The utility of bispectral index monitoring for prevention of rocuronium-induced withdrawal movement in children: A randomized controlled trial.
This study was designed to determine whether a deep hypnotic state with a bispectral index (BIS) value less than 40 could alleviate withdrawal movement (WM) upon rocuronium injection during anesthesia induction in children. Finally, 135 healthy children (3-12 years) scheduled for minor elective surgery were studied. Without premedication, anesthesia was induced with thiopental sodium 5 mg/kg. Patients were randomized into 2 groups (control vs experimental) and then by virtue of rocuronium injection time, patients in the experimental group were allocated into 2 groups, as follows: in the control group (group C; n = 45), rocuronium 0.6 mg/kg was administered at the loss of eyelash reflex; in the 1st experimental group, rocuronium 0.6 mg/kg was administered when BIS fell to less than 40 (group T; n = 45); however, if BIS did not fall below 40 after thiopental sodium administration, manual ventilation was provided with oxygen 6 L/minute using sevoflurane 8% and then rocuronium was administered when BIS fell below 40 (the 2nd experimental group, group S; n = 45). Rocuronium-induced WM was evaluated using a 4-point scale (no movement; movement/withdrawal involving the arm only; generalized response, with movement/withdrawal of more than 1 extremity, but no requirement for restraint of the body; and generalized response which required restraint of the body and caused coughing or breath-holding). No significant differences were found among the groups for patient characteristics including age, sex, height, and location of venous cannula. However, body weight, height, and body mass index in group S were all smaller than those in group T. The incidence of WM caused by rocuronium was 100% in group C, 95.6% in group T, and 80% in group S, and was significantly lower in group S than in group C. The grade of WM was 3.7 ± 0.6 in group C, 3.2 ± 0.9 in group T, and 2.6 ± 1.0 in group S. It was significantly lower in group T than in group C and significantly lower in group S than in groups C and T. The confirmation of a deep hypnotic state with BIS values lower than 40 using BIS monitoring can reduce the grade of rocuronium-induced WMs during anesthesia induction using thiopental sodium or sevoflurane in children.


Colorectal cancer cell intrinsic fibroblast activation protein alpha binds to Enolase1 and activates NF-κB pathway to promote metastasis.
Fibroblast activation protein alpha (FAP) is a marker of cancer-associated fibroblast, which is also expressed in cancer epithelial cells. However, the role of FAP in colorectal cancer (CRC) cells remains to be elucidated. Here we investigate the expression pattern of FAP in CRC tissues and cells to prove that FAP is upregulated in CRC cells. Loss- of and gain-of-function assays identified FAP promotes migration and invasion instead of an effect on cell proliferation. Microarray assays are adopted to identify the different expressed genes after FAP knockdown and gene set enrichment analysis (GSEA) is used to exploit the involved signaling pathway. Our works reveal FAP exerts a function dependent on NF-κB signaling pathway and FAP expression is associated with NF-κB signaling pathway in clinical samples. Our work shows FAP is secreted by CRC cells and soluble FAP could promote metastasis. To investigate the mechanism of FAP influencing the NF-κB signaling pathway, LC/MS is performed to identify the proteins interacting with FAP. We find that FAP binds to ENO1 and activates NF-κB signaling pathway dependent on ENO1. Blocking ENO1 could partially reverse the pro-metastatic effect mediated by FAP. We also provide evidences that both FAP and ENO1 are associated with CRC stages, and high levels of FAP and ENO1 predict a poor survival in CRC patients. In summary, our work could provide a novel mechanism of FAP in CRC cells and a potential strategy for treatment of metastatic CRC.


Gadolinium-Free Cardiac MR Stress T1-Mapping to Distinguish Epicardial From Microvascular Coronary Disease.
Novel cardiac magnetic resonance (CMR) stress T1 mapping can detect ischemia and myocardial blood volume changes without contrast agents and may be a more comprehensive ischemia biomarker than myocardial blood flow. This study describes the performance of the first prospective validation of stress T1 mapping against invasive coronary measurements for detecting obstructive epicardial coronary artery disease (CAD), defined by fractional flow reserve (FFR <0.8), and coronary microvascular dysfunction, defined by FFR ≥0.8 and the index of microcirculatory resistance (IMR ≥25 U), compared with first-pass perfusion imaging. Ninety subjects (60 patients with angina; 30 healthy control subjects) underwent CMR (1.5- and 3-T) to assess left ventricular function (cine), ischemia (adenosine stress/rest T1 mapping and perfusion), and infarction (late gadolinium enhancement). FFR and IMR were assessed ≤7 days post-CMR. Stress and rest images were analyzed blinded to other information. Normal myocardial T1 reactivity (ΔT1) was 6.2 ± 0.4% (1.5-T) and 6.2 ± 1.3% (3-T). Ischemic viable myocardium downstream of obstructive CAD showed near-abolished T1 reactivity (ΔT1 = 0.7 ± 0.7%). Myocardium downstream of nonobstructive coronary arteries with microvascular dysfunction showed less-blunted T1 reactivity (ΔT1 = 3.0 ± 0.9%). Stress T1 mapping significantly outperformed gadolinium-based first-pass perfusion, including absolute quantification of myocardial blood flow, for detecting obstructive CAD (area under the receiver-operating characteristic curve: 0.97 ± 0.02 vs. 0.91 ± 0.03, respectively; p < 0.001). A ΔT1 of 1.5% accurately detected obstructive CAD (sensitivity: 93%; specificity: 95%; p < 0.001), whereas a less-blunted ΔT1 of 4.0% accurately detected microvascular dysfunction (area under the receiver-operating characteristic curve: 0.95 ± 0.03; sensitivity: 94%; specificity: 94%: p < 0.001). CMR stress T1 mapping accurately detected and differentiated between obstructive epicardial CAD and microvascular dysfunction, without contrast agents or radiation.


SARS-CoV-2 in an immunocompromised host: convalescent plasma therapy and viral evolution elucidated by whole genome sequencing.
The evolution of SARS-CoV-2 within immunocompromised hosts who fail to clear the virus over many months has been proposed as a route to the development of Variants of Concern (VoCs). We present a case of an immunocompromised male patient with a prolonged SARS-CoV-2 infection. During hospitalisation, 7 weeks after first diagnosis, his condition worsened to require continuous ventilation support. Resolution of symptoms was observed after convalescent plasma therapy. Whole genome sequencing of the virus showed Pango lineage B.1.221. Between the first sample and the second from bronchoalveolar lavage fluid 7 weeks later, we identified eight mutations, including minor variants, which could be used to estimate the chronology of mutations. This suggests an elevated mutation rate, in-host accumulation of mutations and further evidence for sources of VoCs. Prolonged SARS-CoV-2 infections in immunocompromised hosts increase the likelihood of hospital stays and morbidity, and also pose an increased risk to global public health.


[1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene]chloridogold(I).
The molecule of the title compound, [AuCl(C(27)H(36)N(2))], which belongs to a class of potentially catalytically active N-heterocyclic carbene complexes, has crystallographic C(2) symmetry and approximate C(2v) symmetry. The structure is isostructural with the Cu(I) and Ag(I) analogues. A previous report of the structure of the title compound as its toluene solvate [Fructos et al. (2005). Angew. Chem. Int. Ed. 44, 5284-5288] has inaccurate geometry for the complex molecule as a consequence of probable incorrect refinement in the space group Cc, instead of C2/c [Marsh (2009). Acta Cryst. B65, 782-783]. The Au-C bond length of 1.998 (4) Å in the title compound is more consistent with the mean distance of 1.979 (14) Å found in 52 other reported [AuCl(carbene)] complexes than with the shorter distance of 1.942 (3) Å given for the refinement in the space group Cc for the toluene solvate and the value of 1.939 Å obtained from the recalculation of that structure in C2/c.


Acute respiratory distress in a silversmith.
A 25-year-old young male patient presented in casualty department with severe respiratory distress on the fourth day from onset of symptoms. The patient was nonsmoker and had no antecedent medical or drug history. Prior to admission, patient had dry cough and bilateral pleuritic chest pain for the last three days. He was in severe respiratory distress with use of accessory muscles of respiration. On examination, he had heart rate of 120 beats/min, blood pressure (BP) of 150/80, respiratory rate of 48-52/min and central cyanosis present. On systemic examination, reduced intensity of breath sounds with extensive rhonchi and crepitation was found in both lung fields, with other examination being within normal limits. On pulse oximetry, oxygen saturation was 28% on room air, which increased up to 36% with the help of 4 L oxygen via nasal prongs. PaO2/FiO2 ratio was 100. Chest X-ray analysis was suggestive of non-cardiac pulmonary edema in view of bilateral fluffy opacity without cardiomegaly. In view of 2/3 positive criteria, his provisional diagnosis was Acute Respiratory Distress Syndrome (ARDS). He required mechanical ventilatory support and was gradually weaned over a period of 10 days. The patient was treated with broad spectrum antibiotics and other supportive measures. On re-evaluation of history, we found that he was a goldsmith by occupation, smelting silver and gold for the past 8-10 years. On the day of onset of symptoms, while smelting silver he was exposed to golden yellow fumes for around 15 minutes, with the quantum of exposure more than any other day earlier. From previous experience and analysis of similar silver metals, he was able to tell us that the silver was adulterated with large amount of cadmium on that day than before. Serum level of cadmium was 2.9 μg/L 6 days after initial exposure. At the time of discharge, he had residual opacities in the chest radiograph and resting oxygen saturation was 94% on room air.


The design and rationale of the Australian Cooperative National Registry of Acute Coronary care, Guideline Adherence and Clinical Events (CONCORDANCE).
Cardiovascular observational registries characterise patients and describe the manner and use of therapeutic strategies. They facilitate analyses on the quality of care among participating institutions and document variations in clinical practice which can be benchmarked against best practice recommendations. The Cooperative National Registry of Acute Coronary care, Guideline Adherence and Clinical Events (CONCORDANCE) is an Australian observational registry that describes management and outcomes in patients with acute coronary syndromes (ACS) and feeds back both performance and outcome measures to participating hospitals. The CONCORDANCE registry has been designed within a comparative effectiveness research (CER) framework to collect and report data from hospitals located in geographically diverse regions of Australia. Information including patient demographics, presenting characteristics, past medical history, in-hospital management and outcomes at six months and two years are entered into a web-based database using an electronic clinical record form (eCRF). Individual hospital information is returned to the sites in a real time confidential report detailing information on key performance indicator (KPI) process measures and outcomes benchmarked against the aggregated study cohort. Governance rules ensure data security and protect patient and clinician confidentiality. Consistent with a CER framework, additional characteristics of the registry include: (a) the capacity to evaluate associations between the inter and intra hospital systems and the provision of evidence based care and outcomes, (b) ongoing data collection from representative hospitals which allow spatial and temporal analysis of change in practice and the application of treatment modalities in the real world setting and (c) the provision of a data spine for quality improvement strategies and practical clinical trials. The CONCORDANCE registry is a clinician-driven initiative describing clinical care for ACS patients admitted to Australian hospitals. The registry generates high quality data which is fed back to clinicians, and key stakeholders in ACS care. Using a CER approach, the registry describes the translation of randomised trial evidence into practice, and provides insights into strategies that could improve care and ultimately patient outcomes.


