The New York Times
by Anita A. Davies, Rosilyne M. Borland, Carolyn Blake, Haley E. West
by The PLoS Medicine Editors
by Steven Riley, Kin O. Kwok, Kendra M. Wu, Danny Y. Ning, Benjamin J. Cowling, Joseph T. Wu, Lai-Ming Ho, Thomas Tsang, Su-Vui Lo, Daniel K. W. Chu, Edward S. K. Ma, J. S. Malik PeirisBackground
While patterns of incidence of clinical influenza have been well described, much uncertainty remains over patterns of incidence of infection. The 2009 pandemic provided both the motivation and opportunity to investigate patterns of mild and asymptomatic infection using serological techniques. However, to date, only broad epidemiological patterns have been defined, based on largely cross-sectional study designs with convenience sampling frameworks.Methods and Findings
We conducted a paired serological survey of a cohort of households in Hong Kong, recruited using random digit dialing, and gathered data on severe confirmed cases from the public hospital system (>90% inpatient days). Paired sera were obtained from 770 individuals, aged 3 to 103, along with detailed individual-level and household-level risk factors for infection. Also, we extrapolated beyond the period of our study using time series of severe cases and we simulated alternate study designs using epidemiological parameters obtained from our data. Rates of infection during the period of our study decreased substantially with age: for 3–19 years, the attack rate was 39% (31%–49%); 20–39 years, 8.9% (5.3%–14.7%); 40–59 years, 5.3% (3.5%–8.0%); and 60 years or older, 0.77% (0.18%–4.2%). We estimated parameters for a parsimonious model of infection in which a linear age term and the presence of a child in the household were used to predict the log odds of infection. Patterns of symptom reporting suggested that children experienced symptoms more often than adults. The overall rate of confirmed pandemic (H1N1) 2009 influenza (H1N1pdm) deaths was 7.6 (6.2–9.5) per 100,000 infections. However, there was substantial and progressive increase in deaths per 100,000 infections with increasing age from 0.66 (0.65–0.86) for 3–19 years up to 220 (50–4,000) for 60 years and older. Extrapolating beyond the period of our study using rates of severe disease, we estimated that 56% (43%–69%) of 3–19 year olds and 16% (13%–18%) of people overall were infected by the pandemic strain up to the end of January 2010. Using simulation, we found that, during 2009, larger cohorts with shorter follow-up times could have rapidly provided similar data to those presented here.Conclusions
Should H1N1pdm evolve to be more infectious in older adults, average rates of severe disease per infection could be higher in future waves: measuring such changes in severity requires studies similar to that described here. The benefit of effective vaccination against H1N1pdm infection is likely to be substantial for older individuals. Revised pandemic influenza preparedness plans should include prospective serological cohort studies. Many individuals, of all ages, remained susceptible to H1N1pdm after the main 2009 wave in Hong Kong.
Please see later in the article for the Editors' Summary
by Ana Ivaniš, Darko Hren, Matko Marušić, Ana MarušićBackground
Attitudes towards authorship are connected with authors' research experience and with knowledge of authorship criteria of International Committee of Medical Journal Editors (ICMJE). The objective of this study was to assess association between authors' perceived importance of contributions for authorship qualification and their participation in manuscripts submitted to a journal.Methods
Authors (n = 1181) of 265 manuscripts submitted to the Croatian Medical Journal were asked to identify and rate their contribution in the preparation of the submitted manuscript (0 – none to 4 – full for 11 listed contributions) and the importance of these contributions as authorship qualifications (0 – none to 4 – full). They were randomly allocated into 3 groups: the first (n = 90 manuscripts, n = 404 authors) first received the contribution disclosure form and then contribution importance-rating questionnaire; the second (n = 88 manuscripts, n = 382 authors) first received the rating questionnaire and then the contribution disclosure form, and the third group (n = 87 manuscripts, n = 395 authors) received both questionnaires at the same time. We compared authors' perception of importance of contribution categories.Results
1014 (85.9%) authors of 235 manuscripts responded. Authors who declared contribution to a specific category rated it as more important for authorship than those authors who did not contribute to the same category (P>0.005 for all contribution categories, Mann-Withney test). Authors qualifying for ICMJE authorship rated all contribution categories higher than non-qualifying authors. For all contributions, associations between perceived importance of contribution and actual author's contribution were statistically significant.Conclusions
Authorship seems to be not a normative issue subjective to categorization into criteria, but also a very personal view of the importance and value of one's contributions.
by Pim Cuijpers, Tara Donker, Robert Johansson, David C. Mohr, Annemieke van Straten, Gerhard AnderssonBackground
A number of trials have examined the effects of self-guided psychological intervention, without any contact between the participants and a therapist or coach. The results and sizes of these trials have been mixed. This is the first quantitative meta-analysis, aimed at organizing and evaluating the literature, and estimating effect size.Method
We conducted systematic literature searches in PubMed, PsycINFO and Embase up to January 2010, and identified additional studies through earlier meta-analyses, and the references of included studies. We identified seven randomized controlled trials that met our inclusion criteria, with a total of 1,362 respondents. The overall quality of the studies was high. A post-hoc power calculation showed that the studies had sufficient statistical power to detect an effect size of d = 0.19.Results
The overall mean effect size indicating the difference between self-guided psychological treatment and control groups at post-test was d = 0.28 (p
by Sanaa Al Saleh, Fahd Al Mulla, Yunus A. LuqmaniWe propose the hypothesis that loss of estrogen receptor function which leads to endocrine resistance in breast cancer, also results in trans-differentiation from an epithelial to a mesenchymal phenotype that is responsible for increased aggressiveness and metastatic propensity. siRNA mediated silencing of the estrogen receptor in MCF7 breast cancer cells resulted in estrogen/tamoxifen resistant cells (pII) with altered morphology, increased motility with rearrangement and switch from a keratin/actin to a vimentin based cytoskeleton, and ability to invade simulated components of the extracellular matrix. Phenotypic profiling using an Affymetrix Human Genome U133 plus 2.0 GeneChip indicated geometric fold changes ≥3 in approximately 2500 identifiable unique sequences, with about 1270 of these being up-regulated in pII cells. Changes were associated with genes whose products are involved in cell motility, loss of cellular adhesion and interaction with the extracellular matrix. Selective analysis of the data also showed a shift from luminal to basal cell markers and increased expression of a wide spectrum of genes normally associated with mesenchymal characteristics, with consequent loss of epithelial specific markers. Over-expression of several peptide growth factors and their receptors are indicative of an increased contribution to the higher proliferative rates of pII cells as well as aiding their potential for metastatic activity. Signalling molecules that have been identified as key transcriptional drivers of epithelial to mesenchymal transition were also found to be elevated in pII cells. These data support our hypothesis that induced loss of estrogen receptor in previously estrogen/antiestrogen sensitive cells is a trigger for the concomitant loss of endocrine dependence and onset of a series of possibly parallel events that changes the cell from an epithelial to a mesenchymal type. Inhibition of this transition through targeting of specific mediators may offer a useful supplementary strategy to circumvent the effects of loss of endocrine sensitivity.
by Wei Zhang, Guangjin Liu, Fang Tang, Jing Shao, Yan Lu, Yinli Bao, Huochun Yao, Chengping LuStreptococcus suis serotype 2 (SS2) is a zoonotic pathogen that can cause infections in pigs and humans. Bacterial surface proteins are often investigated as potential vaccine candidates and biomarkers of virulence. In this study, a novel method for identifying bacterial surface proteins is presented, which combines immunoproteomic and immunoserologic techniques. Critical to the success of this new method is an improved procedure for generating two-dimensional electrophoresis gel profiles of S. suis proteins. The S. suis surface proteins identified in this study include muramidase-released protein precursor (MRP) and an ABC transporter protein, while MRP is thought to be one of the main virulence factors in SS2 located on the bacterial surface. Herein, we demonstrate that the ABC transporter protein can bind to HEp-2 cells, which strongly suggests that this protein is located on the bacterial cell surface and may be involved in pathogenesis. An immunofluorescence assay confirmed that the ABC transporter is localized to the bacterial outer surface. This new method may prove to be a useful tool for identifying surface proteins, and aid in the development of new vaccine subunits and disease diagnostics.
