Time to seroconversion in HIV-exposed subjects carrying protective versus non protective KIR3DS1/L1 and HLA-B genotypes.
Natural killer (NK) cells play a role in the clearance of viral infections. Combinations of alleles at the polymorphic HLA-B locus and the NK cell surface killer immunoglobulin-like receptor locus KIR3DL1/S1 have been shown to influence time to AIDS in HIV-infected individuals and risk of seroconversion in HIV exposed seronegative (HESN) subjects. Here, we assessed time to seroconversion or duration of seronegative status in a group of 168 HIV exposed individuals, including 74 seroconverters and 94 HESN based on carriage or not of KIR3DL1/S1/HLA-B genotypes previously shown to be associated with protection from infection and/or slow time to AIDS. KIR3DL1/S1 genotyping was performed by sequence-specific primer polymerase chain reaction using two pairs of specific primers for each locus. The MHC class IB locus was typed to four-position resolution to resolve Bw4 and Bw6 alleles and the amino acid present at position 80. KIR3DL1/S1 heterozygotes became HIV infected significantly faster than KIR3DS1 homozygotes. Individuals who carried both KIR3DS1 and Bw4*80I did not remain HIV seronegative longer than those from a control group who were homozygous for HLA-Bw6 and carried no HLA-A locus Bw4 alleles Subjects who were *h/*y+B*57 showed a trend towards slower time to serconversion than those with other KIR3DL1 homozygous and KIR3DL1/S1 heterozygous genotypes. Thus, KIR3DS1 homozygosity is associated with protection from HIV infection while co-carriage of KIR3DS1 and Bw4*80I is not. The requirements for protection from HIV infection can differ from those that influence time to AIDS in HIV infected individuals.


Allogeneic bone marrow transplantation for children with acute leukemia: long-term follow-up of patients prepared with high-dose cytosine arabinoside and fractionated total body irradiation.
High-dose therapy and allogeneic matched sibling bone marrow transplantation (BMT) is considered to be the treatment of choice for children with relapsed acute lymphoblastic leukemia (ALL), or for children with acute myeloid leukemia (AML) in first remission. However, the rate of bone marrow relapse after transplant for either of these diseases remains high. In this study, we assessed the efficacy and toxicity of high-dose cytosine arabinoside and total body irradiation (TBI) followed by allogeneic BMT, for children with acute leukemia or myelodysplastic syndrome (MDS). Sixty-five pediatric patients underwent allogeneic related (n = 57) or unrelated (n = 8) BMT. Twenty-seven were transplanted for ALL in second remission (CR2), and 16 for AML in first remission (CR1). The other 22 were high risk patients: six were transplanted for ALL in third remission (CR3), two for AML in CR2, two for myelodysplastic syndrome (MDS) and 12 for acute leukemia in relapse. Patients were prepared with cytosine arabinoside 3000 mg/m2 per dose twice daily for 6 days followed by 12000 cGy TBI as 200 cGy fractions twice daily for 3 days. Minimum follow-up is 21 months. Five-year event-free survival (EFS) and the actuarial relapse rate is 59 and 14% for patients with ALL in second remission, and 38 and 14+% for patients with AML in first remission. Twelve patients have relapsed (three are alive in remission after testicular or marrow relapse) and 28 have died of other causes. Acute GVHD with or without infection was the cause of death in 11 patients. Ten of the 11 patients who died of acute GVHD were considered at 'high risk' for GVHD (inadequate GVHD prophylaxis, or mismatched family donor or a matched unrelated donor). Toxicities in the immediate post-BMT period included diarrhea, oropharyngeal mucositis and conjunctivitis. Significant late toxicities included short stature, avascular necrosis of bone, and poor school performance (most often in patients who had received prior cranial irradiation). Our conclusions are that high-dose Ara-C and TBI followed by allogeneic bone marrow transplantation is effective therapy for children in second complete remission of their acute leukemia. However, significant late toxicities occur, and it is clear that more effective, less toxic therapies are necessary for these patients.