Leptin and the intervertebral disc: a biochemical link exists between obesity, intervertebral disc degeneration and low back pain-an in vitro study in a bovine model.
The aim of this study was to identify the effects of leptin upon the intervertebral disc (IVD) and to determine whether these responses are potentiated within an environment of existing degeneration. Obesity is a significant risk factor for low back pain (LBP) and IVD degeneration. Adipokines, such as leptin, are novel cytokines produced primarily by adipose tissue and have been implicated in degradative and inflammatory processes. Obese individuals are known to have higher concentrations of serum leptin, and IVD cells express leptin receptors. We hypothesise that adipokines, such as leptin, mediate a biochemical link between obesity, IVD degeneration and LBP. The bovine intervertebral disc was used as a model system to investigate the biochemical effects of obesity, mediated by leptin, upon the intervertebral disc. Freshly isolated cells, embedded in 3D alginate beads, were subsequently cultured under varying concentrations of leptin, alone or together with the pro-inflammatory cytokines TNF-α, IL-1β or IL-6. Responses in relation to production of nitric oxide, lactate, glycosaminoglycans and expression of anabolic and catabolic genes were analysed. Leptin influenced the cellular metabolism leading particularly to greater production of proteases and NO. Addition of leptin to an inflammatory environment demonstrated a marked deleterious synergistic effect with greater production of NO, MMPs and potentiation of pro-inflammatory cytokine production. Leptin can initiate processes involved in IVD degeneration. This effect is potentiated in an environment of existing degeneration and inflammation. Hence, a biochemical mechanism may underlie the link between obesity, intervertebral disc degeneration and low back pain. These slides can be retrieved under Electronic Supplementary Material.


Content based image retrieval using unclean positive examples.
Conventional content-based image retrieval (CBIR) schemes employing relevance feedback may suffer from some problems in the practical applications. First, most ordinary users would like to complete their search in a single interaction especially on the web. Second, it is time consuming and difficult to label a lot of negative examples with sufficient variety. Third, ordinary users may introduce some noisy examples into the query. This correspondence explores solutions to a new issue that image retrieval using unclean positive examples. In the proposed scheme, multiple feature distances are combined to obtain image similarity using classification technology. To handle the noisy positive examples, a new two-step strategy is proposed by incorporating the methods of data cleaning and noise tolerant classifier. The extensive experiments carried out on two different real image collections validate the effectiveness of the proposed scheme.


Space-Group Symmetries Generate Chaotic Fluid Advection in Crystalline Granular Media.
The classical connection between symmetry breaking and the onset of chaos in dynamical systems harks back to the seminal theory of Noether [Transp. Theory Statist. Phys. 1, 186 (1918)10.1080/00411457108231446]. We study the Lagrangian kinematics of steady 3D Stokes flow through simple cubic and body-centered cubic (bcc) crystalline lattices of close-packed spheres, and uncover an important exception. While breaking of point-group symmetries is a necessary condition for chaotic mixing in both lattices, a further space-group (glide) symmetry of the bcc lattice generates a transition from globally regular to globally chaotic dynamics. This finding provides new insights into chaotic mixing in porous media and has significant implications for understanding the impact of symmetries upon generic dynamical systems.


Two versus three narrow-diameter implants with locator attachments supporting mandibular overdentures: a two-year prospective study.
Purpose. To compare treatment outcome (survival rate, condition of hard and soft peri-implant tissues) and prosthodontic maintenance requirements of two versus three narrow-diameter bone level implants with Locator attachments supporting mandibular overdentures. Materials and Methods. Twenty completely edentulous patients with atrophic mandibles were treated. Ten patients (Group A) were treated with overdentures supported by two narrow (3.3-mm diameter) implants (Straumann AG, Basel, Switzerland) and ten patients (Group B) were treated with overdentures supported by three narrow implants. Locator (Zest Anchors, USA) attachments were used for prosthetic anchorage. Standardized clinical and radiographic parameters (survival rate, plaque index, calculus index, gingival index, bleeding index, probing depth and marginal bone loss) were evaluated at the time of the completion of the prosthetic treatment (baseline) and after 6, 12 and 24 months of functional loading. Prosthodontic maintenance requirements were also scored. Results. Only one implant was lost (Group B) during the healing period. There were no significant differences with regards to any of the studied clinical and radiographic parameters between the two groups (P > 0.05). Few prosthetic complications were recorded. Conclusions. No need to insert more than two narrow-diameter bone level implants with Locator attachments in cases of atrophic mandible to support an overdenture, however, long-term prospective studies are required to support this notion.


A retrospective follow up study on maternal age and infant mortality in two Sicilian districts.
Infant mortality rate (IMR) is a key public health indicator. Maternal age is a well-known determinant of pregnancy and delivery complications and of infant morbidity and mortality. In Italy the Infant Mortality Rate was 3.7/1000 during 2005, lower than the average IMR for the European Union (4.94/1000). Sicily is the Italian region with the highest IMR, 5/1000, and neonatal mortality rate (NMR), 3.8/1000, with substantial variation among its nine districts. The present study compared a high IMR/NMR district (Messina) with a low IMR/NMR district (Palermo) during the period 2004-2006 to evaluate potential determinants of the IMRs' differences between the two districts and specifically the impact of maternal age. The Death Causes Registers identified all deaths during the first year of life recorded among infants born to residents of the two districts in 2004-2006. For every case, available hospital charts records were abstracted using a standardized form designed to capture information on potential determinants of infant death. For each district and for each year, IMRs and NMRs were computed. Chi-squared statistics tested the significance of differences between district-specific IMRs. A Poisson regression model was used to analyze the relationship between maternal age, district of residence and IMR. The 246 death registry-confirmed cases included 143 (58.1%) males and 103 (41.2%) females, with mean age at death of 33.3 days (SD: 64.5, median: 5.5). The average IMR for 2004-2006 was significantly higher for the Messina district than for the Palermo district (p = 0.0001). The IMR ratio was 1.6 (95%CI: 1.2 - 2.1). The IMRs declined from 2004 to 2006. A significant interaction (p = 0.04) between maternal age and district of residence was documented. The association between advanced maternal age and infant deaths in the Messina district was due in part to the excess of newborns from advanced age mothers, but also to increased risk of death among such newborns. The significant interaction between district of residence and maternal age indicated that the IMR excess in the Messina district cannot be explained by disproportionately high live birth rates among older mothers and suggested the hypothesis that health care facilities in the Messina district could be less well prepared to provide assistance to the excess of high risk pregnancies and deliveries, as compared to Palermo district.


Engineering Escherichia coli to synthesize free fatty acids.
Fatty acid metabolism has received significant attention as a route for producing high-energy density, liquid transportation fuels and high-value oleochemicals from renewable feedstocks. If microbes can be engineered to produce these compounds at yields that approach the theoretical limits of 0.3-0.4 g/g glucose, then processes can be developed to replace current petrochemical technologies. Here, we review recent metabolic engineering efforts to maximize production of free fatty acids (FFA) in Escherichia coli, the first step towards production of downstream products. To date, metabolic engineers have succeeded in achieving higher yields of FFA than any downstream products. Regulation of fatty acid metabolism and the physiological effects of fatty acid production will also be reviewed from the perspective of identifying future engineering targets.


Nitric oxide synthase gene polymorphisms and nephropathy in Asians with Type 2 diabetes.
Recent studies on Caucasians have reported an association between diabetic microvascular complications and polymorphisms in the inducible nitric oxide synthase (iNOS) gene. In view of the differences in the pattern of diabetic complications in Asians, we studied these iNOS polymorphisms in Asians with Type 2 diabetes who do and those who do not have nephropathy. Two hundred fifty-eight Asians who have had Type 2 diabetes for at least 10 years, with overt nephropathy or with normoalbuminuria, were genotyped for the (AAAT)(n) and (CCTTT)(n) polymorphisms in the promoter region of the iNOS gene. A subanalysis was made of the findings from the three ethnic groups (Chinese, Malays, and Indians). The (AAAT)(3) polymorphism, which is the most common allele in Caucasians, was completely absent in our entire cohort of 258 Asian diabetics. The (AAAT)(4) polymorphism was the commonest, with a frequency of 0.984 as compared with 0.2 in Caucasians. We also found previously unreported alleles: (AAAT)(5) in 6 patients and (AAAT)(6) in 1 patient. There was no statistically significant association with nephropathy, in view of the highly skewed distribution of the alleles. However, the higher repeats (AAAT)(5) and (AAAT)(6) were found in the patients with a very rapid onset of severe nephropathy. The (CCTTT)(n) polymorphism also showed significant differences in allele distribution between the Asian and the Caucasian and African populations (P=.001). However, there was also no significant association with nephropathy and no significant difference in the ethnic distribution of alleles. We have identified significant differences in the (AAAT)(n) and (CCTTT)(n) polymorphisms in Asian diabetics. We have shown that there are significant differences in the overall allele distribution between the Asian and the Caucasian and African populations. However, our study did not demonstrate an association between iNOS gene polymorphisms and diabetic nephropathy.