by Baltazar Nunes, Cecile Viboud, Ausenda Machado, Corinne Ringholz, Helena Rebelo-de-Andrade, Paulo Nogueira, Mark MillerBackground
Influenza epidemics have a substantial impact on human health, by increasing the mortality from pneumonia and influenza, respiratory and circulatory diseases, and all causes. This paper provides estimates of excess mortality rates associated with influenza virus circulation for 7 causes of death and 8 age groups in Portugal during the period of 1980–2004.Methodology/Principal Findings
We compiled monthly mortality time series data by age for all-cause mortality, cerebrovascular diseases, ischemic heart diseases, diseases of the respiratory system, chronic respiratory diseases, pneumonia and influenza. We also used a control outcome, deaths from injuries. Age- and cause-specific baseline mortality was modelled by the ARIMA approach; excess deaths attributable to influenza were calculated by subtracting expected deaths from observed deaths during influenza epidemic periods. Influenza was associated with a seasonal average of 24.7 all-cause excess deaths per 100,000 inhabitants, approximately 90% of which were among seniors over 65 yrs. Excess mortality was 3–6 fold higher during seasons dominated by the A(H3N2) subtype than seasons dominated by A(H1N1)/B. High excess mortality impact was also seen in children under the age of four years. Seasonal excess mortality rates from all the studied causes of death were highly correlated with each other (Pearson correlation range, 0.65 to 0.95, P0.64, P
by Lilian Lacerda Bueno, Francisco Pereira Lobo, Cristiane Guimarães Morais, Luíza Carvalho Mourão, Ricardo Andrez Machado de Ávila, Irene Silva Soares, Cor Jesus Fontes, Marcus Vinícius Lacerda, Carlos Chavez Olórtegui, Daniella Castanheira Bartholomeu, Ricardo Toshio Fujiwara, Érika Martins BragaApical membrane antigen 1 (AMA-1) is considered to be a major candidate antigen for a malaria vaccine. Previous immunoepidemiological studies of naturally acquired immunity to Plasmodium vivax AMA-1 (PvAMA-1) have shown a higher prevalence of specific antibodies to domain II (DII) of AMA-1. In the present study, we confirmed that specific antibody responses from naturally infected individuals were highly reactive to both full-length AMA-1 and DII. Also, we demonstrated a strong association between AMA-1 and DII IgG and IgG subclass responses. We analyzed the primary sequence of PvAMA-1 for B cell linear epitopes co-occurring with intrinsically unstructured/disordered regions (IURs). The B cell epitope comprising the amino acid sequence 290–307 of PvAMA-1 (SASDQPTQYEEEMTDYQK), with the highest prediction scores, was identified in domain II and further selected for chemical synthesis and immunological testing. The antigenicity of the synthetic peptide was identified by serological analysis using sera from P. vivax-infected individuals who were knowingly reactive to the PvAMA-1 ectodomain only, domain II only, or reactive to both antigens. Although the synthetic peptide was recognized by all serum samples specific to domain II, serum with reactivity only to the full-length protein presented 58.3% positivity. Moreover, IgG reactivity against PvAMA-1 and domain II after depletion of specific synthetic peptide antibodies was reduced by 18% and 33% (P = 0.0001 for both), respectively. These results suggest that the linear epitope SASDQPTQYEEEMTDYQK is highly antigenic during natural human infections and is an important antigenic region of the domain II of PvAMA-1, suggesting its possible future use in pre-clinical studies.
by Carla L. Calvi, Megan Podowski, Franco R. D'Alessio, Shana L. Metzger, Kaori Misono, Hataya Poonyagariyagorn, Armando Lopez-Mercado, Therese Ku, Thomas Lauer, Christopher Cheadle, C. Conover Talbot, Chunfa Jie, Sharon McGrath-Morrow, Landon S. King, Jeremy Walston, Enid R. NeptuneBackground
Respiratory dysfunction is a major contributor to morbidity and mortality in aged populations. The susceptibility to pulmonary insults is attributed to “low pulmonary reserve”, ostensibly reflecting a combination of age-related musculoskeletal, immunologic and intrinsic pulmonary dysfunction.Methods/Principal Findings
Using a murine model of the aging lung, senescent DBA/2 mice, we correlated a longitudinal survey of airspace size and injury measures with a transcriptome from the aging lung at 2, 4, 8, 12, 16 and 20 months of age. Morphometric analysis demonstrated a nonlinear pattern of airspace caliber enlargement with a critical transition occurring between 8 and 12 months of age marked by an initial increase in oxidative stress, cell death and elastase activation which is soon followed by inflammatory cell infiltration, immune complex deposition and the onset of airspace enlargement. The temporally correlative transcriptome showed exuberant induction of immunoglobulin genes coincident with airspace enlargement. Immunohistochemistry, ELISA analysis and flow cytometry demonstrated increased immunoglobulin deposition in the lung associated with a contemporaneous increase in activated B-cells expressing high levels of TLR4 (toll receptor 4) and CD86 and macrophages during midlife. These midlife changes culminate in progressive airspace enlargement during late life stages.Conclusion/Significance
Our findings establish that a tissue-specific aging program is evident during a presenescent interval which involves early oxidative stress, cell death and elastase activation, followed by B lymphocyte and macrophage expansion/activation. This sequence heralds the progression to overt airspace enlargement in the aged lung. These signature events, during middle age, indicate that early stages of the aging immune system may have important correlates in the maintenance of tissue morphology. We further show that time-course analyses of aging models, when informed by structural surveys, can reveal nonintuitive signatures of organ-specific aging pathology.
by Qian Jiang, Yen-Yi Ho, Li Hao, Courtney Nichols Berrios, Aravinda ChakravartiHirschsprung disease (HSCR) is a neurocristopathy characterized by absence of intramural ganglion cells along variable lengths of the gastrointestinal tract. The HSCR phenotype is highly variable with respect to gender, length of aganglionosis, familiality and the presence of additional anomalies. By molecular genetic analysis, a minimum of 11 neuro-developmental genes (RET, GDNF, NRTN, SOX10, EDNRB, EDN3, ECE1, ZFHX1B, PHOX2B, KIAA1279, TCF4) are known to harbor rare, high-penetrance mutations that confer a large risk to the bearer. In addition, two other genes (RET, NRG1) harbor common, low-penetrance polymorphisms that contribute only partially to risk and can act as genetic modifiers. To broaden this search, we examined whether a set of 67 proven and candidate HSCR genes harbored additional modifier alleles. In this pilot study, we utilized a custom-designed array CGH with ∼33,000 test probes at an average resolution of ∼185 bp to detect gene-sized or smaller copy number variants (CNVs) within these 67 genes in 18 heterogeneous HSCR patients. Using stringent criteria, we identified CNVs at three loci (MAPK10, ZFHX1B, SOX2) that are novel, involve regulatory and coding sequences of neuro-developmental genes, and show association with HSCR in combination with other congenital anomalies. Additional CNVs are observed under relaxed criteria. Our research suggests a role for CNVs in HSCR and, importantly, emphasizes the role of variation in regulatory sequences. A much larger study will be necessary both for replication and for identifying the full spectrum of small CNV effects.
by Victor E. Gonzaga, Mariana Ramos, Ryan C. Maves, Randal Freeman, Joel M. MontgomeryAn outbreak of norovirus (NoV) genotype I and Enterotoxigenic Escherichia coli (ETEC) occurred among US Navy Ship personnel following a visit to Lima, Peru, in June 2008. Visiting a specific area in Lima was significantly associated with illness. While ETEC and NoV are commonly recognized as causative agents of outbreaks, co-circulation of both pathogens has been rarely observed in shipboard outbreaks.
by Maarten Demeyer, Peter De Graef, Karl Verfaillie, Johan WagemansHuman observers explore scenes by shifting their gaze from object to object. Before each eye movement, a peripheral glimpse of the next object to be fixated has however already been caught. Here we investigate whether the perceptual organization extracted from such a preview could guide the perceptual analysis of the same object during the next fixation. We observed that participants were indeed significantly faster at grouping together spatially separate elements into an object contour, when the same contour elements had also been grouped together in the peripheral preview display. Importantly, this facilitation occurred despite a change in the grouping cue defining the object contour (similarity versus collinearity). We conclude that an intermediate-level description of object shape persists in the visual system across gaze shifts, providing it with a robust basis for balancing efficiency and continuity during scene exploration.
by Guanqun Shi, Meng-Chih Peng, Tao JiangThe identification of orthologous genes shared by multiple genomes plays an important role in evolutionary studies and gene functional analyses. Based on a recently developed accurate tool, called MSOAR 2.0, for ortholog assignment between a pair of closely related genomes based on genome rearrangement, we present a new system MultiMSOAR 2.0, to identify ortholog groups among multiple genomes in this paper. In the system, we construct gene families for all the genomes using sequence similarity search and clustering, run MSOAR 2.0 for all pairs of genomes to obtain the pairwise orthology relationship, and partition each gene family into a set of disjoint sets of orthologous genes (called super ortholog groups or SOGs) such that each SOG contains at most one gene from each genome. For each such SOG, we label the leaves of the species tree using 1 or 0 to indicate if the SOG contains a gene from the corresponding species or not. The resulting tree is called a tree of ortholog groups (or TOGs). We then label the internal nodes of each TOG based on the parsimony principle and some biological constraints. Ortholog groups are finally identified from each fully labeled TOG. In comparison with a popular tool MultiParanoid on simulated data, MultiMSOAR 2.0 shows significantly higher prediction accuracy. It also outperforms MultiParanoid, the Roundup multi-ortholog repository and the Ensembl ortholog database in real data experiments using gene symbols as a validation tool. In addition to ortholog group identification, MultiMSOAR 2.0 also provides information about gene births, duplications and losses in evolution, which may be of independent biological interest. Our experiments on simulated data demonstrate that MultiMSOAR 2.0 is able to infer these evolutionary events much more accurately than a well-known software tool Notung. The software MultiMSOAR 2.0 is available to the public for free.