The Reproductive Ecology of Industrial Societies, Part I : Why Measuring Fertility Matters.
Is fertility relevant to evolutionary analyses conducted in modern industrial societies? This question has been the subject of a highly contentious debate, beginning in the late 1980s and continuing to this day. Researchers in both evolutionary and social sciences have argued that the measurement of fitness-related traits (e.g., fertility) offers little insight into evolutionary processes, on the grounds that modern industrial environments differ so greatly from those of our ancestral past that our behavior can no longer be expected to be adaptive. In contrast, we argue that fertility measurements in industrial society are essential for a complete evolutionary analysis: in particular, such data can provide evidence for any putative adaptive mismatch between ancestral environments and those of the present day, and they can provide insight into the selection pressures currently operating on contemporary populations. Having made this positive case, we then go on to discuss some challenges of fertility-related analyses among industrialized populations, particularly those that involve large-scale databases. These include "researcher degrees of freedom" (i.e., the choices made about which variables to analyze and how) and the different biases that may exist in such data. Despite these concerns, large datasets from multiple populations represent an excellent opportunity to test evolutionary hypotheses in great detail, enriching the evolutionary understanding of human behavior.


The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS Report No. 20.
To evaluate the association of lipid intake with baseline severity of age-related macular degeneration (AMD) in the Age-Related Eye Disease Study (AREDS). Age-Related Eye Disease Study participants aged 60 to 80 years at enrollment (N = 4519) provided estimates of habitual nutrient intake through a self-administered semiquantitative food frequency questionnaire. Stereoscopic color fundus photographs were used to categorize participants into 4 AMD severity groups and a control group (participants with <15 small drusen). Dietary total omega-3 long-chain polyunsaturated fatty acid (LCPUFA) intake was inversely associated with neovascular (NV) AMD (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.41-0.90), as was docosahexaenoic acid, a retinal omega-3 LCPUFA (OR, 0.54; 95% CI, 0.36-0.80), comparing highest vs lowest quintile of intake, after adjustment for total energy intake and covariates. Higher fish consumption, both total and broiled/baked, was also inversely associated with NV AMD (OR, 0.61; 95% CI, 0.37-1.00 and OR, 0.65; 95% CI, 0.45-0.93, respectively). Dietary arachidonic acid was directly associated with NV AMD prevalence (OR, 1.54; 95% CI, 1.04-2.29). No statistically significant relationships existed for the other lipids or AMD groups. Higher intake of omega-3 LCPUFAs and fish was associated with decreased likelihood of having NV AMD.


Prdm5 suppresses Apc(Min)-driven intestinal adenomas and regulates monoacylglycerol lipase expression.
PRDM proteins are tissue-specific transcription factors often deregulated in diseases, particularly in cancer where different members have been found to act as oncogenes or tumor suppressors. PRDM5 is a poorly characterized member of the PRDM family for which several studies have reported a high frequency of promoter hypermethylation in cancer types of gastrointestinal origin. We report here the characterization of Prdm5 knockout mice in the context of intestinal carcinogenesis. We demonstrate that loss of Prdm5 increases the number of adenomas throughout the murine small intestine on an Apc(Min) background. By using the genome-wide ChIP-seq (chromatin immunoprecipitation (ChIP) followed by DNA sequencing) and transcriptome analyses we identify loci encoding proteins involved in metabolic processes as prominent PRDM5 targets and characterize monoacylglycerol lipase (Mgll) as a direct PRDM5 target in human colon cancer cells and in Prdm5 mutant mouse intestines. Moreover, we report the downregulation of PRDM5 protein expression in human colon neoplastic lesions. In summary, our data provide the first causal link between Prdm5 loss and intestinal carcinogenesis, and uncover an extensive and novel PRDM5 target repertoire likely facilitating the tumor-suppressive functions of PRDM5.