Changes in severity of 2009 pandemic A/H1N1 influenza in England: a Bayesian evidence synthesis.
To assess the impact of the 2009 A/H1N1 influenza pandemic in England during the two waves of activity up to end of February 2010 by estimating the probabilities of cases leading to severe events and the proportion of the population infected. A Bayesian evidence synthesis of all available relevant surveillance data in England to estimate severity of the pandemic. All available surveillance systems relevant to the pandemic 2009 A/H1N1 influenza outbreak in England from June 2009 to February 2010. Pre-existing influenza surveillance systems, including estimated numbers of symptomatic cases based on consultations to the health service for influenza-like illness and cross sectional population serological surveys, as well as systems set up in response to the pandemic, including follow-up of laboratory confirmed cases up to end of June 2009 (FF100 and Fluzone databases), retrospective and prospective follow-up of confirmed hospitalised cases, and reported deaths associated with pandemic 2009 A/H1N1 influenza. Main outcome measures Age specific and wave specific probabilities of infection and symptomatic infection resulting in hospitalisation, intensive care admission, and death, as well as infection attack rates (both symptomatic and total). The probabilities of intensive care admission and death given hospitalisation over time are also estimated to evaluate potential changes in severity across waves. In the summer wave of A/H1N1 influenza, 0.54% (95% credible interval 0.33% to 0.82%) of the estimated 606,100 (419,300 to 886,300) symptomatic cases were hospitalised, 0.05% (0.03% to 0.08%) entered intensive care, and 0.015% (0.010% to 0.022%) died. These correspond to 3200 (2300 to 4700) hospital admissions, 310 (200 to 480) intensive care admissions, and 90 (80 to 110) deaths in the summer wave. In the second wave, 0.55% (0.28% to 0.89%) of the 1,352,000 (829,900 to 2,806,000) estimated symptomatic cases were hospitalised, 0.10% (0.05% to 0.16%) were admitted to intensive care, and 0.025% (0.013% to 0.040%) died. These correspond to 7500 (5900 to 9700) hospitalisations, 1340 (1030 to 1790) admissions to intensive care, and 240 (310 to 380) deaths. Just over a third (35% (26% to 45%)) of infections were estimated to be symptomatic. The estimated probabilities of infections resulting in severe events were therefore 0.19% (0.12% to 0.29%), 0.02% (0.01% to 0.03%), and 0.005% (0.004% to 0.008%) in the summer wave for hospitalisation, intensive care admission, and death respectively. The corresponding second wave probabilities are 0.19% (0.10% to 0.32%), 0.03% (0.02% to 0.06%), and 0.009% (0.004% to 0.014%). An estimated 30% (20% to 43%) of hospitalisations were detected in surveillance systems in the summer, compared with 20% (15% to 25%) in the second wave. Across the two waves, a mid-estimate of 11.2% (7.4% to 18.9%) of the population of England were infected, rising to 29.5% (16.9% to 64.1%) in 5-14 year olds. Sensitivity analyses to the evidence included suggest this infection attack rate could be as low as 5.9% (4.2% to 8.7%) or as high as 28.4% (26.0% to 30.8%). In terms of the probability that an infection leads to death in the second wave, these correspond, respectively, to a high estimate of 0.017% (0.011% to 0.024%) and a low estimate of 0.0027% (0.0024% to 0.0031%). This study suggests a mild pandemic, characterised by case and infection severity ratios increasing between waves. Results suggest low ascertainment rates, highlighting the importance of systems enabling early robust estimation of severity, to inform optimal public health responses, particularly in light of the apparent resurgence of the 2009 A/H1N1 strain in the 2010-11 influenza season.


Functionality of cryopreserved juvenile ovaries from mutant mice in different genetic background strains after allotransplantation.
The rapid expansion of mutant mouse colonies for biomedical research has resulted in lack of space at laboratory animal facilities and increasing risks of losing precious lines. These challenges require cheap and effective methods in addition to freezing embryos and sperm to archive the expanding mutant mouse lines. Cryopreservation of mouse ovarian tissue has been reported, but the application in the diverse mutant lines and genetic backgrounds has not yet been studied. In this study, juvenile ovaries (10-day-old) collected from genetically modified mouse lines were cryopreserved using high concentrations of cryoprotectants (dimethyl sulfoxide (Me(2)SO) and ethylene glycol (EG)) and instrumented ultra-rapid freezing. The validation of the frozen ovary batches was assessed by orthotopically transplanting a thawed ovary into a nearly completely ovariectomized mature female (congenic with the ovary donor). After 2 weeks of recovery, the ovary recipient was continuously paired with a male (congenic with the ovary donor) to evaluate the fertility of the recipient and delivered offspring were genotyped to evaluate the continued functionality of the grafted ovary. The recipient females delivered genetically modified offspring starting 6 weeks after ovary transplantation and lasting up to 6 months. The presented cryopreservation and transplantation protocols enabled retrieval of the genetic modification in 20 (from 22) genetically modified mutant mouse models on a C57BL/6 (17), FVB (2), or BALB/c (1) background. The thawed ovaries functioned after successful orthotopic allotransplantation to congenic wild-type recipients and produced mutant offspring, which allowed recreation of the desired genotype as a heterozygote on the proper genetic background. The results indicate that cryopreservation of mouse ovaries is a promising method to preserve genetic modification of the increasing number of mutant mouse models and can be used as a model for ovary cryopreservation using a variety of mouse mutants.


Negative regulation of mutS and mutH repair gene expression by the Hfq and RpoS global regulators of Escherichia coli K-12.
The MutS, MutL, and MutH proteins play major roles in several DNA repair pathways. We previously reported that the cellular amounts of MutS and MutH decreased by as much as 10-fold in stationary-phase cultures. Consequently, we tested whether the amounts of MutS, MutL, and MutH were regulated by two global regulators, RpoS (sigma38) and Hfq (HF-I [putative RNA chaperone]), which are involved in stationary-phase transition. We report here that mutations in hfq and rpoS reversed the stationary-phase down-regulation of the amounts of MutS and MutH. hfq regulation of the amount of MutS in stationary-phase cultures was mediated by RpoS-dependent and -independent mechanisms, whereas hfq regulation of the amount of MutH was mediated only through RpoS. Consistent with this interpretation, the amount of MutS but not MutH was regulated by Hfq, but not RpoS, in exponentially growing cells. The amount of MutL remained unchanged in rpoS, hfq-1, and rpoS+, hfq+ strains in exponentially growing and stationary-phase cultures and served as a control. The beta-galactosidase activities of single-copy mutS-lacZ operon and gene fusions suggested that hfq regulates mutS posttranscriptionally in exponentially growing cultures. RNase T2 protection assays revealed increased amounts of mutS transcript that are attributed to increased mutS transcript stability in hfq-1 mutants. Lack of Hfq also increased the amounts and stabilities of transcripts initiated from P(miaA) and P1hfqHS, two of the promoters for hfq, suggesting autoregulation, but did not change the half-life of bulk mRNA. These results suggest that the amounts of MutS and MutH may be adjusted in cells subjected to different stress conditions by an RpoS-dependent mechanism. In addition, Hfq directly or indirectly regulates several genes, including mutS, hfq, and miaA, by an RpoS-independent mechanism that destabilizes transcripts.


Kin discrimination and the benefit of helping in cooperatively breeding vertebrates.
In many cooperatively breeding vertebrates, a dominant breeding pair is assisted in offspring care by nonbreeding helpers. A leading explanation for this altruistic behavior is Hamilton's idea that helpers gain indirect fitness benefits by rearing relatives (kin selection). Many studies have shown that helpers typically provide care for relatives, but relatively few have shown that helpers provide closer kin with preferential care (kin discrimination), fueling the suggestion that kin selection only poorly accounts for the evolution of cooperative breeding in vertebrates. We used meta-analysis to show that (i) individuals consistently discriminate between kin, and (ii) stronger discrimination occurs in species where the benefits of helping are greater. These results suggest a general role for kin selection and that the relative importance of kin selection varies across species, as predicted by Hamilton's rule.


Gender specific effect of major dietary patterns on the metabolic syndrome risk in Korean pre-pubertal children.
There is a lack of data on metabolic risk factors during pre-puberty, which is important for identifying the subgroups of youth, at whom early interventions should be targeted. In this study, we evaluated the prevalence of metabolic risk factors and its subsequent relations with dietary patterns in Korean pre-pubertal children through a cross-sectional sample (n = 1,008; boys = 513) of pre-pubertal children (aged 8-9 years) from a sub-study of the Korea Metabolic Syndrome Research Initiatives (KMSRI) in Seoul, Korea. Measures of anthropometry and blood pressure as well as fasting blood samples were used in the analysis. A three-day food records were collected. The metabolic syndrome was defined according to the age-adjusted National Cholesterol Education Program Adult Treatment Panel III guidelines. An added metabolic risk score was calculated for each subject by summing the quintile values of the five individual risk factors. Among the 5 risk components of metabolic syndrome, high waist circumference (WC) was the major factor (P < 0.001). A significant increasing trend of the added metabolic syndrome risk score was observed with the increase of WC (P (trend) < 0.001) among both genders. The cutoff point for high WC for pre-pubertal children was 61.3 cm for boys and 59.9 cm for girls. The prevalence of high triglyceride (TG) values was significantly higher in girls than it was in boys (P < 0.01). Girls in the highest quintile of balanced dietary pattern scores had lower TG values (P (trend) = 0.032) than did those in the lowest quintile. Moreover, girls in the highest quintile of western dietary pattern scores showed increasing trend for the added metabolic risk score (P (trend) = 0.026) compared with those in the lowest quintile. Adverse associations exist between western dietary patterns and the accumulation of metabolic risks among girls, not in boys, even during pre-puberty.


Differential TLR recognition of leptospiral lipid A and lipopolysaccharide in murine and human cells.
Leptospira interrogans is a spirochete that is responsible for leptospirosis, a zoonotic disease. This bacterium possesses an unusual LPS that has been shown to use TLR2 instead of TLR4 for signaling in human cells. The structure of its lipid A was recently deciphered. Although its overall hexa-acylated disaccharide backbone is a classical feature of all lipid A forms, the lipid A of L. interrogans is peculiar. In this article, the functional characterization of this lipid A was studied in comparison to whole parental leptospiral LPS in terms of cell activation and use of TLR in murine and human cells. Lipid A from L. interrogans did not coagulate the Limulus hemolymph. Although leptospiral lipid A activated strongly murine RAW cells, it did not activate human monocytic cells. Results obtained from stimulation of peritoneal-elicited macrophages from genetically deficient mice for TLR2 or TLR4 clearly showed that lipid A stimulated the cells through TLR4 recognition, whereas highly purified leptospiral LPS utilized TLR2 as well as TLR4. In vitro experiments with transfected human HEK293 cells confirmed that activation by lipid A occurred only through murine TLR4-MD2 but not through human TLR4-MD2, nor murine or human TLR2. Similar studies with parental leptospiral LPS showed that TLR2/TLR1 were the predominant receptors in human cells, whereas TLR2 but also TLR4 contributed to activation in murine cells. Altogether these results highlight important differences between human and mouse specificity in terms of TLR4-MD2 recognition that may have important consequences for leptospiral LPS sensing and subsequent susceptibility to leptospirosis.