by Fatma M. Shebl, Sheila C. Dollard, Ruth M. Pfeiffer, Benon Biryahwaho, Minal M. Amin, Stella S. Munuo, Wolfgang Hladik, Ruth Parsons, Barry I. Graubard, Sam M. MbulaiteyeIntroduction
Sexual transmission of human herpesvirus 8 (HHV8) has been implicated among homosexual men, but the evidence for sexual transmission among heterosexual individuals is controversial. We investigated the role of sexual transmission of HHV8 in a nationally representative sample in Uganda, where HHV8 infection is endemic and transmitted mostly during childhood.Materials and Methods
The study population was a subset of participants (n = 2681) from a population-based HIV/AIDS serobehavioral survey of adults aged 15–59 years conducted in 2004/2005. High risk for sexual transmission was assessed by questionnaire and serological testing for HIV and herpes simplex virus 2. Anti-HHV8 antibodies were measured using two enzyme immunoassays targeting synthetic peptides from the K8.1 and orf65 viral genes. The current study was restricted to 2288 sexually active adults. ORs and 95% CIs for HHV8 seropositivity were estimated by fitting logistic regression models with a random intercept using MPLUS and SAS software.Results
The weighted prevalence of HHV8 seropositivity was 56.2%, based on 1302 seropositive individuals, and it increased significantly with age (Ptrend
by Nai-Kuei Huang, Jung-Hsin Lin, Jiun-Tsai Lin, Chia-I Lin, Eric Minwei Liu, Chun-Jung Lin, Wan-Ping Chen, Yuh-Chiang Shen, Hui-Mei Chen, Jhih-Bin Chen, Hsing-Lin Lai, Chieh-Wen Yang, Ming-Chang Chiang, Yu-Shuo Wu, Chen Chang, Jiang-Fan Chen, Jim-Min Fang, Yun-Lian Lin, Yijuang ChernBackground
Huntington's disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The expanded CAG repeats are translated into polyglutamine (polyQ), causing aberrant functions as well as aggregate formation of mutant Htt. Effective treatments for HD are yet to be developed.Methodology/Principal Findings
Here, we report a novel dual-function compound, N6-(4-hydroxybenzyl)adenine riboside (designated T1-11) which activates the A2AR and a major adenosine transporter (ENT1). T1-11 was originally isolated from a Chinese medicinal herb. Molecular modeling analyses showed that T1-11 binds to the adenosine pockets of the A2AR and ENT1. Introduction of T1-11 into the striatum significantly enhanced the level of striatal adenosine as determined by a microdialysis technique, demonstrating that T1-11 inhibited adenosine uptake in vivo. A single intraperitoneal injection of T1-11 in wildtype mice, but not in A2AR knockout mice, increased cAMP level in the brain. Thus, T1-11 enters the brain and elevates cAMP via activation of the A2AR in vivo. Most importantly, addition of T1-11 (0.05 mg/ml) to the drinking water of a transgenic mouse model of HD (R6/2) ameliorated the progressive deterioration in motor coordination, reduced the formation of striatal Htt aggregates, elevated proteasome activity, and increased the level of an important neurotrophic factor (brain derived neurotrophic factor) in the brain. These results demonstrate the therapeutic potential of T1-11 for treating HD.Conclusions/Significance
The dual functions of T1-11 enable T1-11 to effectively activate the adenosinergic system and subsequently delay the progression of HD. This is a novel therapeutic strategy for HD. Similar dual-function drugs aimed at a particular neurotransmitter system as proposed herein may be applicable to other neurotransmitter systems (e.g., the dopamine receptor/dopamine transporter and the serotonin receptor/serotonin transporter) and may facilitate the development of new drugs for other neurodegenerative diseases.
by Isabelle Schmutz, Sabrina Wendt, Anna Schnell, Achim Kramer, Isabelle M. Mansuy, Urs AlbrechtCircadian clocks coordinate the timing of important biological processes. Interconnected transcriptional and post-translational feedback loops based on a set of clock genes generate and maintain these rhythms with a period of about 24 hours. Many clock proteins undergo circadian cycles of post-translational modifications. Among these modifications, protein phosphorylation plays an important role in regulating activity, stability and intracellular localization of clock components. Several protein kinases were characterized as regulators of the circadian clock. However, the function of protein phosphatases, which balance phosphorylation events, in the mammalian clock mechanism is less well understood. Here, we identify protein phosphatase 1 (PP1) as regulator of period and light-induced resetting of the mammalian circadian clock. Down-regulation of PP1 activity in cells by RNA interference and in vivo by expression of a specific inhibitor in the brain of mice tended to lengthen circadian period. Moreover, reduction of PP1 activity in the brain altered light-mediated clock resetting behavior in mice, enhancing the phase shifts in either direction. At the molecular level, diminished PP1 activity increased nuclear accumulation of the clock component PER2 in neurons. Hence, PP1, may reduce PER2 phosphorylation thereby influencing nuclear localization of this protein. This may at least partially influence period and phase shifting properties of the mammalian circadian clock.
by Clement Zeh, Pauli N. Amornkul, Seth Inzaule, Pascale Ondoa, Boaz Oyaro, Dufton M. Mwaengo, Hilde Vandenhoudt, Anthony Gichangi, John Williamson, Timothy Thomas, Kevin M. DeCock, Clyde Hart, John Nkengasong, Kayla LasersonBackground
There is need for locally-derived age-specific clinical laboratory reference ranges of healthy Africans in sub-Saharan Africa. Reference values from North American and European populations are being used for African subjects despite previous studies showing significant differences. Our aim was to establish clinical laboratory reference values for African adolescents and young adults that can be used in clinical trials and for patient management.Methods and Findings
A panel of 298, HIV-seronegative individuals aged 13–34 years was randomly selected from participants in two population-based cross-sectional surveys assessing HIV prevalence and other sexually transmitted infections in western Kenya. The adolescent (
by Sebastiaan J. van Hal, Mark Jones, Iain B. Gosbell, David L. PatersonBackground
Despite hVISA infections being associated with vancomycin treatment failure, no previous study has been able to detect a mortality difference between heteroresistant vancomycin intermediate Staphylococcus aureus (hVISA) and vancomycin susceptible Staphylococcus aureus (VSSA) bloodstream infections (BSI).Methodology
Consecutive methicillin-resistant S. aureus (MRSA) BSI episodes between 1996 and 2008 were reviewed. Patient demographics, clinical presentation, treatment and overall mortality at 30 days were extracted from the medical records. All isolates underwent vancomycin minimum inhibitory concentration (VMIC) testing by broth microdilution and Etest. hVISA was confirmed by population analysis profiling using the area under the curve method (PAP-AUC).Principal Findings
401 evaluable MRSA BSI episodes were identified over the 12 years. Of these, 46 (11.5%) and 2 (0.5%) were confirmed as hVISA and VISA by PAP-AUC respectively. hVISA predominantly occurred in ST239-like MRSA isolates with high VMIC (2 mg/L). Compared to VSSA, hVISA was associated with chronic renal failure (p
by Yoichiro Takayanagi, Tsutomu Takahashi, Lina Orikabe, Yuriko Mozue, Yasuhiro Kawasaki, Kazue Nakamura, Yoko Sato, Masanari Itokawa, Hidenori Yamasue, Kiyoto Kasai, Masayoshi Kurachi, Yuji Okazaki, Michio SuzukiBackground
Although structural magnetic resonance imaging (MRI) studies have repeatedly demonstrated regional brain structural abnormalities in patients with schizophrenia, relatively few MRI-based studies have attempted to distinguish between patients with first-episode schizophrenia and healthy controls.Method
Three-dimensional MR images were acquired from 52 (29 males, 23 females) first-episode schizophrenia patients and 40 (22 males, 18 females) healthy subjects. Multiple brain measures (regional brain volume and cortical thickness) were calculated by a fully automated procedure and were used for group comparison and classification by linear discriminant function analysis.Results
Schizophrenia patients showed gray matter volume reductions and cortical thinning in various brain regions predominantly in prefrontal and temporal cortices compared with controls. The classifiers obtained from 66 subjects of the first group successfully assigned 26 subjects of the second group with accuracy above 80%.Conclusion
Our results showed that combinations of automated brain measures successfully differentiated first-episode schizophrenia patients from healthy controls. Such neuroimaging approaches may provide objective biological information adjunct to clinical diagnosis of early schizophrenia.
by Irene Cervelló, Aymara Mas, Claudia Gil-Sanchis, Laura Peris, Amparo Faus, Philippa T. K. Saunders, Hilary O. D. Critchley, Carlos SimónEndometrial regeneration is mediated, at least in part, by the existence of a specialized somatic stem cell (SSC) population recently identified by several groups using the side population (SP) technique. We previously demonstrated that endometrial SP displays genotypic, phenotypic and the functional capability to develop human endometrium after subcutaneous injection in NOD-SCID mice. We have now established seven human endometrial SP (hESP) cell lines (ICE 1–7): four from the epithelial and three from the stromal fraction, respectively. SP cell lines were generated under hypoxic conditions based on their cloning efficiency ability, cultured for 12–15 passages (20 weeks) and cryopreserved. Cell lines displayed normal 46XX karyotype, intermediate telomerase activity pattern and expressed mRNAs encoding proteins that are considered characteristic of undifferentiated cells (Oct-4, GDF3, DNMT3B, Nanog, GABR3) and those of mesodermal origin (WT1, Cardiac Actin, Enolase, Globin, REN). Phenotype analysis corroborated their epithelial (CD9+) or stromal (vimentin+) cell origin and mesenchymal (CD90+, CD73+ and CD45−) attributes. Markers considered characteristic of ectoderm or endoderm were not detected. Cells did not express either estrogen receptor alpha (ERα) or progesterone receptor (PR). The hESP cell lines were able to differentiate in vitro into adipocytes and osteocytes, which confirmed their mesenchymal origin. Finally, we demonstrated their ability to generate human endometrium when transplanted beneath the renal capsule of NOD-SCID mice. These findings confirm that SP cells exhibit key features of human endometrial SSC and open up new possibilities for the understanding of gynecological disorders such as endometriosis or Asherman syndrome. Our cell lines can be a valuable model to investigate new targets for endometrium proliferation in endometriosis.
