-Xiang
Published: June 2012

Background

Mass spectrometers can produce a large number of tandem mass spectra. They are unfortunately noise-contaminated. Noises can affect the quality of tandem mass spectra and thus increase the false positives and false negatives in the peptide identification. Therefore, it is appealing to develop an approach to denoising tandem mass spectra.

Results

We propose a novel approach to denoising tandem mass spectra. The proposed approach consists of two modules: spectral peak intensity adjustment and intensity local maximum extraction. In the spectral peak intensity adjustment module, we introduce five features to describe the quality of each peak. Based on these features, a score is calculated for each peak and is used to adjust its intensity. As a result, the intensity will be adjusted to a local maximum if a peak is a signal peak, and it will be decreased if the peak is a noisy one. The second module uses a morphological reconstruction filter to remove the peaks whose intensities are not the local maxima of the spectrum. Experiments have been conducted on two ion trap tandem mass spectral datasets: ISB and TOV. Experimental results show that our algorithm can remove about 69% of the peaks of a spectrum. At the same time, the number of spectra that can be identified by Mascot algorithm increases by 31.23% and 14.12% for the two tandem mass spectra datasets, respectively.

Conclusion

The proposed denoising algorithm can be integrated into current popular peptide identification algorithms such as Mascot to improve the reliability of assigning peptides to spectra.

Availability of the software

The software created from this work is available upon request.
The detrimental danger of water-pipe (Hookah) transcends the hazardous consequences of general health to the driving behavior
Authors: Elias Wafa , Assy Nimer , Elias Ibrahim , Toledo Tomer , Yassin Mustafa , Bowirrat Abdalla
Published: June 2012

Objective

To determine whether the consumption of tobacco used in Water-Pipe by drivers increases the risk of a motor vehicle collision as a consequence of hypoxia.

Design

Analytical case–control study.

Data sources

Seventy exclusive Water-Pipe smokers (Experimental Group - EG) - mean age ± SD: 29.47 ± 10.45 years; mean number of weekly WPS, (6.9 ± 3.7); mean duration of WPS (WPS) is (7.5 ± 2.1 years) - and thirty non-smoker (Control Group – CG; mean age ± SD: 36.33 ± 13.92 years) were recruited during 2011 from two Arab villages located in the Galilee, northern Israel.

Methods

We performed a case–control study exclusively among Water-Pipe smokers with an appropriate non smokers control group. Demographic questionnaire, Pulse Oxymeter for blood oxygenation measure and a driver simulator for measuring various participants driving behaviors were utilized. Statistical analysis for analyzing the different variables, Pearson’s x
2 analysis for the comparison of categorical variables, continuous variable is compared using Student’s t-test and for testing the correlation between the different variables and bivariate correlation analysis were applied.

Results

In the (EG) following WPS, we observed increase in the pulse rate - from 80 to 95 (t = 11.84, p < 0.05) and decrease in saturation level from 97.9 to 97.32, the decrease is statistically significant (t = 3.01, p < 0.05) versus no change in (CG). An increased number of accidents among EG (OR is 1.333 with CI of 1.008–1.776), while in CG, an insignificantly decrease (t = 3.08, p < 0.05). In EG an increase in centerline crossings (OR is 1.306 with CI of 1.016–1.679), also the total time not being within the lane was increased and the estimated (OR: 1.329; CI: 1.025–1.722). WPS increases the number of accidents by 33% and Hypoxia can cause driving behavioral turbulences.

Conclusion

The results show that WPS has a significant impact on driving behavior and on the risk of being involved in road accidents and causing driving to become riskier and less careful and stable. To the best of our knowledge, this is the first time such relationships have been tested. After WPS the total number of traffic accidents and driving violations increase. The results show a significant increase in the pulse rate immediately after WPS with a decrease in the saturation rate (the level of blood oxygenation); these changes continue half an hour after WPS.
Lipopolysaccharide impairs amyloid beta efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood–brain barrier
Authors: Erickson Michelle A , Hartvigson Pehr E , Morofuji Yoichi , Owen Joshua B , Butterfield D Allan , Banks William A
Published: June 2012

Background

Defects in the low density lipoprotein receptor-related protein-1 (LRP-1) and p-glycoprotein (Pgp) clearance of amyloid beta (Aβ) from brain are thought to contribute to Alzheimer’s disease (AD). We have recently shown that induction of systemic inflammation by lipopolysaccharide (LPS) results in impaired efflux of Aβ from the brain. The same treatment also impairs Pgp function. Here, our aim is to determine which physiological routes of Aβ clearance are affected following systemic inflammation, including those relying on LRP-1 and Pgp function at the blood–brain barrier.