The Mitoscriptome in Aging and Disease.
Mitochondria are the major sites where energy is produced in the cell. Functions of organs such as the heart which has high energy demand are seriously affected by dysfunction of mitochondria. The functional changes in energy-dependent organs such as heart due to aging or any other cause are expected to be reflected in changes in expression of genes related to mitochondrial structure and function. Conversely, alteration of mitochondrial gene expression by any reason may also adversely affect function of organs such as heart that are energy-dependent. Molecular profiling of mitochondrial gene expression is therefore critical to understanding the mechanism of organ dysfunction. Mitochondrial structure and function are controlled by genes in the nuclear DNA and those in the mitochondrial DNA (mtDNA). The transcriptome from these two sources, together, contributing to the structure and function of mitochondria may be called mitoscriptome. This review elaborates on data gathered using a gene chip, RoMitochip, developed in our laboratory to study mitochondrial functional alteration in cardiomyocytes and left ventricular tissue following hypoxia or hemorrhagic injury. RoMitochip consists of probesets representing genes from nuclear DNA and mtDNA of both mice and rats. Our experiments using this chip in in vitro model of hypoxia and in vivo hemorrhagic injury model determined mitoscriptome signatures following hypoxia and hemorrhage, respectively. In addition, we also discuss past initiatives from other investigators that led to the development of microarray tools to profile mitoscriptome.


Detection of NRG1 Gene Fusions in Solid Tumors.
NRG1 gene fusions are rare but potentially actionable oncogenic drivers that are present in some solid tumors. Details regarding the incidence of these gene rearrangements are lacking. Here, we assessed the incidence of NRG1 fusions across multiple tumor types and described fusion partners. Tumor specimens submitted for molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory and that underwent fusion testing by anchored multiplex PCR for targeted RNA sequencing were retrospectively identified. The overall and tumor-specific incidence was noted, as was the specific fusion partner. Out of 21,858 tumor specimens profiled from September 2015 to December 2018, 41 cases (0.2%) harbored an NRG1 fusion. Multiple fusion partners were identified. Fusion events were seen across tumor types. The greatest incidence was in non-small cell lung cancer (NSCLC, 25), though this represented only 0.3% of NSCLC cases tested. Other tumor types harboring an NRG1 fusion included gallbladder cancer, renal cell carcinoma, bladder cancer, ovarian cancer, pancreatic cancer, breast cancer, neuroendocrine tumor, sarcoma, and colorectal cancer. NRG1 fusions can be detected at a low incidence across multiple tumor types with significant heterogeneity in fusion partner.See related commentary by Dimou and Camidge, p. 4865.


Absence of apparent phenotype in mice lacking Cdc25C protein phosphatase.
The Cdc25 family of protein phosphatases positively regulate the cell division cycle by activating cyclin-dependent protein kinases. In humans and rodents, three Cdc25 family members denoted Cdc25A, -B, and -C have been identified. The murine forms of Cdc25 exhibit distinct patterns of expression both during development and in adult mouse tissues. In order to determine unique contributions made by the Cdc25C protein phosphatase to embryonic and adult cell cycles, mice lacking Cdc25C were generated. We report that Cdc25C(-/-) mice are viable and do not display any obvious abnormalities. Among adult tissues in which Cdc25C is detected, its transcripts are most abundant in testis, followed by thymus, ovary, spleen, and intestine. Mice lacking Cdc25C were fertile, indicating that Cdc25C does not contribute an essential function during spermatogenesis or oogenesis in the mouse. T- and B-cell development was also found to be normal in Cdc25C(-/-) mice, and Cdc25C(-/-) mouse splenic T and B cells exhibited normal proliferative responses in vitro. Finally, the phosphorylation status of Cdc2, the timing of entry into mitosis, and the cellular response to DNA damage were unperturbed in mouse embryo fibroblasts lacking Cdc25C. These findings indicate that Cdc25A and/or Cdc25B may compensate for loss of Cdc25C in the mouse.


Spectroscopy of single nanocrystals.
As colloidal semiconductor nanocrystals are developed for a wider range of diverse applications, it becomes more important to gain a deeper understanding of their properties in order to direct synthetic efforts. While most synthetic developments are guided by changes in ensemble properties, certain applications such as those in nano-electronics and nano-photonics rely on properties of nanocrystals at the individual level. For such applications and even for a more detailed understanding of the ensemble behavior, single nanocrystal spectroscopy becomes a vital tool. This review looks at how single nanocrystal spectroscopy has been applied to materials based on modern synthetic techniques and how these studies are elucidating properties that remain hidden at the ensemble level. First, recent theoretical models that are important for understanding many observed phenomena are explored. Then the review highlights new insights into many of the photophysical properties that are of interest in semiconductor nanocrystal materials, such as the ubiquitous spectral instability, magneto-optical identification of the band-edge exciton fine structure, emission from multi-excitons, and the spectroscopic properties of charged nanocrystals that challenge long standing theories on photoluminescence blinking behavior. To date most of the research has been conducted on materials based on cadmium selenide primarily due to its many years of development as a prototypical nanocrystal system. The review ends with a discussion of new materials that would also benefit from a detailed photophysical understanding afforded by single nanocrystal spectroscopy.


Barriers to acceptance and adherence of antiretroviral therapy in urban Zambian women: a qualitative study.
Sub-Saharan Africa contains over 60% of the world's HIV infections and Zambia is among the most severely affected countries in the region. As antiretroviral programs have been rapidly expanding, the long-term success of these programs depends on a good understanding of the behavioral determinants of acceptance and adherence to antiretroviral therapy (ART). The study used qualitative methods to gain local insight into potentially important factors affecting HIV-infected women's decision to accept or continue with ART. Some of the barriers identified by this study are consistent with factors cited in the existing adherence literature from both developed and developing nations such as side effects, hunger and stigma; other factors have not been previously reported. One major theme was unfamiliarity with the implications of having a chronic, potentially deadly disease. Other emerging themes from this study include the complicated effect of ART on interpersonal relationship, particularly between husbands and wives, the presence of depression and hopelessness, and lack of accurate information. The results suggest that the reasons for non-uptake of treatment include issues related to local cultural frameworks (e.g., illness ideology), mental and behavioral health (e.g., depression and/or interpersonal challenges), stigma, and motivating factors (e.g., values of church or marriage) of different cultures that affect the ability and willingness to take life-saving medicine for a long period of time. Qualitative studies are critical to better understand why ART eligible individuals are choosing not to initiate or continue treatment to achieve needed adherence levels.


Martian relief and the coming opposition.
In the report "Martian relief and the coming opposition" (3 Mar., p. 1100), D. H. Harris stated that, "... the reduced contrast with decreasing (terminator distance) just balances the increase in visibility due to shadow length." This is obviously erroneous. A more careful examination of the problem shows that for favorable values of the Aerocentric EarthSun Sun angle, visibility of relief increases toward the terminator, clouds not withstanding.


Posterior calvarial distraction in craniosynostosis - an evolving technique.
Posterior advancement of the occiput is an established surgical option for the treatment of raised intracranial pressure (ICP) secondary to craniocerebral disproportion in syndromic craniosynostoses. Distraction osteogenesis has gained popularity in a variety of craniofacial procedures to achieve greater advancement in the anterior craniofacial skeleton, but has only relatively recently been used in the posterior calvarium. We report the Oxford Craniofacial Unit's experience of using distraction techniques to expand the occiput. We preformed a retrospective casenote review of all patients with syndromic craniosynostoses who underwent posterior distraction at our centre from 2007 to 2010, as identified by the Oxford Craniofacial Database. Ten syndromic patients underwent posterior distraction (mean age of 18.1 months). Successful calvarial expansion (mean advancement of 19.7 mm) was achieved in all patients clinically and radiologically. There were 6 minor and 1 major complications. Posterior distraction was successfully performed in 10 patients including babies as young as 3 months of age. It achieved a reduction in turricephaly, an improvement in the cephalic index, and a resolution of raised ICP. We have customised our surgical technique to address individual patient needs. The use of distraction techniques in the occiput appears to increase the reliability of expansion in this region.


Dichroism of the macular pigment and Haidinger's brushes.
It seems quite certain that the visual entoptic phenomenon called Haidinger's brushes is a consequence of dichroism of the macular pigment; this dichroism is usually ascribed to orientation of the pigment molecules. An alternative explanation of the dichroism, an explanation that requires no orientation of pigment molecules, investigated and shown to be feasible. Specifically, it is shown that form dichroism that is due to the structure of the Henle fiber layer can account for Haidinger's brushes if the macular pigment is almost entirely confined to the Henle layer, if individual fibers have an index about 5% higher than that of the interfiber medium, and if the fibers form a tightly packed array.


Mild cognitive impairment status and mobility performance: an analysis from the Boston RISE study.
The prevalence of mild cognitive impairment (MCI) and mobility limitations is high among older adults. The aim of this study was to investigate the association between MCI status and both performance-based and self-report measures of mobility in community-dwelling older adults. An analysis was conducted on baseline data from the Boston Rehabilitative Impairment Study in the Elderly study, a cohort study of 430 primary care patients aged 65 or older. Neuropsychological tests identified participants with MCI and further subclassified those with impairment in memory domains (aMCI), nonmemory domains (naMCI), and multiple domains (mdMCI). Linear regression models were used to assess the association between MCI status and mobility performance in the Habitual Gait Speed, Figure of 8 Walk, Short Physical Performance Battery, and self-reported Late Life Function and Disability Instrument's Basic Lower Extremity and Advanced Lower Extremity function scales. Participants had a mean age of 76.6 years, and 42% were characterized with MCI. Participants with MCI performed significantly worse than participants without MCI (No-MCI) on all performance and self-report measures (p < .01). All MCI subtypes performed significantly worse than No-MCI on all mobility measures (p < .05) except for aMCI versus No-MCI on the Figure of 8 Walk (p = .054) and Basic Lower Extremity (p = .11). Moreover, compared with aMCI, mdMCI manifested worse performance on the Figure of 8 Walk and Short Physical Performance Battery, and naMCI manifested worse performance on Short Physical Performance Battery and Basic Lower Extremity. Among older community-dwelling primary care patients, performance on a broad range of mobility measures was worse among those with MCI, appearing poorest among those with nonmemory MCI.