Death During Simulation: A Literature Review.
One of the goals of simulation is to teach subjects critical skills and knowledge applicable to live encounters, without the risk of harming actual patients. Although simulation education has surged in medical training over the last two decades, several ethically challenging educational methods have arisen. Simulated death has arisen as one of these challenging issues and currently there is no consensus regarding how to best manage this controversial topic in the simulated environment. The goal of this review is to analyze how simulated mortality has been used and discover whether or not this tool is beneficial to learners. In May 2016, the authors performed a literature search on both Pubmed and the Cochrane database using multiple variations of keywords; they then searched bibliographies and related articles. There were 901 articles acquired in the initial search. The authors eliminated articles that were not relevant to the subject matter. After adding articles from bibliographies and related articles, the authors included the 43 articles cited in this article. As a result, the authors of this article believe that death, when used appropriately in simulation, can be an effective teaching tool and can be used in a responsible manner.


Computed tomographic arthrography of the intercarpal ligaments of the equine carpus.
Injuries of the intercarpal ligaments are an important cause of lameness in performance horses. The purpose of this prospective cadaver study was to determine whether computed tomography (CT) arthrography would be a feasible method for visualizing and characterizing intercarpal ligaments in the horse. One cadaver limb from each of eight nonlame horses was collected immediately after euthanasia. For each limb, overlapping 2.0 mm CT images were acquired before and after injection of iodinated contrast medium into the antebrachiocarpal joint, middle carpal joint, and carpal sheath. Spin echo magnetic resonance imaging (MRI) sequences were acquired in three planes using a 1.5 Tesla MRI scanner in three limbs. Following MRI, colored resin was injected into the synovial structures of these three limbs, limbs were frozen, and anatomic sections were obtained in three planes. Findings from CT arthrograms were compared to findings from precontrast CT, MRI, anatomic slices, and arthroscopy. Medial and lateral palmar intercarpal ligaments, radiocarpal and transverse intercarpal ligaments, and palmar carpal ligament were visible in CT arthrograms of all limbs. The proximal and distal entheses of all ligaments were readily identifiable. Findings indicated that CT arthrography is feasible for visualizing intercarpal ligaments and may be a useful adjunct imaging technique for diagnosing lameness due to suspected carpal ligament injury in horses.


Benchmark and performance of long-range corrected time-dependent density functional tight binding (LC-TD-DFTB) on rhodopsins and light-harvesting complexes.
The chromophores of rhodopsins (Rh) and light-harvesting (LH) complexes still represent a major challenge for a quantum chemical description due to their size and complex electronic structure. Since gradient corrected and hybrid density functional approaches have been shown to fail for these systems, only range-separated functionals seem to be a promising alternative to the more time consuming post-Hartree-Fock approaches. For extended sampling of optical properties, however, even more approximate approaches are required. Recently, a long-range corrected (LC) functional has been implemented into the efficient density functional tight binding (DFTB) method, allowing to sample the excited states properties of chromophores embedded into proteins using quantum mechanical/molecular mechanical (QM/MM) with the time-dependent (TD) DFTB approach. In the present study, we assess the accuracy of LC-TD-DFT and LC-TD-DFTB for rhodopsins (bacteriorhodopsin (bR) and pharaonis phoborhodopsin (ppR)) and LH complexes (light-harvesting complex II (LH2) and Fenna-Matthews-Olson (FMO) complex). This benchmark study shows the improved description of the color tuning parameters compared to standard DFT functionals. In general, LC-TD-DFTB can exhibit a similar performance as the corresponding LC functionals, allowing a reliable description of excited states properties at significantly reduced cost. The two chromophores investigated here pose complementary challenges: while huge sensitivity to external field perturbation (color tuning) and charge transfer excitations are characteristic for the retinal chromophore, the multi-chromophoric character of the LH complexes emphasizes a correct description of inter-chromophore couplings, giving less importance to color tuning. None of the investigated functionals masters both systems simultaneously with satisfactory accuracy. LC-TD-DFTB, at the current stage, although showing a systematic improvement compared to TD-DFTB cannot be recommended for studying color tuning in retinal proteins, similar to some of the LC-DFT functionals, because the response to external fields is still too weak. For sampling of LH-spectra, however, LC-TD-DFTB is a viable tool, allowing to efficiently sample absorption energies, as shown for three different LH complexes. As the calculations indicate, geometry optimization may overestimate the importance of local minima, which may be averaged over when using trajectories. Fast quantum chemical approaches therefore may allow for a direct sampling of spectra in the near future.