by Ayelet Caspi-Fluger, Moshe Inbar, Netta Mozes-Daube, Laurence Mouton, Martha S. Hunter, Einat Zchori-FeinIntracellular symbionts of arthropods have diverse influences on their hosts, and their functions generally appear to be associated with their localization within the host. The effect of localization pattern on the role of a particular symbiont cannot normally be tested since the localization pattern within hosts is generally invariant. However, in Israel, the secondary symbiont Rickettsia is unusual in that it presents two distinct localization patterns throughout development and adulthood in its whitefly host, Bemisia tabaci (B biotype). In the “scattered” pattern, Rickettsia is localized throughout the whitefly hemocoel, excluding the bacteriocytes, where the obligate symbiont Portiera aleyrodidarum and some other secondary symbionts are housed. In the “confined” pattern, Rickettsia is restricted to the bacteriocytes. We examined the effects of these patterns on Rickettsia densities, association with other symbionts (Portiera and Hamiltonella defensa inside the bacteriocytes) and on the potential for horizontal transmission to the parasitoid wasp, Eretmocerus mundus, while the wasp larvae are developing within the whitefly nymph. Sequences of four Rickettsia genes were found to be identical for both localization patterns, suggesting that they are closely related strains. However, real-time PCR analysis showed very different dynamics for the two localization types. On the first day post-adult emergence, Rickettsia densities were 21 times higher in the “confined” pattern vs. “scattered” pattern whiteflies. During adulthood, Rickettsia increased in density in the “scattered” pattern whiteflies until it reached the “confined” pattern Rickettsia density on day 21. No correlation between Rickettsia densities and Hamiltonella or Portiera densities were found for either localization pattern. Using FISH technique, we found Rickettsia in the gut of the parasitoid wasps only when they developed on whiteflies with the “scattered” pattern. The results suggest that the localization pattern of a symbiont may influence its dynamics within the host.
by Sameer R. Oak, Lynne Murray, Athula Herath, Matthew Sleeman, Ian Anderson, Amrita D. Joshi, Ana Lucia Coelho, Kevin R. Flaherty, Galen B. Toews, Darryl Knight, Fernando J. Martinez, Cory M. HogaboamBackground
Idiopathic pulmonary fibrosis exhibits differential progression from the time of diagnosis but the molecular basis for varying progression rates is poorly understood. The aim of the present study was to ascertain whether differential miRNA expression might provide one explanation for rapidly versus slowly progressing forms of IPF.Methodology and Principal Findings
miRNA and mRNA were isolated from surgical lung biopsies from IPF patients with a clinically documented rapid or slow course of disease over the first year after diagnosis. A quantitative PCR miRNA array containing 88 of the most abundant miRNA in the human genome was used to profile lung biopsies from 9 patients with rapidly progressing IPF, 6 patients with slowly progressing IPF, and 10 normal lung biopsies. Using this approach, 11 miRNA were significantly increased and 36 were significantly decreased in rapid biopsies compared with normal biopsies. Slowly progressive biopsies exhibited 4 significantly increased miRNA and 36 significantly decreased miRNA compared with normal lung. Among the miRNA present in IPF with validated mRNA targets were those with regulatory effects on epithelial-mesenchymal transition (EMT). Five miRNA (miR-302c, miR-423-5p, miR-210, miR-376c, and miR-185) were significantly increased in rapid compared with slow IPF lung biopsies. Additional analyses of rapid biopsies and fibroblasts grown from the same biopsies revealed that the expression of AGO1 and AGO2 (essential components of the miRNA processing RISC complex) were lower compared with either slow or normal lung biopsies and fibroblasts.Conclusion
These findings suggest that the development and/or clinical progression of IPF might be the consequence of aberrant miRNA processing.
by Hideyuki Takeuchi, Hiroyuki Mizoguchi, Yukiko Doi, Shijie Jin, Mariko Noda, Jianfeng Liang, Hua Li, Yan Zhou, Rarami Mori, Satoko Yasuoka, Endong Li, Bijay Parajuli, Jun Kawanokuchi, Yoshifumi Sonobe, Jun Sato, Koji Yamanaka, Gen Sobue, Tetsuya Mizuno, Akio SuzumuraBackground
Glutamate released by activated microglia induces excitotoxic neuronal death, which likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for these neurodegenerative diseases, glutamate receptor blockers also perturbed physiological and essential glutamate signals, and inhibitors of microglial activation suppressed both neurotoxic/neuroprotective roles of microglia and hardly affected disease progression. We previously demonstrated that activated microglia release a large amount of glutamate specifically through gap junction hemichannel. Hence, blockade of gap junction hemichannel may be potentially beneficial in treatment of neurodegenerative diseases.Methods and Findings
In this study, we generated a novel blood-brain barrier permeable gap junction hemichannel blocker based on glycyrrhetinic acid. We found that pharmacologic blockade of gap junction hemichannel inhibited excessive glutamate release from activated microglia in vitro and in vivo without producing notable toxicity. Blocking gap junction hemichannel significantly suppressed neuronal loss of the spinal cord and extended survival in transgenic mice carrying human superoxide dismutase 1 with G93A or G37R mutation as an amyotrophic lateral sclerosis mouse model. Moreover, blockade of gap junction hemichannel also significantly improved memory impairments without altering amyloid β deposition in double transgenic mice expressing human amyloid precursor protein with K595N and M596L mutations and presenilin 1 with A264E mutation as an Alzheimer's disease mouse model.Conclusions
Our results suggest that gap junction hemichannel blockers may represent a new therapeutic strategy to target neurotoxic microglia specifically and prevent microglia-mediated neuronal death in various neurodegenerative diseases.
by Ankit Shah, Ashish S. Verma, Kalpeshkumar H. Patel, Richard Noel, Vanessa Rivera-Amill, Peter S. Silverstein, Suman Chaudhary, Hari K. Bhat, Leonidas Stamatatos, Dhirendra P. Singh, Shilpa Buch, Anil KumarIn addition to its role in virus entry, HIV-1 gp120 has also been implicated in HIV-associated neurocognitive disorders. However, the mechanism(s) responsible for gp120-mediated neuroinflammation remain undefined. In view of increased levels of IL-6 in HIV-positive individuals with neurological manifestations, we sought to address whether gp120 is involved in IL-6 over-expression in astrocytes. Transfection of a human astrocyte cell line with a plasmid encoding gp120 resulted in increased expression of IL-6 at the levels of mRNA and protein by 51.3±2.1 and 11.6±2.2 fold respectively; this effect of gp120 on IL-6 expression was also demonstrated using primary human fetal astrocytes. A similar effect on IL-6 expression was observed when primary astrocytes were treated with gp120 protein derived from different strains of X4 and R5 tropic HIV-1. The induction of IL-6 could be abrogated by use of gp120-specific siRNA. Furthermore, this study showed that the NF-κB pathway is involved in gp120-mediated IL-6 over-expression, as IKK-2 and IKKβ inhibitors inhibited IL-6 expression by 56.5% and 60.8%, respectively. These results were also confirmed through the use of NF-κB specific siRNA. We also showed that gp120 could increase the phosphorylation of IκBα. Furthermore, gp120 transfection in the SVGA cells increased translocation of NF-κB from cytoplasm to nucleus. These results demonstrate that HIV-1 gp120-mediated over-expression of IL-6 in astrocytes is one mechanism responsible for neuroinflammation in HIV-infected individuals and this is mediated by the NF-κB pathway.
by Mathilde Allard, Romain Oger, Virginie Vignard, Jean-Michel Percier, Giulia Fregni, Aurélie Périer, Anne Caignard, Béatrice Charreau, Karine Bernardeau, Amir Khammari, Brigitte Dréno, Nadine GervoisBackground
Tumor-derived soluble factors, including soluble HLA molecules, can contribute to cancer immune escape and therefore impact on clinical course of malignant diseases. We previously reported that melanoma cells produce, in vitro, soluble forms of the non-classical MHC class I molecule HLA-E (sHLA-E). In order to investigate sHLA-E production by various tumors and to address its potential value as a tumor-associated marker, we developed a specific ELISA for the quantification of sHLA-E in biological fluids.Methodology/Principal Findings
We developed a sHLA-E specific and sensitive ELISA and we showed that serum sHLA-E levels were significantly elevated (P
by Mani Chopra, Honey B. Golden, Srinivas Mullapudi, William Dowhan, David E. Dostal, Avadhesh C. SharmaBackground
We tested the hypothesis that 5-Hydroxydecanoic acid (5HD), a putative mitoKATP channel blocker, will reverse sepsis-induced cardiodynamic and adult rat ventricular myocyte (ARVM) contractile dysfunction, restore mitochondrial membrane permeability alterations and improve survival.Methodology/Principal Findings
Male Sprague-Dawley rats (350–400 g) were made septic using 400 mg/kg cecal inoculum, ip. Sham animals received 5% dextrose water, ip. The Voltage Dependent Anion Channels (VDAC1), Bax and cytochrome C levels were determined in isolated single ARVMs obtained from sham and septic rat heart. Mitochondria and cytosolic fractions were isolated from ARVMs treated with norepinephrine (NE, 10 µmoles) in the presence/absence of 5HD (100 µmoles). A continuous infusion of 5HD using an Alzet pump reversed sepsis-induced mortality when administered at the time of induction of sepsis (−40%) and at 6 hr post-sepsis (−20%). Electrocardiography revealed that 5HD reversed sepsis-induced decrease in the average ejection fraction, Simpsons+m Mode (53.5±2.5 in sepsis and 69.2±1.2 at 24 hr in sepsis+5HD vs. 79.9±1.5 basal group) and cardiac output (63.3±1.2 mL/min sepsis and 79.3±3.9 mL/min at 24 hr in sepsis+5HD vs. 85.8±1.5 mL/min basal group). The treatment of ARVMs with 5HD also reversed sepsis-induced depressed contractility in both the vehicle and NE-treated groups. Sepsis produced a significant downregulation of VDAC1, and upregulation of Bax levels, along with mitochondrial membrane potential collapse in ARVMs. Pretreatment of septic ARVMs with 5HD blocked a NE-induced decrease in the VDAC1 and release of cytochrome C.Conclusion
The data suggest that Bax activation is an upstream event that may precede the opening of the mitoKATP channels in sepsis. We concluded that mitoKATP channel inhibition via decreased mitochondrial membrane potential and reduced release of cytochrome C provided protection against sepsis-induced ARVM and myocardial contractile dysfunction.