Methods

CD-1 mice aged between 6 and 8 weeks were treated with 3 intraperitoneal injections of 3 mg/kg LPS at 0, 6, and 24 hours and studied at 28 hours.125I-Aβ1-42or125I-alpha-2-macroglobulin injected into the lateral ventricle of the brain (intracerebroventricular (ICV)) or into the jugular vein (intravenous (IV)) was used to quantify LRP-1-dependent partitioning between the brain vasculature and parenchyma and peripheral clearance, respectively. Disappearance of ICV-injected14 C-inulin from brain was measured to quantify bulk flow of cerebrospinal fluid (CSF). Brain microvascular protein expression of LRP-1 and Pgp was measured by immunoblotting. Endothelial cell localization of LRP-1 was measured by immunofluorescence microscopy. Oxidative modifications to LRP-1 at the brain microvasculature were measured by immunoprecipitation of LRP-1 followed by immunoblotting for 4-hydroxynonenal and 3-nitrotyrosine.

Results

We found that LPS: caused an LRP-1-dependent redistribution of ICV-injected Aβ from brain parenchyma to brain vasculature and decreased entry into blood; impaired peripheral clearance of IV-injected Aβ; inhibited reabsorption of CSF; did not significantly alter brain microvascular protein levels of LRP-1 or Pgp, or oxidative modifications to LRP-1; and downregulated LRP-1 protein levels and caused LRP-1 mislocalization in cultured brain endothelial cells.

Conclusions

These results suggest that LRP-1 undergoes complex functional regulation following systemic inflammation which may depend on cell type, subcellular location, and post-translational modifications. Our findings that systemic inflammation causes deficits in both Aβ transport and bulk flow like those observed in AD indicate that inflammation could induce and promote the disease.
High virologic response rate after second-line boosted protease inhibitor-based antiretroviral therapy regimens in children from a resource limited setting
Authors: Puthanakit Thanyawee , Jourdain Gonzague , Suntarattiwong Piyarat , Chokephaibulkit Kulkanya , Siangphoe Umaporn , Suwanlerk Tulathip , Prasitsuebsai Wasana , Sirisanthana Virat , Kosalaraksa Pope , Petdachai Witaya , Hansudewechakul Rawiwan , Waranawat Naris , Ananworanich Jintanat ,   the HIV-NAT 086 study team
Published: June 2012

Background

Limited data exist for the efficacy of second-line antiretroviral therapy among children in resource limited settings. We assessed the virologic response to protease inhibitor-based ART after failing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens.

Methods

A retrospective chart review was conducted at 8 Thai sites of children who switched to PI –based regimens due to failure of NNRTI –based regimens. Primary endpoints were HIV RNA < 400 copies/ml and CD4 change over 48 weeks.

Results

Data from 241 children with median baseline values before starting PI-based regimens of 9.1 years for age, 10% for CD4%, and 4.8 log10copies/ml for HIV RNA were included; 104 (41%) received a single ritonavir-boosted PI (sbPI) with 2 NRTIs and 137 (59%) received double-boosted PI (dbPI) with/without NRTIs based on physician discretion. SbPI children had higher baseline CD4 (17% vs. 6%, p < 0.001), lower HIV RNA (4.5 vs. 4.9 log10copies/ml, p < 0.001), and less frequent high grade multi-NRTI resistance (12.4% vs 60.5%, p < 0.001) than the dbPI children. At week 48, 81% had HIV RNA < 400 copies/ml (sbPI 83.1% vs. dbPI 79.8%, p = 0.61) with a median CD4 rise of 9% (+7%vs. + 10%, p < 0.005). However, only 63% had HIV RNA < 50 copies/ml, with better viral suppression seen in sbPI (76.6% vs. 51.4%, p 0.002).

Conclusion

Second-line PI therapy was effective for children failing first line NNRTI in a resource-limited setting. DbPI were used in patients with extensive drug resistance due to limited treatment options. Better access to antiretroviral drugs is needed.
Manipulation of immunodominant dengue virus E protein epitopes reduces potential antibody-dependent enhancement
Authors: Hughes Holly R , Crill Wayne D , Chang Gwong-Jen J
Published: June 2012

Background

Dengue viruses (DENV) are the most important arboviruses of humans and cause significant disease. Infection with DENV elicits antibody responses to the envelope glycoprotein, predominantly against immunodominant, cross-reactive, weakly-neutralizing epitopes. These weakly-neutralizing antibodies are implicated in enhancing infection via Fcγ receptor bearing cells and can lead to increased viral loads that are associated with severe disease. Here we describe results from the development and testing of cross-reactivity reduced DENV-2 DNA vaccine candidates that contain substitutions in immunodominant B cell epitopes of the fusion peptide and domain III of the envelope protein.

Results

Cross-reactivity reduced and wild-type vaccine candidates were similarly immunogenic in outbred mice and elicited high levels of neutralizing antibody, however mice immunized with cross-reactivity reduced vaccines produced significantly reduced levels of immunodominant cross-reactive antibodies. Sera from mice immunized with wild-type, fusion peptide-, or domain III- substitution containing vaccines enhanced heterologous DENV infectionin vitro, unlike sera from mice immunized with a vaccine containing a combination of both fusion peptide and domain III substitutions. Passive transfer of immune sera from mice immunized with fusion peptide and domain III substitutions also reduced the development of severe DENV disease in AG129 mice when compared to mice receiving wild type immune sera.