On-treatment monitoring of adefovir therapy in chronic hepatitis B: virologic response can be assessed at 24 weeks.
Patients with chronic hepatitis B (CHB) who will and those who will not respond to adefovir (ADV) monotherapy need to be identified at an early stage in order to adjust treatment and prevent future development of antiviral resistance. In a single-centre cohort study, we investigated 76 CHB patients [50% hepatitis B e antigen (HBeAg)-positive] treated with long-term ADV monotherapy. During a median follow-up of 122 (24-185) weeks, 42 (55%) patients achieved virologic response (VR), defined as HBV-DNA levels <10(3) copies/mL, and 10 patients (13%) developed genotypic ADV resistance. Independent baseline predictors of VR were HBeAg negativity [hazard ratio (HR) 2.98; 95% confidence interval (CI) 1.24-7.19; P = 0.02], high alanine aminotransferase (ALT) levels (HR 1.11; 95% CI 1.05-1.18; P = 0.001), and low HBV-DNA levels (HR 0.56; 95% CI 0.41-0.75; P < 0.001). HBV-DNA at week 24 demonstrated a higher predictive value for VR than HBV-DNA at week 48. Important predictors of genotypic resistance were presence of cirrhosis (HR 6.54; 95% CI 1.39-30.9; P = 0.018), and not achieving VR during treatment (HR 6.60; 95% CI 1.35-32.4; P = 0.008). Patients without VR at week 24 already demonstrated a trend towards the emergence of ADV resistance (P = 0.07). HBV-DNA at week 24 was a better on-treatment predictor of VR than HBV-DNA at week 48, and ADV-resistant mutations developed more frequently in patients without VR at week 24. Therefore, our study suggests that virologic response to ADV therapy can be assessed at 24 weeks, instead of the generally recommended 48 weeks.


Death after discharge: predictors of mortality in older brain-injured patients.
Older patients with traumatic brain injury (TBI) may be at high risk of death after hospitalization. The purpose of this study was to characterize long-term mortality of older TBI patients who survived to discharge. We hypothesized that predictors of postdischarge mortality differed from those of inpatient mortality. A retrospective cohort study was performed on TBI patients older than 55 years admitted to our Level I trauma center between July 1, 2006, and December 31, 2011. Postdischarge deaths were identified by matching patient data with local vital records up to December 31, 2011, when data collection was terminated (censoring). Patients were categorized by age, comorbidities, history of preinjury anticoagulant/prescription antiplatelet agent therapy, injury severity indices, initial TBI type, prehospital living status, discharge location, and discharge condition. The effect of risk factors on postdischarge mortality was evaluated by Cox proportional hazards modeling. Of 353 patients, 322 (91.2%) survived to discharge. Postdischarge mortality was 19.8% (n = 63) for the study period. Of the postdischarge deaths, 54.0% died within 6 months of discharge, and 68.3% died within 1 year. Median days to death after discharge or censoring were 149 and 410, respectively. Factors associated with death after discharge included age, preinjury anticoagulant use, higher number of Charlson comorbidities, discharge to a long-term care facility, and severe disability. Factors related to injury severity (i.e., Injury Severity Score [ISS], initial Glasgow Coma Scale [GCS] score) and preinjury prescription antiplatelet agent use, previously found to predict inpatient death, did not predict postdischarge mortality. Older TBI patients who survive to discharge have a significant risk of death within 1 year. Predictors of postdischarge mortality and inpatient death differ. Death after discharge is largely a function of overall health status. Monitoring health status and continued aggressive management of comorbidities after discharge may be essential in determining long-term outcomes. Epidemiologic study, level III.