by Ping Lu, Guo Rong Zhang, Xing Hui Song, Xiao Hui Zou, Lin Lin Wang, Hong Wei OuyangThe presence of uniformly small collagen fibrils in tendon repair is believed to play a major role in suboptimal tendon healing. Collagen V is significantly elevated in healing tendons and plays an important role in fibrillogenesis. The objective of this study was to investigate the effect of a particular chain of collagen V on the fibrillogenesis of Sprague-Dawley rat tenocytes, as well as the efficacy of Col V siRNA engineered tenocytes for tendon tissue engineering. RNA interference gene therapy and a scaffold free tissue engineered tendon model were employed. The results showed that scaffold free tissue engineered tendon had tissue-specific tendon structure. Down regulation of collagen V α1 or α2 chains by siRNAs (Col5α1 siRNA, Col5α2 siRNA) had different effects on collagen I and decorin gene expressions. Col5α1 siRNA treated tenocytes had smaller collagen fibrils with abnormal morphology; while those Col5α2 siRNA treated tenocytes had the same morphology as normal tenocytes. Furthermore, it was found that tendons formed by coculture of Col5α1 siRNA treated tenocytes with normal tenocytes at a proper ratio had larger collagen fibrils and relative normal contour. Conclusively, it was demonstrated that Col V siRNA engineered tenocytes improved tendon tissue regeneration. And an optimal level of collagen V is vital in regulating collagen fibrillogenesis. This may provide a basis for future development of novel cellular- and molecular biology-based therapeutics for tendon diseases.
by Gerardo Chowell, Cécile Viboud, Cesar V. Munayco, Jorge Gómez, Lone Simonsen, Mark A. Miller, James Tamerius, Victor Fiestas, Eric S. Halsey, Victor A. Laguna-TorresBackground
Highly refined surveillance data on the 2009 A/H1N1 influenza pandemic are crucial to quantify the spatial and temporal characteristics of the pandemic. There is little information about the spatial-temporal dynamics of pandemic influenza in South America. Here we provide a quantitative description of the age-specific morbidity pandemic patterns across administrative areas of Peru.Methods
We used daily cases of influenza-like-illness, tests for A/H1N1 influenza virus infections, and laboratory-confirmed A/H1N1 influenza cases reported to the epidemiological surveillance system of Peru's Ministry of Health from May 1 to December 31, 2009. We analyzed the geographic spread of the pandemic waves and their association with the winter school vacation period, demographic factors, and absolute humidity. We also estimated the reproduction number and quantified the association between the winter school vacation period and the age distribution of cases.Results
The national pandemic curve revealed a bimodal winter pandemic wave, with the first peak limited to school age children in the Lima metropolitan area, and the second peak more geographically widespread. The reproduction number was estimated at 1.6–2.2 for the Lima metropolitan area and 1.3–1.5 in the rest of Peru. We found a significant association between the timing of the school vacation period and changes in the age distribution of cases, while earlier pandemic onset was correlated with large population size. By contrast there was no association between pandemic dynamics and absolute humidity.Conclusions
Our results indicate substantial spatial variation in pandemic patterns across Peru, with two pandemic waves of varying timing and impact by age and region. Moreover, the Peru data suggest a hierarchical transmission pattern of pandemic influenza A/H1N1 driven by large population centers. The higher reproduction number of the first pandemic wave could be explained by high contact rates among school-age children, the age group most affected during this early wave.
by Christopher Dye, Bernadette Bourdin Trunz, Knut Lönnroth, Gojka Roglic, Brian G. WilliamsBackground
Diabetes prevalence and body mass index reflect the nutritional profile of populations but have opposing effects on tuberculosis risk. Interactions between diabetes and BMI could help or hinder TB control in growing, aging, urbanizing populations.Methods and Findings
We compiled data describing temporal changes in BMI, diabetes prevalence and population age structure in rural and urban areas for men and women in countries with high (India) and low (Rep. Korea) TB burdens. Using published data on the risks of TB associated with these factors, we calculated expected changes in TB incidence between 1998 and 2008. In India, TB incidence cases would have increased (28% from 1.7 m to 2.1 m) faster than population size (22%) because of adverse effects of aging, urbanization, changing BMI and rising diabetes prevalence, generating an increase in TB incidence per capita of 5.5% in 10 years. In India, general nutritional improvements were offset by a fall in BMI among the majority of men who live in rural areas. The growing prevalence of diabetes in India increased the annual number of TB cases in people with diabetes by 46% between 1998 and 2008. In Korea, by contrast, the number of TB cases increased more slowly (6.1% from 40,200 to 42,800) than population size (14%) because of positive effects of urbanization, increasing BMI and falling diabetes prevalence. Consequently, TB incidence per capita fell by 7.8% in 10 years. Rapid population aging was the most significant adverse effect in Korea.Conclusions
Nutritional and demographic changes had stronger adverse effects on TB in high-incidence India than in lower-incidence Korea. The unfavourable effects in both countries can be overcome by early drug treatment but, if left unchecked, could lead to an accelerating rise in TB incidence. The prevention and management of risk factors for TB would reinforce TB control by chemotherapy.
by Humira Sonah, Rupesh K. Deshmukh, Anshul Sharma, Vinay P. Singh, Deepak K. Gupta, Raju N. Gacche, Jai C. Rana, Nagendra K. Singh, Tilak R. SharmaPlant genomes are complex and contain large amounts of repetitive DNA including microsatellites that are distributed across entire genomes. Whole genome sequences of several monocot and dicot plants that are available in the public domain provide an opportunity to study the origin, distribution and evolution of microsatellites, and also facilitate the development of new molecular markers. In the present investigation, a genome-wide analysis of microsatellite distribution in monocots (Brachypodium, sorghum and rice) and dicots (Arabidopsis, Medicago and Populus) was performed. A total of 797,863 simple sequence repeats (SSRs) were identified in the whole genome sequences of six plant species. Characterization of these SSRs revealed that mono-nucleotide repeats were the most abundant repeats, and that the frequency of repeats decreased with increase in motif length both in monocots and dicots. However, the frequency of SSRs was higher in dicots than in monocots both for nuclear and chloroplast genomes. Interestingly, GC-rich repeats were the dominant repeats only in monocots, with the majority of them being present in the coding region. These coding GC-rich repeats were found to be involved in different biological processes, predominantly binding activities. In addition, a set of 22,879 SSR markers that were validated by e-PCR were developed and mapped on different chromosomes in Brachypodium for the first time, with a frequency of 101 SSR markers per Mb. Experimental validation of 55 markers showed successful amplification of 80% SSR markers in 16 Brachypodium accessions. An online database ‘BraMi’ (Brachypodium microsatellite markers) of these genome-wide SSR markers was developed and made available in the public domain. The observed differential patterns of SSR marker distribution would be useful for studying microsatellite evolution in a monocot–dicot system. SSR markers developed in this study would be helpful for genomic studies in Brachypodium and related grass species, especially for the map based cloning of the candidate gene(s).
by Caroline Tapparel, Samuel Cordey, Thomas Junier, Laurent Farinelli, Sandra Van Belle, Paola M. Soccal, John-David Aubert, Evgeny Zdobnov, Laurent KaiserRoutine screening of lung transplant recipients and hospital patients for respiratory virus infections allowed to identify human rhinovirus (HRV) in the upper and lower respiratory tracts, including immunocompromised hosts chronically infected with the same strain over weeks or months. Phylogenetic analysis of 144 HRV-positive samples showed no apparent correlation between a given viral genotype or species and their ability to invade the lower respiratory tract or lead to protracted infection. By contrast, protracted infections were found almost exclusively in immunocompromised patients, thus suggesting that host factors rather than the virus genotype modulate disease outcome, in particular the immune response. Complete genome sequencing of five chronic cases to study rhinovirus genome adaptation showed that the calculated mutation frequency was in the range observed during acute human infections. Analysis of mutation hot spot regions between specimens collected at different times or in different body sites revealed that non-synonymous changes were mostly concentrated in the viral capsid genes VP1, VP2 and VP3, independent of the HRV type. In an immunosuppressed lung transplant recipient infected with the same HRV strain for more than two years, both classical and ultra-deep sequencing of samples collected at different time points in the upper and lower respiratory tracts showed that these virus populations were phylogenetically indistinguishable over the course of infection, except for the last month. Specific signatures were found in the last two lower respiratory tract populations, including changes in the 5′UTR polypyrimidine tract and the VP2 immunogenic site 2. These results highlight for the first time the ability of a given rhinovirus to evolve in the course of a natural infection in immunocompromised patients and complement data obtained from previous experimental inoculation studies in immunocompetent volunteers.
by Sijie Tan, John A. Rudd, David T. YewKetamine is a well-known anesthetic agent and a drug of abuse. Despite its widespread use and abuse, little is known about its long-term effects on the central nervous system. The present study was designed to evaluate the effect of long-term (1- and 3-month) ketamine administration on learning and memory and associated gene expression levels in the brain. The Morris water maze was used to assess spatial memory and gene expression changes were assayed using Affymetrix Genechips; a focus on the expression of GABAA receptors that mediate a tonic inhibition in the brain, was confirmed by quantitative real-time PCR and western blot. Compared with saline controls, there was a decline in learning and memory performance in the ketamine-treated mice. Genechip results showed that 110 genes were up-regulated and 136 genes were down-regulated. An ontology analysis revealed the most significant effects of ketamine were on GABAA receptors. In particular, there was a significant up-regulation of both mRNA and protein levels of the alpha 5 subunit (Gabra5) of the GABAA receptors in the prefrontal cortex. In conclusion, chronic exposure to ketamine impairs working memory in mice, which may be explained at least partly by up-regulation of Gabra5 subunits in the prefrontal cortex.