A novel locus (RP24) for X-linked retinitis pigmentosa maps to Xq26-27.
Two genetic loci, RP2 and RP3, for X-linked retinitis pigmentosa (XLRP) have been localized to Xp11.3-11.23 and Xp21.1, respectively. RP3 appears to account for 70% of XLRP families; however, mutations in the RPGR gene (isolated from the RP3 region) are identified in only 20% of affected families. Close location of XLRP loci at Xp and a lack of unambiguous clinical criteria do not permit assignment of genetic subtype in a majority of XLRP families; nonetheless, in some pedigrees, both RP2 and RP3 could be excluded as the causative locus. We report the mapping of a novel locus, RP24, by haplotype and linkage analysis of a single XLRP pedigree. The RP24 locus was identified at Xq26-27 by genotyping 52 microsatellite markers spanning the entire X chromosome. A maximum LOD score of 4.21 was obtained with DXS8106. Haplotype analysis assigned RP24 within a 23-cM region between the DXS8094 (proximal) and DXS8043 (distal) markers. Other chromosomal regions and known XLRP loci were excluded by obligate recombination events between markers in those regions and the disease locus. Hemizygotes from the RP24 family have early onset of rod photoreceptor dysfunction; cone receptor function is normal at first, but there is progressive loss. Patients at advanced stages show little or no detectable rod or cone function and have clinical hallmarks of typical RP. Mapping of the RP24 locus expands our understanding of the genetic heterogeneity in XLRP and will assist in development of better tools for diagnosis.


Characterization of an N-Terminal Non-Core Domain of RAG1 Gene Disrupted Syrian Hamster Model Generated by CRISPR Cas9.
The accumulating evidence demonstrates that Syrian hamsters have advantages as models for various diseases. To develop a Syrian hamster (Mesocricetus auratus) model of human immunodeficiency caused by RAG1 gene mutations, we employed the CRISPR/Cas9 system and introduced an 86-nucleotide frameshift deletion in the hamster RAG1 gene encoding part of the N-terminal non-core domain of RAG1. Histological and immunohistochemical analyses demonstrated that these hamsters (referred herein as RAG1-86nt hamsters) had atrophic spleen and thymus, and developed significantly less white pulp and were almost completely devoid of splenic lymphoid follicles. The RAG1-nt86 hamsters had barely detectable CD3⁺ and CD4⁺ T cells. The expression of B and T lymphocyte-specific genes (CD3γ and CD4 for T cell-specific) and (CD22 and FCMR for B cell-specific) was dramatically reduced, whereas the expression of macrophage-specific (CD68) and natural killer (NK) cell-specific (CD94 and KLRG1) marker genes was increased in the spleen of RAG1-nt86 hamsters compared to wildtype hamsters. Interestingly, despite the impaired development of B and T lymphocytes, the RAG1-86nt hamsters still developed neutralizing antibodies against human adenovirus type C6 (HAdV-C6) upon intranasal infection and were capable of clearing the infectious viruses, albeit with slower kinetics. Therefore, the RAG1-86nt hamster reported herein (similar to the hypomorphic RAG1 mutations in humans that cause Omenn syndrome), may provide a useful model for studying the pathogenesis of the specific RAG1-mutation-induced human immunodeficiency, the host immune response to adenovirus infection and other pathogens as well as for evaluation of cell and gene therapies for treatment of this subset of RAG1 mutation patients.


Three-wave scattering in magnetized plasmas: From cold fluid to quantized Lagrangian.
Large amplitude waves in magnetized plasmas, generated either by external pumps or internal instabilities, can scatter via three-wave interactions. While three-wave scattering is well known in collimated geometry, what happens when waves propagate at angles with one another in magnetized plasmas remains largely unknown, mainly due to the analytical difficulty of this problem. In this paper, we overcome this analytical difficulty and find a convenient formula for three-wave coupling coefficient in cold, uniform, magnetized, and collisionless plasmas in the most general geometry. This is achieved by systematically solving the fluid-Maxwell model to second order using a multiscale perturbative expansion. The general formula for the coupling coefficient becomes transparent when we reformulate it as the scattering matrix element of a quantized Lagrangian. Using the quantized Lagrangian, it is possible to bypass the perturbative solution and directly obtain the nonlinear coupling coefficient from the linear response of the plasma. To illustrate how to evaluate the cold coupling coefficient, we give a set of examples where the participating waves are either quasitransverse or quasilongitudinal. In these examples, we determine the angular dependence of three-wave scattering, and demonstrate that backscattering is not necessarily the strongest scattering channel in magnetized plasmas, in contrast to what happens in unmagnetized plasmas. Our approach gives a more complete picture, beyond the simple collimated geometry, of how injected waves can decay in magnetic confinement devices, as well as how lasers can be scattered in magnetized plasma targets.


CXCR3 antagonism of SDF-1(5-67) restores trabecular function and prevents retinal neurodegeneration in a rat model of ocular hypertension.
Glaucoma, the most common cause of irreversible blindness, is a neuropathy commonly initiated by pathological ocular hypertension due to unknown mechanisms of trabecular meshwork degeneration. Current antiglaucoma therapy does not target the causal trabecular pathology, which may explain why treatment failure is often observed. Here we show that the chemokine CXCL12, its truncated form SDF-1(5-67), and the receptors CXCR4 and CXCR3 are expressed in human glaucomatous trabecular tissue and a human trabecular cell line. SDF-1(5-67) is produced under the control of matrix metallo-proteinases, TNF-α, and TGF-β2, factors known to be involved in glaucoma. CXCL12 protects in vitro trabecular cells from apoptotic death via CXCR4 whereas SDF-1(5-67) induces apoptosis through CXCR3 and caspase activation. Ocular administration of SDF-1(5-67) in the rat increases intraocular pressure. In contrast, administration of a selective CXCR3 antagonist in a rat model of ocular hypertension decreases intraocular pressure, prevents retinal neurodegeneration, and preserves visual function. The protective effect of CXCR3 antagonism is related to restoration of the trabecular function. These data demonstrate that proteolytic cleavage of CXCL12 is involved in trabecular pathophysiology, and that local administration of a selective CXCR3 antagonist may be a beneficial therapeutic strategy for treating ocular hypertension and subsequent retinal degeneration.


Balancing systematic and flexible exploration of social networks.
Social network analysis (SNA) has emerged as a powerful method for understanding the importance of relationships in networks. However, interactive exploration of networks is currently challenging because: (1) it is difficult to find patterns and comprehend the structure of networks with many nodes and links, and (2) current systems are often a medley of statistical methods and overwhelming visual output which leaves many analysts uncertain about how to explore in an orderly manner. This results in exploration that is largely opportunistic. Our contributions are techniques to help structural analysts understand social networks more effectively. We present SocialAction, a system that uses attribute ranking and coordinated views to help users systematically examine numerous SNA measures. Users can (1) flexibly iterate through visualizations of measures to gain an overview, filter nodes, and find outliers, (2) aggregate networks using link structure, find cohesive subgroups, and focus on communities of interest, and (3) untangle networks by viewing different link types separately, or find patterns across different link types using a matrix overview. For each operation, a stable node layout is maintained in the network visualization so users can make comparisons. SocialAction offers analysts a strategy beyond opportunism, as it provides systematic, yet flexible, techniques for exploring social networks.


Likelihood that a woman with screen-detected breast cancer has had her "life saved" by that screening.
Perhaps the most persuasive messages promoting screening mammography come from women who argue that the test "saved my life." Because other possibilities exist, we sought to determine how often lives were actually saved by mammography screening. We created a simple method to estimate the probability that a woman with screen-detected breast cancer has had her life saved because of screening. We used DevCan, the National Cancer Institute's software for analyzing Surveillance Epidemiology and End Results (SEER) data, to estimate the 10-year risk of diagnosis and the 20-year risk of death--a time horizon long enough to capture the downstream benefits of screening. Using a range of estimates on the ability of screening mammography to reduce breast cancer mortality (relative risk reduction [RRR], 5%-25%), we estimated the risk of dying from breast cancer in the presence and absence of mammography in women of various ages (ages 40, 50, 60, and 70 years). We found that for a 50-year-old woman, the estimated risk of having a screen-detected breast cancer in the next 10 years is 1910 per 100,000. Her observed 20-year risk of breast cancer death is 990 per 100,000. Assuming that mammography has already reduced this risk by 20%, the risk of death in the absence of screening would be 1240 per 100,000, which suggests that the mortality benefit accrued to 250 per 100,000. Thus, the probability that a woman with screen-detected breast cancer avoids a breast cancer death because of mammography is 13% (250/1910). This number falls to 3% if screening mammography reduces breast cancer mortality by 5%. Similar analyses of women of different ages all yield probability estimates below 25%. Most women with screen-detected breast cancer have not had their life saved by screening. They are instead either diagnosed early (with no effect on their mortality) or overdiagnosed.


Outcomes in Patients with Helicobacter pylori Undergoing Laparoscopic Sleeve Gastrectomy.
In vertical sleeve gastrectomy (VSG), the majority of the stomach is resected and much of the tissue colonized with Helicobacter pylori and the bulk of acid producing cells are removed. In addition, the effect of H. pylori colonization of the stomach of patients undergoing stapling procedures is unclear. As a result, the need for detection and treatment of H. pylori in patients undergoing VSG is unknown. Four hundred and eighty patients undergoing VSG are the subject of this study. Three surgeons at a single institution performed the procedures. The remnant stomach was sent to pathology and tested for the presence of H. pylori using immunohistochemistry. All patients were discharged on proton pump inhibitors. Of the 480 patients who underwent VSG, 52 were found to be H. pylori positive based on pathology. There was no statistically significant difference in age (p = 0.77), sex (p = 0.48), or BMI (p = 0.39) between the groups. There were 17 readmissions post-op. Five of these were in the H. pylori positive cohort. Six of these complications were classified as severe (anastomotic leak, intra-abdominal collection, or abscess), with two in the H. pylori positive cohort (Table 1). There was no statistically significant difference in the severe complication rates between the two groups (p = 0.67). There were no readmissions for gastric or duodenal ulceration or perforation. Our data suggests that there is no increase in early complications in patients with H. pylori undergoing VSG. If these findings are confirmed in a long-term follow-up, it would mean that preoperative H. pylori screening in patients scheduled for VSG is not necessary.