Association of mood disturbance and arrhythmia events in patients after cardioverter defibrillator implantation.
Life stresses and negative emotions, such as anxiety and depression, are associated with adverse cardiac events, including arrhythmia. Patients undergoing implantation of an automatic internal cardioverter defibrillator provide a unique opportunity to characterize these relationships since all tachyarrhythmia episodes are recorded by the device. The purpose of this study was to examine the association of emotional status after internal cardioverter defibrillator (ICD) implantation and subsequent arrhythmia events. An analysis of data obtained in a prospective longitudinal study of responses to the ICD measured mood disturbance (Profile of Mood States; POMS) before implant and at 1, 3, 6, and 9 months postoperatively. Subjects included 144 men and 32 women with a mean age of 60 +/- 13 years and a mean left ventricular ejection fraction (LVEF) of 33 +/- 12%. Arrhythmia events were measured by self-report of shocks and by ICD device interrogation to obtain the number and type (defibrillation, cardioversion, and antitachycardia pacing) of therapies delivered by the ICD. For each time point, POMS scores of subjects who had arrhythmia events were compared with those who did not. For subjects who had ICD shocks, pre-event and post-event POMS scores were also compared. Multiple logistic regression was used at each time point to determine if clinical, demographic and psychological data could predict arrhythmia events. Patients with arrhythmia events had higher POMS scores throughout the 9 months of follow-up. Higher level of mood disturbance (specifically anxiety, fatigue, and confusion) at 1 and 3 months were independent predictors of subsequent arrhythmia events at 3 and 6 months after controlling for LVEF, the presence of coronary artery disease, pre-implant arrhythmia history, and the use of amiodarone and beta-blocking agents. There were no differences in POMS scores before and after ICD shocks, reinforcing the notion that negative emotions were a cause, rather than a consequence, of arrhythmia events. Mood disturbances, such as anxiety, may increase the risk for arrhythmia events after ICD insertion.


Self-mode-locked 2 μm Tm(3+)-doped double-clad fiber laser with a simple linear cavity.
We demonstrate the self-mode-locking operation of a thulium (Tm)-doped fiber laser (TDFL) with a simple linear cavity. Since the laser cavity does not include any specific mode-locker, we experimentally investigate and analyze the self-mode-locking mechanism. The mode-locking operation is attributed to the combination of the self-phase modulation effect and the weak saturable absorption of the high-concentration Tm-doped fiber. The mode-locked TDFL operates at a central wavelength of 1985.5 nm with the 3 dB spectral linewidth of 0.18 nm. The self-mode-locking generates a large pulse energy of 32.7 nJ with a pulsed repetition rate of 2.05 MHz and is stable with a radio-frequency signal-to-noise ratio of more than 54 dB. To the best of our knowledge, it is the first demonstration of a 2 μm Tm-doped fiber laser mode-locked by such technique.


Role of mitomycin C in pterygium surgery.
Mitomycin C in the form of eye drops in a concentration of 0.4 mg/ml (0.04%) was used as adjunctive treatment for primary and recurrent pterygium after surgical excision. The study was concurrent in nature and consisted of 32 pterygia in 30 patients and was done over a period of 36 months. The object was to observe the effect of mitomycin C drops on pterygium recurrence after surgical excision. Fifteen eyes of 15 patients were treated with 'bare sclera technique' for pterygium excision. Nine patients showed recurrence occurring within first 6 months of surgery. On the other hand 17 eyes of 15 patients after bare sclera pterygium excision received mitomycin 0.4 mg/ml (0.04%) eye drops four times a day for 2 weeks from first postoperative day. There was no recurrence of pterygium in this group. Follow up time for these cases ranged from 13-19 months.