PLoS Neglected Tropical Diseases
by Fernando Abad-Franch, M. Celeste Vega, Miriam S. Rolón, Walter S. Santos, Antonieta Rojas de AriasBackground
Vector control has substantially reduced Chagas disease (ChD) incidence. However, transmission by household-reinfesting triatomines persists, suggesting that entomological surveillance should play a crucial role in the long-term interruption of transmission. Yet, infestation foci become smaller and harder to detect as vector control proceeds, and highly sensitive surveillance methods are needed. Community participation (CP) and vector-detection devices (VDDs) are both thought to enhance surveillance, but this remains to be thoroughly assessed.Methodology/Principal Findings
We searched Medline, Web of Knowledge, Scopus, LILACS, SciELO, the bibliographies of retrieved studies, and our own records. Data from studies describing vector control and/or surveillance interventions were extracted by two reviewers. Outcomes of primary interest included changes in infestation rates and the detection of infestation/reinfestation foci. Most results likely depended on study- and site-specific conditions, precluding meta-analysis, but we re-analysed data from studies comparing vector control and detection methods whenever possible. Results confirm that professional, insecticide-based vector control is highly effective, but also show that reinfestation by native triatomines is common and widespread across Latin America. Bug notification by householders (the simplest CP-based strategy) significantly boosts vector detection probabilities; in comparison, both active searches and VDDs perform poorly, although they might in some cases complement each other.Conclusions/Significance
CP should become a strategic component of ChD surveillance, but only professional insecticide spraying seems consistently effective at eliminating infestation foci. Involvement of stakeholders at all process stages, from planning to evaluation, would probably enhance such CP-based strategies.
by Khoa T. D. Thai, Hiroshi Nishiura, Phuong Lan Hoang, Nga Thanh Thi Tran, Giao Trong Phan, Hung Quoc Le, Binh Quang Tran, Nam Van Nguyen, Peter J. de VriesBackground
This study aims to estimate the age-specific risks of clinical dengue attack (i.e., the risk of symptomatic dengue among the total number of dengue virus (DENV) infections) during primary and secondary infections.Methods
We analyzed two pieces of epidemiological information in Binh Thuan province, southern Vietnam, i.e., age-specific seroprevalence and a community-wide longitudinal study of clinical dengue attack. The latter data set stratified febrile patients with DENV infection by age as well as infection parity. A simple modeling approach was employed to estimate the age-specific risks of clinical dengue attack during primary and secondary infections.Results
Using the seroprevalence data, the force of infection was estimated to be 11.7% (95% confidence intervals (CI): 10.8–12.7) per year. Median age (and the 25–75 percentiles) of dengue fever patients during primary and secondary infections were 12 (9–20) and 20 (14–31) years, respectively. The estimated age-specific risk of clinical dengue increases as a function of age for both primary and secondary infections; the estimated proportion of symptomatic patients among the total number of infected individuals was estimated to be
by Scott R. Fry, Michelle Meyer, Matthew G. Semple, Cameron P. Simmons, Shamala Devi Sekaran, Johnny X. Huang, Catriona McElnea, Chang-Yi Huang, Andrea Valks, Paul R. Young, Matthew A. CooperBackground
Serological tests for IgM and IgG are routinely used in clinical laboratories for the rapid diagnosis of dengue and can differentiate between primary and secondary infections. Dengue virus non-structural protein 1 (NS1) has been identified as an early marker for acute dengue, and is typically present between days 1–9 post-onset of illness but following seroconversion it can be difficult to detect in serum.Aims
To evaluate the performance of a newly developed Panbio® Dengue Early Rapid test for NS1 and determine if it can improve diagnostic sensitivity when used in combination with a commercial IgM/IgG rapid test.Methodology
The clinical performance of the Dengue Early Rapid was evaluated in a retrospective study in Vietnam with 198 acute laboratory-confirmed positive and 100 negative samples. The performance of the Dengue Early Rapid in combination with the IgM/IgG Rapid test was also evaluated in Malaysia with 263 laboratory-confirmed positive and 30 negative samples.Key Results
In Vietnam the sensitivity and specificity of the test was 69.2% (95% CI: 62.8% to 75.6%) and 96% (95% CI: 92.2% to 99.8) respectively. In Malaysia the performance was similar with 68.9% sensitivity (95% CI: 61.8% to 76.1%) and 96.7% specificity (95% CI: 82.8% to 99.9%) compared to RT-PCR. Importantly, when the Dengue Early Rapid test was used in combination with the IgM/IgG test the sensitivity increased to 93.0%. When the two tests were compared at each day post-onset of illness there was clear differentiation between the antigen and antibody markers.Conclusions
This study highlights that using dengue NS1 antigen detection in combination with anti-glycoprotein E IgM and IgG serology can significantly increase the sensitivity of acute dengue diagnosis and extends the possible window of detection to include very early acute samples and enhances the clinical utility of rapid immunochromatographic testing for dengue.
by Mercy M. Ackumey, Cynthia Kwakye-Maclean, Edwin O. Ampadu, Don de Savigny, Mitchell G. WeissBackground
Buruli ulcer (BU), caused by Mycobacterium ulcerans infection, is a debilitating disease of the skin and underlying tissue. The first phase of a BU prevention and treatment programme (BUPaT) was initiated from 2005–2008, in the Ga-West and Ga-South municipalities in Ghana to increase access to BU treatment and to improve early case detection and case management. This paper assesses achievements of the BUPaT programme and lessons learnt. It also considers the impact of the programme on broader interests of the health system.Methods
A mixed-methods approach included patients' records review, review of programme reports, a stakeholder forum, key informant interviews, focus group discussions, clinic visits and observations.Principal Findings
Extensive collaboration existed across all levels, (national, municipality, and community), thus strengthening the health system. The programme enhanced capacities of all stakeholders in various aspects of health services delivery and demonstrated the importance of health education and community-based surveillance to create awareness and encourage early treatment. A patient database was also created using recommended World Health Organisation (WHO) forms which showed that 297 patients were treated from 2005–2008. The proportion of patients requiring only antibiotic treatment, introduced in the course of the programme, was highest in the last year (35.4% in the first, 23.5% in the second and 42.5% in the third year). Early antibiotic treatment prevented recurrences which was consistent with programme aims.Conclusions
To improve early case management of BU, strengthening existing clinics to increase access to antibiotic therapy is critical. Intensifying health education and surveillance would ultimately increase early reporting and treatment for all cases. Further research is needed to explain the role of environmental factors for BU contagion. Programme strategies reported in our study: collaboration among stakeholders, health education, community surveillance and regular antibiotic treatment can be adopted for any BU-endemic area in Ghana.
by Cristina Mendes, Fernanda Dias, Joana Figueiredo, Vicenta Gonzalez Mora, Jorge Cano, Bruno de Sousa, Virgílio E. do Rosário, Agustin Benito, Pedro Berzosa, Ana Paula ArezBackground
Plasmodium vivax shows a small prevalence in West and Central Africa due to the high prevalence of Duffy negative people. However, Duffy negative individuals infected with P. vivax have been reported in areas of high prevalence of Duffy positive people who may serve as supply of P. vivax strains able to invade Duffy negative erythrocytes. We investigated the presence of P. vivax in two West African countries, using blood samples and mosquitoes collected during two on-going studies.Methodology/Findings
Blood samples from a total of 995 individuals were collected in seven villages in Angola and Equatorial Guinea, and 820 Anopheles mosquitoes were collected in Equatorial Guinea. Identification of the Plasmodium species was achieved by nested PCR amplification of the small-subunit rRNA genes; P. vivax was further characterized by csp gene analysis. Positive P. vivax-human isolates were genotyped for the Duffy blood group through the analysis of the DARC gene. Fifteen Duffy-negative individuals, 8 from Equatorial Guinea (out of 97) and 7 from Angola (out of 898), were infected with two different strains of P. vivax (VK210 and VK247).Conclusions
In this study we demonstrated that P. vivax infections were found both in humans and mosquitoes, which means that active transmission is occurring. Given the high prevalence of infection in mosquitoes, we may speculate that this hypnozoite-forming species at liver may not be detected by the peripheral blood samples analysis. Also, this is the first report of Duffy negative individuals infected with two different strains of P. vivax (VK247 and classic strains) in Angola and Equatorial Guinea. This finding reinforces the idea that this parasite is able to use receptors other than Duffy to invade erythrocytes, which may have an enormous impact in P. vivax current distribution.