Conclusions

Reducing cross-reactivity in the envelope glycoprotein of DENV may be an approach to improve the quality of the anti-DENV immune response.
Myofibrillar protein synthesis following ingestion of soy protein isolate at rest and after resistance exercise in elderly men
Authors: Yang Yifan , Churchward-Venne Tyler A , Burd Nicholas A , Breen Leigh , Tarnopolsky Mark A , Phillips Stuart M
Published: June 2012

Background

Increased amino acid availability stimulates muscle protein synthesis, however, aged muscle appears less responsive to the anabolic effects of amino acids when compared to the young. We aimed to compare changes in myofibrillar protein synthesis (MPS) in elderly men at rest and after resistance exercise following ingestion of different doses of soy protein and compare the responses to those we previously observed with ingestion of whey protein isolate.

Methods

Thirty elderly men (age 71 ± 5 y) completed a bout of unilateral knee-extensor resistance exercise prior to ingesting no protein (0 g), or either 20 g or 40 g of soy protein isolate (0, S20, and S40 respectively). We compared these responses to previous responses from similar aged men who had ingested 20 g and 40 g of whey protein isolate (W20 and W40). A primed constant infusion of L-[1-13 C]leucine and L-[ring-13 C6]phenylalanine and skeletal muscle biopsies were used to measure whole-body leucine oxidation and MPS over 4 h post-protein consumption in both exercised and non-exercised legs.

Results

Whole-body leucine oxidation increased with protein ingestion and was significantly greater for S20 vs. W20 (P = 0.003). Rates of MPS for S20 were less than W20 (P = 0.02) and not different from 0 g (P = 0.41) in both exercised and non-exercised leg muscles. For S40, MPS was also reduced compared with W40 under both rested and post-exercise conditions (bothP < 0.005); however S40 increased MPS greater than 0 g under post-exercise conditions (P = 0.04).

Conclusions

The relationship between protein intake and MPS is both dose and protein source-dependent, with isolated soy showing a reduced ability, as compared to isolated whey protein, to stimulate MPS under both rested and post-exercise conditions. These differences may relate to the lower postprandial leucinemia and greater rates of amino acid oxidation following ingestion of soy versus whey protein.
Complement factor I deficiency: a not so rare immune defect. Characterization of new mutations and the first large gene deletion
Authors: Alba-Domínguez María , López-Lera Alberto , Garrido Sofía , Nozal Pilar , González-Granado Ignacio , Melero Josefa , Soler-Palacín Pere , Cámara Carmen , López-Trascasa Margarita
Published: June 2012

Background

Complement Factor I (CFI) is a serine protease with an important role in complement alternative pathway regulation. Complete factor I deficiency is strongly associated with severe infections. Approximately 30 families with this deficiency have been described worldwide.

Patients and methods

We have studied five new Spanish families suffering from CFI deficiency. From 19 screened people, 7 homozygous, 10 heterozygous and 2 healthy subjects were identified. Clinical, biochemical and genetic descriptions are included.

Results

Molecular studies demonstrated 4 novel mutations in the screened individuals; amongst them, we describe here the first great gene deletion reported in the CFI locus, which includes full exon 2 and part of the large intron 1.

Conclusion

CFI deficiency is possibly an underestimated defect and the eventual existence of this deficiency should be tested in those patients exhibiting low C3 and recurrent bacterial infections. We propose a simple diagnostic flowchart to help clinicians in the identification and correct diagnosis of such patients.
Transgenic APP expression during postnatal development causes persistent locomotor hyperactivity in the adult
Authors: Rodgers Shaefali P , Born Heather A , Das Pritam , Jankowsky Joanna L
Published: June 2012

Background

Transgenic mice expressing disease-associated proteins have become standard tools for studying human neurological disorders. Transgenes are often expressed using promoters chosen to drive continuous high-level expression throughout life rather than temporal and spatial fidelity to the endogenous gene. This approach has allowed us to recapitulate diseases of aging within the two-year lifespan of the laboratory mouse, but has the potential for creating aberrant phenotypes by mechanisms unrelated to the human disorder.

Results

We show that overexpression of the Alzheimer’s-related amyloid precursor protein (APP) during early postnatal development leads to severe locomotor hyperactivity that can be significantly attenuated by delaying transgene onset until adulthood. Our data suggest that exposure to transgenic APP during maturation influences the development of neuronal circuits controlling motor activity. Both when matched for total duration of APP overexpression and when matched for cortical amyloid burden, animals exposed to transgenic APP as juveniles are more active in locomotor assays than animals in which APP overexpression was delayed until adulthood. In contrast to motor activity, the age of APP onset had no effect on thigmotaxis in the open field as a rough measure of anxiety, suggesting that the interaction between APP overexpression and brain development is not unilateral.

Conclusions

Our findings indicate that locomotor hyperactivity displayed by the tet-off APP transgenic mice and several other transgenic models of Alzheimer’s disease may result from overexpression of mutant APP during postnatal brain development. Our results serve as a reminder of the potential for unexpected interactions between foreign transgenes and brain development to cause long-lasting effects on neuronal function in the adult. The tet-off APP model provides an easy means of avoiding developmental confounds by allowing transgene expression to be delayed until the mice reach adulthood.