Genome evolution and the emergence of pathogenicity in avian Escherichia coli.
Chickens are the most common birds on Earth and colibacillosis is among the most common diseases affecting them. This major threat to animal welfare and safe sustainable food production is difficult to combat because the etiological agent, avian pathogenic Escherichia coli (APEC), emerges from ubiquitous commensal gut bacteria, with no single virulence gene present in all disease-causing isolates. Here, we address the underlying evolutionary mechanisms of extraintestinal spread and systemic infection in poultry. Combining population scale comparative genomics and pangenome-wide association studies, we compare E. coli from commensal carriage and systemic infections. We identify phylogroup-specific and species-wide genetic elements that are enriched in APEC, including pathogenicity-associated variation in 143 genes that have diverse functions, including genes involved in metabolism, lipopolysaccharide synthesis, heat shock response, antimicrobial resistance and toxicity. We find that horizontal gene transfer spreads pathogenicity elements, allowing divergent clones to cause infection. Finally, a Random Forest model prediction of disease status (carriage vs. disease) identifies pathogenic strains in the emergent ST-117 poultry-associated lineage with 73% accuracy, demonstrating the potential for early identification of emergent APEC in healthy flocks.


Acute lethal graft-versus-host reaction induced by major histocompatibility complex class II-reactive T helper cell clones.
T cell clones isolated from class II MHC-disparate MLR combinations, and specific for I-Ak and I-Ek molecules, respectively, are shown to induce acute lethal graft-vs-host disease in unirradiated recipients. Cytolytic and noncytolytic clones are equally efficient in this respect. The lethal disease is dependent on recognition of the stimulatory class II molecules in the host. The clones home to lungs and liver, and become activated in these organs as demonstrated by an in vivo thymidine incorporation assay. After activation, a severe vascular leak syndrome develops causing death of the recipients within 5 d after the injection of 5 x 10(6) to 10(7) cloned cells. The disease develops without the participation of secondary host-derived inflammatory mechanisms, such as mast cell degranulation, complement activation, and the release of prostaglandins, oxygen radicals, or proteolytic enzymes. The results raise the possibility that Th cells can directly influence vascular permeability, and control, thereby, the acute inflammatory reaction of blood vessels.


Organic fertilizer as a vehicle for the entry of microplastic into the environment.
The contamination of the environment with microplastic, defined as particles smaller than 5 mm, has emerged as a global challenge because it may pose risks to biota and public health. Current research focuses predominantly on aquatic systems, whereas comparatively little is known regarding the sources, pathways, and possible accumulation of plastic particles in terrestrial ecosystems. We investigated the potential of organic fertilizers from biowaste fermentation and composting as an entry path for microplastic particles into the environment. Particles were classified by size and identified by attenuated total reflection-Fourier transform infrared spectroscopy. All fertilizer samples from plants converting biowaste contained plastic particles, but amounts differed significantly with substrate pretreatment, plant, and waste (for example, household versus commerce) type. In contrast, digestates from agricultural energy crop digesters tested for comparison contained only isolated particles, if any. Among the most abundant synthetic polymers observed were those used for common consumer products. Our results indicate that depending on pretreatment, organic fertilizers from biowaste fermentation and composting, as applied in agriculture and gardening worldwide, are a neglected source of microplastic in the environment.