by Ruklanthi de Alwis, Martina Beltramello, William B. Messer, Soila Sukupolvi-Petty, Wahala M. P. B. Wahala, Annette Kraus, Nicholas P. Olivarez, Quang Pham, James Brian, Wen-Yang Tsai, Wei-Kung Wang, Scott Halstead, Srisakul Kliks, Michael S. Diamond, Ralph Baric, Antonio Lanzavecchia, Federica Sallusto, Aravinda M. de SilvaHumans who experience a primary dengue virus (DENV) infection develop antibodies that preferentially neutralize the homologous serotype responsible for infection. Affected individuals also generate cross-reactive antibodies against heterologous DENV serotypes, which are non-neutralizing. Dengue cross-reactive, non-neutralizing antibodies can enhance infection of Fc receptor bearing cells and, potentially, exacerbate disease. The actual binding sites of human antibody on the DENV particle are not well defined. We characterized the specificity and neutralization potency of polyclonal serum antibodies and memory B-cell derived monoclonal antibodies (hMAbs) from 2 individuals exposed to primary DENV infections. Most DENV-specific hMAbs were serotype cross-reactive and weakly neutralizing. Moreover, many hMAbs bound to the viral pre-membrane protein and other sites on the virus that were not preserved when the viral envelope protein was produced as a soluble, recombinant antigen (rE protein). Nonetheless, by modifying the screening procedure to detect rare antibodies that bound to rE, we were able to isolate and map human antibodies that strongly neutralized the homologous serotype of DENV. Our MAbs results indicate that, in these two individuals exposed to primary DENV infections, a small fraction of the total antibody response was responsible for virus neutralization.
by Sébastien Marcombe, Frédéric Darriet, Michel Tolosa, Philip Agnew, Stéphane Duchon, Manuel Etienne, Marie Michèle Yp Tcha, Fabrice Chandre, Vincent Corbel, André YébakimaBackground
Dengue fever is reemerging on the island of Martinique and is a serious threat for the human population. During dengue epidemics, adult Aedes aegypti control with pyrethroid space sprays is implemented in order to rapidly reduce transmission. Unfortunately, vector control programs are facing operational challenges with the emergence of pyrethroid resistant Ae. aegypti populations.Methodology/Principal Findings
To assess the impact of pyrethroid resistance on the efficacy of treatments, applications of deltamethrin and natural pyrethrins were performed with vehicle-mounted thermal foggers in 9 localities of Martinique, where Ae. aegypti populations are strongly resistant to pyrethroids. Efficacy was assessed by monitoring mortality rates of naturally resistant and laboratory susceptible mosquitoes placed in sentinel cages. Before, during and after spraying, larval and adult densities were estimated. Results showed high mortality rates of susceptible sentinel mosquitoes treated with deltamethrin while resistant mosquitoes exhibited very low mortality. There was no reduction of either larval or adult Ae. aegypti population densities after treatments.Conclusions/Significance
This is the first documented evidence that pyrethroid resistance impedes dengue vector control using pyrethroid-based treatments. These results emphasize the need for alternative tools and strategies for dengue control programs.
by Neil E. Anderson, Joseph Mubanga, Eric M. Fevre, Kim Picozzi, Mark C. Eisler, Robert Thomas, Susan C. WelburnBackground
Animal and human trypanosomiasis are constraints to both animal and human health in Sub-Saharan Africa, but there is little recent evidence as to how these parasites circulate in wild hosts in natural ecosystems. The Luangwa Valley in Zambia supports high densities of tsetse flies (Glossina species) and is recognised as an historical sleeping sickness focus. The objective of this study was to characterise the nature of the reservoir community for trypanosomiasis in the absence of influence from domesticated hosts.Methodology/Principal Findings
A cross-sectional survey of trypanosome prevalence in wildlife hosts was conducted in the Luangwa Valley from 2005 to 2007. Samples were collected from 418 animals and were examined for the presence of Trypanosoma brucei s.l., T. b. rhodesiense, Trypanosoma congolense and Trypanosoma vivax using molecular diagnostic techniques. The overall prevalence of infection in all species was 13.9% (95% confidence interval [CI]: 10.71–17.57%). Infection was significantly more likely to be detected in waterbuck (Kobus ellipsiprymnus) (Odds ratio [OR] = 10.5, 95% CI: 2.36–46.71), lion (Panthera leo) (OR = 5.3, 95% CI: 1.40–19.69), greater kudu (Tragelaphus strepsiceros) (OR = 4.7, 95% CI: 1.41–15.41) and bushbuck (Tragelaphus scriptus) (OR = 4.5, 95% CI: 1.51–13.56). Bushbucks are important hosts for T. brucei s.l. while the Bovidae appear the most important for T. congolense. The epidemiology of T. vivax was less clear, but parasites were detected most frequently in waterbuck. Human infective T. b. rhodesiense were identified for the first time in African buffalo (Syncerus caffer) and T. brucei s.l. in leopard (Panthera pardus). Variation in infection rates was demonstrated at species level rather than at family or sub-family level. A number of significant risk factors interact to influence infection rates in wildlife including taxonomy, habitat and blood meal preference.Conclusion and Significance
Trypanosoma parasites circulate within a wide and diverse host community in this bio-diverse ecosystem. Consistent land use patterns over the last century have resulted in epidemiological stability, but this may be threatened by the recent influx of people and domesticated livestock into the mid-Luangwa Valley.
by Matthew Yeo, Isabel L. Mauricio, Louisa A. Messenger, Michael D. Lewis, Martin S. Llewellyn, Nidia Acosta, Tapan Bhattacharyya, Patricio Diosque, Hernan J. Carrasco, Michael A. MilesBackground
Multilocus sequence typing (MLST) is a powerful and highly discriminatory method for analysing pathogen population structure and epidemiology. Trypanosoma cruzi, the protozoan agent of American trypanosomiasis (Chagas disease), has remarkable genetic and ecological diversity. A standardised MLST protocol that is suitable for assignment of T. cruzi isolates to genetic lineage and for higher resolution diversity studies has not been developed.Methodology/Principal Findings
We have sequenced and diplotyped nine single copy housekeeping genes and assessed their value as part of a systematic MLST scheme for T. cruzi. A minimum panel of four MLST targets (Met-III, RB19, TcGPXII, and DHFR-TS) was shown to provide unambiguous assignment of isolates to the six known T. cruzi lineages (Discrete Typing Units, DTUs TcI-TcVI). In addition, we recommend six MLST targets (Met-II, Met-III, RB19, TcMPX, DHFR-TS, and TR) for more in depth diversity studies on the basis that diploid sequence typing (DST) with this expanded panel distinguished 38 out of 39 reference isolates. Phylogenetic analysis implies a subdivision between North and South American TcIV isolates. Single Nucleotide Polymorphism (SNP) data revealed high levels of heterozygosity among DTUs TcI, TcIII, TcIV and, for three targets, putative corresponding homozygous and heterozygous loci within DTUs TcI and TcIII. Furthermore, individual gene trees gave incongruent topologies at inter- and intra-DTU levels, inconsistent with a model of strict clonality.Conclusions/Significance
We demonstrate the value of systematic MLST diplotyping for describing inter-DTU relationships and for higher resolution diversity studies of T. cruzi, including presence of recombination events. The high levels of heterozygosity will facilitate future population genetics analysis based on MLST haplotypes.
by Christopher M. Parry, Ha Vinh, Nguyen Tran Chinh, John Wain, James I. Campbell, Tran Tinh Hien, Jeremy J. Farrar, Stephen BakerBackground
Infection with Salmonella enterica serovar Typhi (S. Typhi) with reduced susceptibility to fluoroquinolones has been associated with fluoroquinolone treatment failure. We studied the relationship between ofloxacin treatment response and the ofloxacin minimum inhibitory concentration (MIC) of the infecting isolate. Individual patient data from seven randomised controlled trials of antimicrobial treatment in enteric fever conducted in Vietnam in which ofloxacin was used in at least one of the treatment arms was studied. Data from 540 patients randomised to ofloxacin treatment was analysed to identify an MIC of the infecting organism associated with treatment failure.Principal Findings
The proportion of patients failing ofloxacin treatment was significantly higher in patients infected with S. Typhi isolates with an MIC≥0.25 µg/mL compared with those infections with an MIC of ≤0.125 µg/mL (p
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Clinical Pharmacology & Therapeutics
In This Issue
Clinical Pharmacology & Therapeutics 90, 1 (July 2011). doi:10.1038/clpt.2011.136
The Male Genital Tract Is Not a Pharmacological Sanctuary From Efavirenz
Clinical Pharmacology & Therapeutics 90, 151 (July 2011). doi:10.1038/clpt.2011.99
Authors: L B Avery, R P Bakshi, Y J Cao & C W Hendrix
The Paradox of Obesity and Cardiovascular Disease Risk: Time to Change Labels
Clinical Pharmacology & Therapeutics 90, 3 (July 2011). doi:10.1038/clpt.2011.121
Author: J Vincent
Impact of Smoking, Smoking Cessation, and Genetic Polymorphisms on CYP1A2 Activity and Inducibility
Clinical Pharmacology & Therapeutics 90, 117 (July 2011). doi:10.1038/clpt.2011.70
Authors: M Dobrinas, J Cornuz, B Oneda, M Kohler Serra, M Puhl & C B Eap
Clinical Pharmacology as a Foundation for Translational Science
Clinical Pharmacology & Therapeutics 90, 10 (July 2011). doi:10.1038/clpt.2011.80
Authors: S A Waldman, R J Hohl, G L Kearns, S J Swan & A Terzic
Childhood Obesity: A Ticking Time Bomb for Cardiovascular Disease?