Periprocedural blood pressure management in neurointerventional surgery.
With the increasing range of conditions currently amenable to endovascular therapies, the knowledge of periprocedural blood pressure management is essential for the neurointerventional surgeon. This review discusses the physiology of cerebral blood flow and blood pressure, monitoring options for neurointerventional patients, useful agents for blood pressure elevation and reduction and neuroanesthetic considerations during procedures with an emphasis on practical decision-making. Also included are parameters for conditions typically encountered in the neurointerventional suite based on best available evidence, with reference to blood pressure management before, during and after neurointerventional therapy.


Single-dose therapy of Falciparum malaria using pyrimethamine in combination with diformyldapsone or sulfadoxine.
Patients with naturally acquired chloroquine-resistant falciparum malaria were studied in Thailand. The fixed combination of pyrimethamine 75 mg and sulfadoxine 1,500 mg (adult dose) cured 85% of patients with an average pretreatment parasite count of 60,000 per mm(3). The fixed combination of pyrimethamine 50 mg and 800 mg diformyldapsone (DFD) cured 43% of patients with an average pretreatment parasite count of only 17,000 per mm(3). The difference in cure rates was statistically significant (p less than 0.01). Pyrimethamine alone was ineffective. Pyrimethamine-DFD, in the dose tested, was not sufficiently active for the treatment of established infections. Pyrimethamine-sulfadoxine did produce an acceptable cure rate but clinical improvement was often slow. We do not recommend that pyrimethamine-sulfadoxine be administered alone. Optimal results are obtained when a short course of quinine (2 to 6 days) is given until parasitemia has been eliminated, then a dose of pyrimethamine-sulfadoxine to assist in the radical cure of the falciparum infection. A modification to the W.H.O. classification is suggested. An RIII response (early treatment failure) is diagnosed if the patient's clinical condition and/or parsite density worsens within a few hours after administration of the test regimen; distinct improvement occurring within a few hours of the subsequent initiation of an intravenous infusion of quinine confirms the diagnosis of an RIII response. The RII response has been defined as marked reduction, but not clearance of asexual parasitemia. It is suggested that an RII response may be diagnosed before 7 days have elapsed.


The elbow.
Computed tomography (CT) and magnetic resonance imaging (MRI) are noninvasive methods of imaging the canine cubital joint. CT images are typically acquired using contiguous 1-mm slices, a bone reconstruction algorithm, and a field of view large enough to scan both elbows simultaneously. CT provides a detailed assessment of the medial coronoid process (MCP), radial incisure, anconeal process, and trochlear notch of the ulna; the humeral condyle; joint congruity; and osteoarthrosis. With MRI, use of a surface coil and 3D Fourier transformation gradient echo fast imaging sequences allow contiguous thin slices to be obtained. Both imaging techniques appear to be highly effective in the evaluation of elbow dysplasia, particularly for the detection of MCP fragmentation, although MRI is superior to CT for identifying nonmineralized cartilaginous fragments.


Covalent modification of the homeodomain-interacting protein kinase 2 (HIPK2) by the ubiquitin-like protein SUMO-1.
Posttranslational modifications such as ubiquitination and phosphorylation play an important role in the regulation of cellular protein function. Homeodomain-interacting protein kinase 2 (HIPK2) is a member of the recently identified family of nuclear protein kinases that act as corepressors for homeodomain transcription factors. Here, we show that HIPK2 is regulated by a ubiquitin-like protein, SUMO-1. We demonstrate that HIPK2 localizes to nuclear speckles (dots) by means of a speckle-retention signal. This speckle-retention signal contains a domain that interacts with a mouse ubiquitin-like protein conjugating (E2) enzyme, mUBC9. In cultured cells, HIPK2 is covalently modified by SUMO-1, and the SUMO-1 modification of HIPK2 correlates with its localization to nuclear speckles (dots). Thus, our results provide firm evidence that the nuclear protein kinase HIPK2 can be covalently modified by SUMO-1, which directs its localization to nuclear speckles (dots).


Traveling reference spectroradiometer for routine quality assurance of spectral solar ultraviolet irradiance measurements.
A transportable reference spectroradiometer for measuring spectral solar ultraviolet irradiance has been developed and validated. The expanded uncertainty of solar irradiance measurements with this reference spectroradiometer, based on the described methodology, is 8.8% to 4.6%, depending on the wavelength and the solar zenith angle. The accuracy of the spectroradiometer was validated by repeated site visits to two European UV monitoring sites as well as by regular comparisons with the reference spectroradiometer of the European Reference Centre for UV radiation measurements in Ispra, Italy. The spectral solar irradiance measurements of the Quality Assurance of Spectral Ultraviolet Measurements in Europe through the Development of a Transportable Unit (QASUME) spectroradiometer and these three spectroradiometers have agreed to better than 6% during the ten intercomparison campaigns held from 2002 to 2004. If the differences in irradiance scales of as much as 2% are taken into account, the agreement is of the order of 4% over the wavelength range of 300-400 nm.


Role of isozymes of cytochrome P-450 in the metabolism of N,N-dimethyl-4-aminoazobenzene in the rat.
The metabolism of N,N-dimethyl-4-aminoazobenzene (DAB) was investigated in vitro by use of hepatic 10,000g supernatant fraction, microsomes, and purified cytochromes P-450 prepared from rats. Position-selective metabolism was studied in response to induction by 3-methylcholanthrene (MC), phenobarbital (PB), beta-naphthoflavone (BNF), and pregnenolone-16 alpha-carbonitrile (PCN) as well as inhibition by SKF 525-A, metyrapone, alpha-naphthoflavone, and piperonyl butoxide. The principal phase I pathways are demethylation of the tertiary (DAB) and secondary (MAB) amines and ring hydroxylation. When metabolism was measured with 10,000g supernatant fractions, each pathway responded differently and often independently to the inducers and inhibitors, suggesting that they are catalyzed preferentially by different isozymes of cytochrome P-450. Microsomes from PB-treated animals demethylated and hydroxylated DAB at the same rate as did control microsomes, based on cytochrome P-450 content, whereas microsomes from BNF- or MC-treated animals demethylated more rapidly and hydroxylated more slowly. Microsomes from PB-treated animals demethylated the secondary amine, MAB, more rapidly than the tertiary amine, DAB. Purified cytochrome P-448 from MC-treated animals catalyzed DAB demethylation very readily but hydroxylation very poorly. The turnover number was 10 times that seen in microsomes from MC-treated animals. Only one of the four cytochrome P-450 fractions isolated from PB-treated animals had significant activity with DAB and the turnover number of one of these (fraction B) was approximately that seen in microsomes. This study supports the concept of selectivity of various isozymes of cytochrome P-450 for the different steps in phase I metabolism of DAB. Furthermore, it is apparent that the association of certain inhibitors with specific isozymes of cytochrome P-450 is a generalization that requires qualification in terms of the substrates(s) involved.


Molecular epidemiology of Chagas disease in the wild transmission cycle: the evaluation in the sylvatic vector Mepraia spinolai from an endemic area of Chile.
The sylvatic transmission cycle of Chagas disease in Chile is composed of wild mammals and insects of the genus Mepraia. We determined infection rates and Trypanosoma cruzi genotypes in Mepraia spinolai. We collected 227 insects from two ecologically contrasting areas to assess T. cruzi infection. Polymerase chain reaction (PCR)-amplified minicircle DNAs were characterized by Southern blot and hybridization tests with genotype-specific probes. Infection in insects from the more fertile area was almost 2-fold higher than in the poorer area. The genotype TCI was the most prevalent and other genotypes such as TCIIb, TCIId, and TCIIe were found at lower rates. The areas differed in their genotype distribution but not in their genotype diversity. We suggest that the difference in abundance and richness of mammals between the areas may be producing the detected infection levels in vectors. Our results are compared with those reported for mammals from the same area.


Biocatalytic carbon nanotube paper: a 'one-pot' route for fabrication of enzyme-immobilized membranes for organophosphate bioremediation.
Recent world events have demonstrated the critical need for facile and miniaturized bioremediation technologies for organophosphates (OPs). These compounds are among the most toxic substances synthesized to date and are used as pesticides and nerve agents. Biotechnological methods based on the use of organophosphate hydrolase (OPH) for detoxification of OPs have drawn significant attention. This work presents a new 'one-pot' methodology for a rapid and straightforward fabrication of enzymatically active carbon nanotube (CNT) paper for OP bioremediation. Carboxylated CNTs are ultrasonically dispersed in an aqueous surfactant solution followed by a microfiltration process to generate a paper-like membrane, which is assembled from entangled nanotubes. Herein, OPH conjugation to the CNTs is carried out by carbodiimide chemistry during the microfiltration process. Successful covalent immobilization of the enzyme onto the nanotube surface is confirmed by cryo-transmission electron microscopy and infrared spectroscopy. To study the potential of this platform for OP bioremediation, an aqueous solution of methyl paraoxon (used as a model OP) is filtered with the resulting OPH-CNT membranes. A significant decrease of methyl paraoxon concentration is achieved, which is ascribed to its in situ hydrolysis by the immobilized OPH during the filtration process. These thin membranes allow many subsequent filtration cycles to be performed, while maintaining their enzymatic activity, owing to the unique combination of the mechanically robust CNT scaffold and high OPH loading. This study presents a new generic approach for the design of bioactive paper-like scaffolds, which can be rationally tailored for a variety of applications.