Clinical Pharmacology & Therapeutics 90, 174 (July 2011). doi:10.1038/clpt.2011.88
Authors: J Logue & N Sattar
Clinical Pharmacology & Therapeutics 90, 14 (July 2011). doi:10.1038/clpt.2011.135
Sensitivity of Intravenous and Oral Alfentanil and Pupillary Miosis as Minimal and Noninvasive Probes for Hepatic and First-Pass CYP3A Induction
Clinical Pharmacology & Therapeutics 90, 100 (July 2011). doi:10.1038/clpt.2011.59
Authors: E D Kharasch, A Francis, A London, K Frey, T Kim & J Blood
Clinical Pharmacology & Therapeutics 90, 16 (July 2011). doi:10.1038/clpt.2011.118
Detecting Drug Interactions From Adverse-Event Reports: Interaction Between Paroxetine and Pravastatin Increases Blood Glucose Levels
Clinical Pharmacology & Therapeutics 90, 133 (July 2011). doi:10.1038/clpt.2011.83
Authors: N P Tatonetti, J C Denny, S N Murphy, G H Fernald, G Krishnan, V Castro, P Yue, P S Tsau, I Kohane, D M Roden & R B Altman
The Metabolic Syndrome: Looking Beyond the Debates
Clinical Pharmacology & Therapeutics 90, 19 (July 2011). doi:10.1038/clpt.2011.116
Authors: D Prabhakaran & K S Reddy
Cigarette Smoking, Nicotine, and Body Weight
Clinical Pharmacology & Therapeutics 90, 164 (July 2011). doi:10.1038/clpt.2011.105
Authors: J Audrain-McGovern & N L Benowitz
Obesity and the “Obesity Paradox” in Cardiovascular Diseases
Clinical Pharmacology & Therapeutics 90, 23 (July 2011). doi:10.1038/clpt.2011.87
Authors: C J Lavie, R V Milani & H O Ventura
Dietary Management of the Metabolic Syndrome
Clinical Pharmacology & Therapeutics 90, 184 (July 2011). doi:10.1038/clpt.2011.92
Authors: R W Kimokoti & L S Brown
Practical Ethics: Establishing a Pathway to Benefit for Complex Pharmacogenomic Tests
Clinical Pharmacology & Therapeutics 90, 25 (July 2011). doi:10.1038/clpt.2011.71
Authors: S B Haga & W Burke
Predicting Adverse Drug Reactions Using Publicly Available PubChem BioAssay Data
Clinical Pharmacology & Therapeutics 90, 90 (July 2011). doi:10.1038/clpt.2011.81
Authors: Y Pouliot, A P Chiang & A J Butte
The Importance of High-Quality Evidence of the Long-Term Impact of Nonfatal Events Used in Randomized Controlled Trials: A Case Study of Prasugrel
Clinical Pharmacology & Therapeutics 90, 27 (July 2011). doi:10.1038/clpt.2011.61
Authors: C Y Lu, J Karnon & M J Sorich
Alendronate Adherence and Its Impact on Hip-Fracture Risk in Patients With Established Osteoporosis in Taiwan
Clinical Pharmacology & Therapeutics 90, 109 (July 2011). doi:10.1038/clpt.2011.62
Authors: T-C Lin, C-Y Yang, Y-H Kao Yang & S-J Lin
Regulatory Science as a Bridge Between Science and Society
Clinical Pharmacology & Therapeutics 90, 29 (July 2011). doi:10.1038/clpt.2011.89
Authors: T Tominaga, Y Asahina, Y Uyama & T Kondo
Population Pharmacokinetic-Pharmacodynamic Analysis of Trastuzumab-Associated Cardiotoxicity
Clinical Pharmacology & Therapeutics 90, 126 (July 2011). doi:10.1038/clpt.2011.74
Authors: J G C van Hasselt, A H Boekhout, J H Beijnen, J H M Schellens & A D R Huitema
A Randomized Study of the Efficacy and Safety of Intravenous Acetaminophen vs. Intravenous Placebo for the Treatment of Fever
Clinical Pharmacology & Therapeutics 90, 32 (July 2011). doi:10.1038/clpt.2011.98
Authors: D H Kett, J B Breitmeyer, R Ang & M A Royal
Genetically Polymorphic OCT1: Another Piece in the Puzzle of the Variable Pharmacokinetics and Pharmacodynamics of the Opioidergic Drug Tramadol
Clinical Pharmacology & Therapeutics 90, 143 (July 2011). doi:10.1038/clpt.2011.56
Authors: M V Tzvetkov, A R Saadatmand, J Lötsch, I Tegeder, J C Stingl & J Brockmöller
New Drug Targets for the Treatment of Obesity
Clinical Pharmacology & Therapeutics 90, 40 (July 2011). doi:10.1038/clpt.2011.82
Authors: A G Powell, C M Apovian & L J Aronne
Pharmacokinetic Impact of SLCO1A2 Polymorphisms on Imatinib Disposition in Patients With Chronic Myeloid Leukemia
Clinical Pharmacology & Therapeutics 90, 157 (July 2011). doi:10.1038/clpt.2011.102
Authors: Y Yamakawa, A Hamada, T Shuto, M Yuki, T Uchida, H Kai, T Kawaguchi & H Saito
Biomarkers for the Prediction of Type 2 Diabetes and Cardiovascular Disease
Clinical Pharmacology & Therapeutics 90, 52 (July 2011). doi:10.1038/clpt.2011.93
Authors: C Herder, M Karakas & W Koenig
Obesity, the Metabolic Syndrome, and Sexual Dysfunction in Men
Clinical Pharmacology & Therapeutics 90, 169 (July 2011). doi:10.1038/clpt.2011.91
Authors: K Esposito & D Giugliano
The Human Placental Perfusion Model: A Systematic Review and Development of a Model to Predict In Vivo Transfer of Therapeutic Drugs
Clinical Pharmacology & Therapeutics 90, 67 (July 2011). doi:10.1038/clpt.2011.66
Authors: J R Hutson, F Garcia-Bournissen, A Davis & G Koren
Mechanisms and Genetics of Antipsychotic-Associated Weight Gain
Clinical Pharmacology & Therapeutics 90, 179 (July 2011). doi:10.1038/clpt.2011.97
Authors: S L Balt, G P Galloway, M J Baggott, Z Schwartz & J Mendelson
Implications of Obesity for Drug Therapy: Limitations and Challenges
Clinical Pharmacology & Therapeutics 90, 77 (July 2011). doi:10.1038/clpt.2011.104
Authors: R Jain, S M Chung, L Jain, M Khurana, S W J Lau, J E Lee, J Vaidyanathan, I Zadezensky, S Choe & C G Sahajwalla
The Obesity Paradox in Heart Failure: Accepting Reality and Making Rational Decisions
Clinical Pharmacology & Therapeutics 90, 188 (July 2011). doi:10.1038/clpt.2011.72
Authors: S D Anker & S von Haehling
British Journal of Cancer
Targeting colon cancer stem cells using a new curcumin analogue, GO-Y030
British Journal of Cancer advance online publication, June 21, 2011. doi:10.1038/bjc.2011.200
Authors: L Lin, Y Liu, H Li, P-K Li, J Fuchs, H Shibata, Y Iwabuchi & J Lin
Stability of BRAF V600E mutation in metastatic melanoma: new insights for therapeutic success?
British Journal of Cancer advance online publication, June 21, 2011. doi:10.1038/bjc.2011.239
Authors: L Sigalotti, E Fratta, G Parisi, S Coral & M Maio
EGFR gene copy number assessment from areas with highest EGFR expression predicts response to anti-EGFR therapy in colorectal cancer
British Journal of Cancer advance online publication, June 21, 2011. doi:10.1038/bjc.2011.223
Authors: A Ålgars, M Lintunen, O Carpén, R Ristamäki & J Sundström
Health-related quality of life anticipated with different management strategies for paediatric febrile neutropaenia
British Journal of Cancer advance online publication, June 21, 2011. doi:10.1038/bjc.2011.213
Authors: S Cheng, O Teuffel, M C Ethier, C Diorio, J Martino, C Mayo, D Regier, R Wing, S M H Alibhai & L Sung
Dietary cadmium exposure and risk of epithelial ovarian cancer in a prospective cohort of Swedish women
British Journal of Cancer advance online publication, June 21, 2011. doi:10.1038/bjc.2011.238
Authors: B Julin, A Wolk & A Åkesson
The treatment of early breast cancer in women over the age of 70
British Journal of Cancer advance online publication, June 21, 2011. doi:10.1038/bjc.2011.234
Authors: A Ring, M Reed, R Leonard, I Kunkler, H Muss, H Wildiers, L Fallowfield, A Jones & R Coleman
Transcription factors and molecular epigenetic marks underlying EpCAM overexpression in ovarian cancer
British Journal of Cancer advance online publication, June 21, 2011. doi:10.1038/bjc.2011.231
Authors: B T F van der Gun, M L de Groote, H G Kazemier, A J Arendzen, P Terpstra, M H J Ruiters, P M J McLaughlin & M G Rots
Supreme Court ruling is good, bad and ugly
Nature 474, 7352 (2011). http://www.nature.com/news/2011/110621/full/474421a.html
Author: Douglas Kysar
Monday's key US legal decision on emissions regulation was influenced by the unjustified attacks on climate science, says Douglas Kysar.
Worth a dam?
Nature 474, 7352 (2011). http://www.nature.com/news/2011/110621/full/474430a.html
Author: Jeff Tollefson
Voluntary agreement enables rating of hydroelectric impacts.