Angioplasty versus stenting for iliac artery lesions.
Atherosclerosis of the iliac artery may result in a stenosis or occlusion, which is defined as iliac artery occlusive disease. A range of surgical and endovascular treatment options are available. Open surgical procedures have excellent patency rates but at the cost of substantial morbidity and mortality. Endovascular treatment has good safety and short-term efficacy with decreased morbidity, complications and costs compared with open surgical procedures. Both percutaneous transluminal angioplasty (PTA) and stenting are commonly used endovascular treatment options for iliac artery occlusive disease. A stenotic or occlusive lesion of the iliac artery can be treated successfully by PTA alone. If PTA alone is technically unsuccessful, additional stent placement is indicated. Alternatively, a stent could be placed primarily to treat an iliac artery stenosis or occlusion (primary stenting, PS). However, there is limited evidence to prove which endovascular treatment strategy is superior for stenotic and occlusive lesions of the iliac arteries. To assess the effects of percutaneous transluminal angioplasty versus primary stenting for stenotic and occlusive lesions of the iliac artery. The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2015) and Cochrane Register of Studies (CRS) (2015, Issue 3). The TSC searched trial databases for details of ongoing and unpublished studies. We included all randomised controlled trials (RCTs) comparing percutaneous transluminal angioplasty and primary stenting for iliac artery occlusive disease. We excluded quasi-randomised trials, case reports, case-control or cohort studies. We excluded no studies based on the language of publication. Two authors (JB, NA) independently selected suitable trials. JB and HJ independently performed data extraction and trial quality assessment. When there was disagreement, consensus would be reached first by discussion among both authors and, if still no consensus could be reached, through consultation with BF. We identified two RCTs with a combined total of 397 participants as meeting the selection criteria. One study included mostly stenotic lesions (95%), whereas the second study included only iliac artery occlusions. Both studies were of moderate methodological quality with some risk of bias relating to selective reporting and non-blinding of participants and personnel. The overall quality of evidence was low due to the small number of included studies, the differences in study populations and definitions of the outcome variables. Due to the heterogeneity among these two studies it was not possible to pool the data. Percutaneous transluminal angioplasty (PTA) with selective stenting and primary stenting (PS) resulted in similar improvement in the stage of peripheral arterial occlusive disease according to Rutherford's criteria, resolution of symptoms and signs, improvement of quality of life, technical success of the procedure and patency of the treated vessel. Improvement in walking distance as reported by the patient, measured claudication distance, ulcer healing, major amputation-free survival and delayed complications (> 72 hours) were not reported in either of the studies. In one trial, PTA of iliac artery occlusions resulted in a significantly higher rate of major complications, especially distal embolisation. The other trial showed a significantly higher mean ankle brachial index (ABI) at two years in the PTA group (1.0) compared to the mean ABI in the PS group (0.91); mean difference (MD) 0.09 (95% confidence interval (CI) 0.04 to 0.14; P value = 0.001, analysis performed by review authors). However, at other time points there was no difference. We consider it unlikely that this difference is attributable to the study procedure, and also believe this difference may not be clinically relevant. There is insufficient evidence to assess the effects of PTA versus PS for stenotic and occlusive lesions of the iliac artery. From one study it appears that PS in iliac artery occlusions may result in lower distal embolisation rates. More studies are required to come to a firm conclusion.


Factors affecting maternal nutrition and health: A qualitative study in a matrilineal community in Indonesia.
The Minangkabau people of West Sumatra in Indonesia are renowned for their matrilineal culture with property and land passing down from mother to daughter. Despite there being a fairly balanced social status for women in the community, the impact of health inequalities is uneven. This study was therefore carried out to explore the relationship between the social, cultural and economic contexts in such a distinctive community with maternal nutrition and pregnancy-related health outcomes, from the perspectives of the mothers, fathers and care providers. Qualitative methods were used to undertake this study in collaboration with partners from the University of Andalas in a suburban area of Padang district. The data collection method was qualitative, semi-structured interviews (n = 19) with women, men, midwives and community health workers. The data were recorded with informed consent, transcribed in the local language and then translated into English prior to being thematically analysed. The major themes which emerged from the data included 'Minangkabau matrilineality and role of women'; 'culture and supportive attitude towards pregnant women'; 'dietary patterns, attitude and access to food'; and 'limited access to information about food and nutrition'. The findings showed healthy dietary patterns such as regular consumption of vegetables and fruit among the participants. However, the issues of poverty, access to food, dietary taboos and inadequate nutritional information remained major challenges for the mothers and the families who participated in the study. The evidence from this study suggests that the matrilineal culture of the Minangkabau promotes the empowerment of women and offers an encouraging environment for enhancing reproductive health. This lends itself to co-developing locally sensitive and sustainable complex interventions incorporating professional support and building on family and community back-up, enhancing knowledge and demystifying dietary misinformation to improve maternal health and nutrition.


Genome Complexity Reduction High-Throughput Genome Sequencing of Green Iguana (Iguana iguana) Reveal a Paradigm Shift in Understanding Sex-Chromosomal Linkages on Homomorphic X and Y Sex Chromosomes.
The majority of lizards classified in the superfamily Iguanoidea have an XX/XY sex-determination system in which sex-chromosomal linkage shows homology with chicken (Gallus gallus) chromosome 15 (GGA15). However, the genomics of sex chromosomes remain largely unexplored owing to the presence of homomorphic sex chromosomes in majority of the species. Recent advances in high-throughput genome complexity reduction sequencing provide an effective approach to the identification of sex-specific loci with both single-nucleotide polymorphisms (SNPs) and restriction fragment presence/absence (PA), and a better understanding of sex chromosome dynamics in Iguanoidea. In this study, we applied Diversity Arrays Technology (DArTseqTM) in 29 phenotypic sex assignments (14 males and 15 females) of green iguana (Iguana iguana). We confirmed a male heterogametic (XX/XY) sex determination mode in this species, identifying 29 perfectly sex-linked SNP/PA loci and 164 moderately sex-linked SNP/PA loci, providing evidence probably indicative of XY recombination. Three loci from among the perfectly sex-linked SNP/PA loci showed partial homology with several amniote sex chromosomal linkages. The results support the hypothesis of an ancestral super-sex chromosome with overlaps of partial sex-chromosomal linkages. However, only one locus among the moderately sex-linked loci showed homology with GGA15, which suggests that the specific region homologous to GGA15 was located outside the non-recombination region but in close proximity to this region of the sex chromosome in green iguana. Therefore, the location of GGA15 might be further from the putative sex-determination locus in green iguana. This is a paradigm shift in understanding linkages on homomorphic X and Y sex chromosomes. The DArTseq platform provides an easy-to-use strategy for future research on the evolution of sex chromosomes in Iguanoidea, particularly for non-model species with homomorphic or highly cryptic sex chromosomes.


Developing and Implementing a Quality Assurance Strategy for Electroconvulsive Therapy.
The literature provides scant guidance in effective quality assurance strategies concerning the use of electroconvulsive therapy (ECT) for the treatment of psychiatric conditions. Numerous guidelines are published that provide guidance in the delivery of care; however, little has been done to determine how a program or facility might ensure compliance to best practice for safety, tolerability, and efficacy in performing ECT. The objective of this project was to create a quality assurance strategy specific to ECT. Determining standards for quality care and clarifying facility policy were key outcomes in establishing an effective quality assurance strategy. An audit tool was developed utilizing quality criteria derived from a systematic review of ECT practice guidelines, peer review, and facility policy. All ECT procedures occurring over a 2-month period of May to June 2017 were retrospectively audited and compared against target compliance rates set for the facility's ECT program. Facility policy was adapted to reflect quality standards, and audit findings were used to inform possible practice change initiatives, were used to create benchmarks for continuous quality monitoring, and were integrated into regular hospital quality meetings. Clarification on standards of care and the use of clinical auditing in ECT was an effective starting point in the development of a quality assurance strategy. Audit findings were successfully integrated into the hospital's overall quality program, and recognition of practice compliance informed areas for future quality development and policy revision in this small community-based hospital in the southeastern United States. This project sets the foundation for a quality assurance strategy that can be used to help monitor procedural safety and guide future improvement efforts in delivering ECT. Although it is just the first step in creating meaningful quality improvement, setting clear standards and identifying areas of greatest clinical need were crucial beginning for this hospital's growing program.


Medullar Kock without Pott: 13 cases observed at the university hospital center of Conakry, Guinea.
Background: The diagnostic certainty of medullar tuberculosis (TB) without Pott disease is difficult to establish in a tropical environment with the large group of infectious, parasitic, and systemic myelopathies, despite the increasing availability of magnetic resonance imaging (MRI) data and improvement of biological exploration platforms. Methods: We retrospectively analyzed the files of 186 patients hospitalized in the Department of Neurology and Neurosurgery of the University Hospital Center of Conakry, Guinea, between 2008 and 2016 for the management of non-compressive and compressive myelopathy. Biological evidence of TB infection was demonstrated for 13 (6.9%) patients. Results: Infectious clinical picture prior to the development of neurological signs was reported in 11 patients (84.6%). The neurological signs were summed up by the existence of a sensitivo-motor semiology of progressive evolution (100% of cases) with sphincter disorders in 11 patients (84.6%) and a medullary compression symptomatology with a lesion and under lesion syndrome from the outset in 4 patients (30.8%). Medullary MRI revealed an extensive intramedullary hypersignal in 9 patients with non-compressive myelopathy and in 4 cases, the lesions appeared in T1 hypersignal and T2 isosignal were localized. Lumbar puncture (LP) revealed lymphocytic pleocytosis, hypoglucorrhage (0.3 to 0.5 g/l), and leukocytosis. Conclusion: This study reveals a classic clinical, biological, neuroradiological, and evolutionary profile of compressive and non-compressive myelopathies. These results are important for the therapeutic and evolutionary discussion of TB myelopathies for good management.


A quantitative analysis of contractility in active cytoskeletal protein networks.
Cells actively produce contractile forces for a variety of processes including cytokinesis and motility. Contractility is known to rely on myosin II motors which convert chemical energy from ATP hydrolysis into forces on actin filaments. However, the basic physical principles of cell contractility remain poorly understood. We reconstitute contractility in a simplified model system of purified F-actin, muscle myosin II motors, and alpha-actinin cross-linkers. We show that contractility occurs above a threshold motor concentration and within a window of cross-linker concentrations. We also quantify the pore size of the bundled networks and find contractility to occur at a critical distance between the bundles. We propose a simple mechanism of contraction based on myosin filaments pulling neighboring bundles together into an aggregated structure. Observations of this reconstituted system in both bulk and low-dimensional geometries show that the contracting gels pull on and deform their surface with a contractile force of approximately 1 microN, or approximately 100 pN per F-actin bundle. Cytoplasmic extracts contracting in identical environments show a similar behavior and dependence on myosin as the reconstituted system. Our results suggest that cellular contractility can be sensitively regulated by tuning the (local) activity of molecular motors and the cross-linker density and binding affinity.


High vancomycin resistance among biofilms produced by Staphylococcus species isolated from central venous catheters.
Biofilm production is an important mechanism that allows microbes to escape host defences and antimicrobial therapy. Vancomycin has been used largely for the treatment of methicillin-resistant staphylococcal infections. Here, we determined the minimal inhibitory concentration (MIC) and minimal biofilm eradication concentration (MBEC) for 82 Staphylococcus species isolated from central venous catheters (CVC). Our results showed that the 41 strong and moderate-biofilm-producing isolates presented a higher MBEC/MIC ratio for vancomycin than the 24 weak-biofilm-producing isolates, illustrating the importance of biofilm production ability and the difficulty in treating biofilm-related infections. The MBEC was significantly higher in moderate-biofilm-producing isolates than in weak-biofilm-producing isolates (p < 0.001) and in strong-biofilm-producing isolates than in weak-biofilm-producing isolates (p = 0.001). The correlation between the MIC and the MBEC was poor. Based on our results, we recommend that bacterial biofilms be suspected in all cases of CVC infection.


Nitrate from Drinking Water and Diet and Bladder Cancer Among Postmenopausal Women in Iowa.
Nitrate is a drinking water contaminant arising from agricultural sources, and it is a precursor in the endogenous formation of N-nitroso compounds (NOC), which are possible bladder carcinogens. We investigated the ingestion of nitrate and nitrite from drinking water and diet and bladder cancer risk in women. We identified incident bladder cancers among a cohort of 34,708 postmenopausal women in Iowa (1986-2010). Dietary nitrate and nitrite intakes were estimated from a baseline food frequency questionnaire. Drinking water source and duration were assessed in a 1989 follow-up. For women using public water supplies (PWS) > 10 years (n = 15,577), we estimated average nitrate (NO3-N) and total trihalomethane (TTHM) levels and the number of years exceeding one-half the maximum contaminant level (NO3-N: 5 mg/L, TTHM: 40 μg/mL) from historical monitoring data. We computed hazard ratios (HRs) and 95% confidence intervals (CIs), and assessed nitrate interactions with TTHM and with modifiers of NOC formation (smoking, vitamin C). We identified 258 bladder cancer cases, including 130 among women > 10 years at their PWS. In multivariable-adjusted models, we observed nonsignificant associations among women in the highest versus lowest quartile of average drinking water nitrate concentration (HR = 1.48; 95% CI: 0.92, 2.40; ptrend = 0.11), and we found significant associations among those exposed ≥ 4 years to drinking water with > 5 mg/L NO3-N (HR = 1.62; 95% CI: 1.06, 2.47; ptrend = 0.03) compared with women having 0 years of comparable exposure. TTHM adjustment had little influence on associations, and we observed no modification by vitamin C intake. Relative to a common reference group of never smokers with the lowest nitrate exposures, associations were strongest for current smokers with the highest nitrate exposures (HR = 3.67; 95% CI: 1.43, 9.38 for average water NO3-N and HR = 3.48; 95% CI: 1.20, 10.06 and ≥ 4 years > 5 mg/L, respectively). Dietary nitrate and nitrite intakes were not associated with bladder cancer. Long-term ingestion of elevated nitrate in drinking water was associated with an increased risk of bladder cancer among postmenopausal women. Citation: Jones RR, Weyer PJ, DellaValle CT, Inoue-Choi M, Anderson KE, Cantor KP, Krasner S, Robien K, Beane Freeman LE, Silverman DT, Ward MH. 2016. Nitrate from drinking water and diet and bladder cancer among postmenopausal women in Iowa. Environ Health Perspect 124:1751-1758; http://dx.doi.org/10.1289/EHP191.


Harm Reduction and electronic gambling machines: does this pair make a happy couple or is divorce foreseen?
Recent empirical studies have evaluated if modifying electronic gambling machine (EGM) structural features could encourage safer gambling behaviors and decrease gambling-related problems. Several of these studies refer to Harm Reduction (HR), suggesting that the HR paradigm is useful to design, implement and test the efficacy of various prevention and treatment programs applied to EGM users. After reviewing the origins of HR and specifying its operational definition, this paper discusses the relevance of the HR framework for the study of measures related to EGM use and gambling in general. Examples are given to illustrate the arguments. The results show that HR has been over-inclusive in the field of gambling. A specific and operational definition and application of the HR framework is required for HR to be useful for the advancement of research in the gambling field.


Ubiquitous interplay between charge ordering and high-temperature superconductivity in cuprates.
Besides superconductivity, copper-oxide high-temperature superconductors are susceptible to other types of ordering. We used scanning tunneling microscopy and resonant elastic x-ray scattering measurements to establish the formation of charge ordering in the high-temperature superconductor Bi2Sr2CaCu2O(8+x). Depending on the hole concentration, the charge ordering in this system occurs with the same period as those found in Y-based or La-based cuprates and displays the analogous competition with superconductivity. These results indicate the similarity of charge organization competing with superconductivity across different families of cuprates. We observed this charge ordering to leave a distinct electron-hole asymmetric signature (and a broad resonance centered at +20 milli-electron volts) in spectroscopic measurements, indicating that it is likely related to the organization of holes in a doped Mott insulator.


Integrating circadian activity and gene expression profiles to predict chronotoxicity of Drosophila suzukii response to insecticides.
Native to Southeast Asia, Drosophila suzukii (Matsumura) is a recent invader that infests intact ripe and ripening fruit, leading to significant crop losses in the U.S., Canada, and Europe. Since current D. suzukii management strategies rely heavily on insecticide usage and insecticide detoxification gene expression is under circadian regulation in the closely related Drosophila melanogaster, we set out to determine if integrative analysis of daily activity patterns and detoxification gene expression can predict chronotoxicity of D. suzukii to insecticides. Locomotor assays were performed under conditions that approximate a typical summer or winter day in Watsonville, California, where D. suzukii was first detected in North America. As expected, daily activity patterns of D. suzukii appeared quite different between 'summer' and 'winter' conditions due to differences in photoperiod and temperature. In the 'summer', D. suzukii assumed a more bimodal activity pattern, with maximum activity occurring at dawn and dusk. In the 'winter', activity was unimodal and restricted to the warmest part of the circadian cycle. Expression analysis of six detoxification genes and acute contact bioassays were performed at multiple circadian times, but only in conditions approximating Watsonville summer, the cropping season, when most insecticide applications occur. Five of the genes tested exhibited rhythmic expression, with the majority showing peak expression at dawn (ZT0, 6am). We observed significant differences in the chronotoxicity of D. suzukii towards malathion, with highest susceptibility at ZT0 (6am), corresponding to peak expression of cytochrome P450s that may be involved in bioactivation of malathion. High activity levels were not found to correlate with high insecticide susceptibility as initially hypothesized. Chronobiology and chronotoxicity of D. suzukii provide valuable insights for monitoring and control efforts, because insect activity as well as insecticide timing and efficacy are crucial considerations for pest management. However, field research is necessary for extrapolation to agricultural settings.


Apathy is associated with poor prognosis in amyotrophic lateral sclerosis.
Apathy is the most commonly reported behavioural change in amyotrophic lateral sclerosis (ALS). However, the degree to which it affects prognosis and overlaps with depression in this population is unknown. The present study examined the relationship between level of apathy, mortality and survival time and whether apathy was linked to specific symptom clusters of depression. A cohort of 76 consecutive ALS patients attending specialized multidisciplinary clinics were classified according to level of apathy. The effects of clinical factors and apathy on survival time were analysed using univariate and multivariate methods. The majority of patients with moderate to severe apathy died during the study (P = 0.003) and had a median survival time of 21.7 months, considerably shorter than patients with mild apathy (46.9 months) and no apathy (51.9 months) (P = 0.0001). Apathy remained a significant predictor of survival even after controlling for clinical factors and symptom duration at the time of study entry (hazard ratio 3.8, 95% confidence interval 1.9-7.5, P = 0.0001). Depression with demoralization was not associated with level of apathy (P = 0.172) whereas depression with anhedonia was more common in patients with apathy than in those without apathy (P = 0.006). The presence of severe apathy is an independent, negative prognostic factor in ALS.


Comparative genomics of the major parasitic worms.
Parasitic nematodes (roundworms) and platyhelminths (flatworms) cause debilitating chronic infections of humans and animals, decimate crop production and are a major impediment to socioeconomic development. Here we report a broad comparative study of 81 genomes of parasitic and non-parasitic worms. We have identified gene family births and hundreds of expanded gene families at key nodes in the phylogeny that are relevant to parasitism. Examples include gene families that modulate host immune responses, enable parasite migration though host tissues or allow the parasite to feed. We reveal extensive lineage-specific differences in core metabolism and protein families historically targeted for drug development. From an in silico screen, we have identified and prioritized new potential drug targets and compounds for testing. This comparative genomics resource provides a much-needed boost for the research community to understand and combat parasitic worms.


Effect of freezing conditions on distances and their distributions derived from Double Electron Electron Resonance (DEER): a study of doubly-spin-labeled T4 lysozyme.
Pulsed dipolar ESR spectroscopy, DEER and DQC, require frozen samples. An important issue in the biological application of this technique is how the freezing rate and concentration of cryoprotectant could possibly affect the conformation of biomacromolecule and/or spin-label. We studied in detail the effect of these experimental variables on the distance distributions obtained by DEER from a series of doubly spin-labeled T4 lysozyme mutants. We found that the rate of sample freezing affects mainly the ensemble of spin-label rotamers, but the distance maxima remain essentially unchanged. This suggests that proteins frozen in a regular manner in liquid nitrogen faithfully maintain the distance-dependent structural properties in solution. We compared the results from rapidly freeze-quenched (≤100 μs) samples to those from commonly shock-frozen (slow freeze, 1 s or longer) samples. For all the mutants studied we obtained inter-spin distance distributions, which were broader for rapidly frozen samples than for slowly frozen ones. We infer that rapid freezing trapped a larger ensemble of spin label rotamers; whereas, on the time-scale of slower freezing the protein and spin-label achieve a population showing fewer low-energy conformers. We used glycerol as a cryoprotectant in concentrations of 10% and 30% by weight. With 10% glycerol and slow freezing, we observed an increased slope of background signals, which in DEER is related to increased local spin concentration, in this case due to insufficient solvent vitrification, and therefore protein aggregation. This effect was considerably suppressed in slowly frozen samples containing 30% glycerol and rapidly frozen samples containing 10% glycerol. The assignment of bimodal distributions to tether rotamers as opposed to protein conformations is aided by comparing results using MTSL and 4-Bromo MTSL spin-labels. The latter usually produce narrower distance distributions.


Operable conditions of the beam-fanning novelty filter for the c axis and the incident angle.
We analyze the operable angle range of the c axis and the incident angle of the input beam in the beam-fanning novelty filter (BFNF). With Fourier transforms we show the analysis method for the beam-fanning phenomenon. We investigate the beam-fanning phenomenon for not only the c axis but also the incident angle of the input beam in order to operate the BFNF sufficiently. Consequently, we clarify the angle range of the c axis and the incident angle, from which sufficient strong beam-fanning effect can be obtained to operate the BFNF. In addition, we verify the numerical results experimentally.