PAR1b takes the stage in the morphogenetic and motogenetic activity of Helicobacter pylori CagA oncoprotein.
Helicobacter pylori CagA oncoprotein is critically involved in gastric carcinogenesis. Upon delivery into gastric epithelial cells via type IV secretion, CagA induces an extremely elongated cell-shape known as the hummingbird phenotype, which is associated with massive changes in actin cytoskeleton and elevated motility. With the notion that the hummingbird phenotype reflects pathogenic/oncogenic activity of CagA, many studies have focused on the mechanism through which CagA induces the morphological change. Once delivered, CagA interacts with host proteins such as oncogenic phosphatase SHP2 and polarity-regulating kinase PAR1b. Whereas the essential role of the CagA-SHP2 interaction in inducing the hummingbird phenotype has been extensively investigated, involvement of the CagA-PAR1b interaction in the morphological change has remained uncertain. Recently, we found that the CagA-PAR1b interaction, which inhibits PAR1b kinase activity, influences the actin cytoskeletal system and potentiates the magnitude of the hummingbird phenotype. We also found that PAR1b inactivates a RhoA-specific GEF, GEF-H1, via phosphorylation and thereby inhibits cortical actin and stress fiber formation. Collectively, these findings indicate that CagA-mediated inhibition of PAR1b promotes RhoA-dependent actin-cytoskeletal rearrangement and thereby strengthens the hummingbird phenotype induced by CagA-stimulated SHP2 during infection with H. pylori cagA-positive strains.


A Review of the Water and Energy Sectors and the Use of a Nexus Approach in Abu Dhabi.
Rapid population increase coupled with urbanization and industrialization has resulted in shortages of water in the Middle East. This situation is further exacerbated by global climate change due to greenhouse gas emissions. Recent research advocates that solutions to the global water security and scarcity crisis must involve water-energy nexus approaches. This means adopting policies and strategies that harmonize these inter-related sectors to minimize environmental impact while maximizing human benefit. In the case of Abu Dhabi, when designing and locating oil/gas refineries and associated power generation facilities, previous relevant decisions were based on simple economic and geographical grounds, such as nearness to oil rigs, pipelines, existing industries and port facilities, etc. The subsequent design and location of water abstraction and treatment works operated by the waste heat from these refining and/or power generation processes was catered for as an afterthought, meaning that there is now a mismatch between the water and energy supplies and demands. This review study was carried out to show how Abu Dhabi is trying now to integrate its water-energy sectors using a nexus approach so that future water/power infrastructure is designed optimally and operated in harmony, especially in regard to future demand. Based upon this review work, some recommendations are made for designers and policy makers alike to bolster the nexus approach that Abu Dhabi is pursuing.


Global assessment of nitrogen deposition effects on terrestrial plant diversity: a synthesis.
Atmospheric nitrogen (N) deposition is a recognized threat to plant diversity in temperate and northern parts of Europe and North America. This paper assesses evidence from field experiments for N deposition effects and thresholds for terrestrial plant diversity protection across a latitudinal range of main categories of ecosystems, from arctic and boreal systems to tropical forests. Current thinking on the mechanisms of N deposition effects on plant diversity, the global distribution of G200 ecoregions, and current and future (2030) estimates of atmospheric N-deposition rates are then used to identify the risks to plant diversity in all major ecosystem types now and in the future. This synthesis paper clearly shows that N accumulation is the main driver of changes to species composition across the whole range of different ecosystem types by driving the competitive interactions that lead to composition change and/or making conditions unfavorable for some species. Other effects such as direct toxicity of nitrogen gases and aerosols, long-term negative effects of increased ammonium and ammonia availability, soil-mediated effects of acidification, and secondary stress and disturbance are more ecosystem- and site-specific and often play a supporting role. N deposition effects in mediterranean ecosystems have now been identified, leading to a first estimate of an effect threshold. Importantly, ecosystems thought of as not N limited, such as tropical and subtropical systems, may be more vulnerable in the regeneration phase, in situations where heterogeneity in N availability is reduced by atmospheric N deposition, on sandy soils, or in montane areas. Critical loads are effect thresholds for N deposition, and the critical load concept has helped European governments make progress toward reducing N loads on sensitive ecosystems. More needs to be done in Europe and North America, especially for the more sensitive ecosystem types, including several ecosystems of high conservation importance. The results of this assessment show that the vulnerable regions outside Europe and North America which have not received enough attention are ecoregions in eastern and southern Asia (China, India), an important part of the mediterranean ecoregion (California, southern Europe), and in the coming decades several subtropical and tropical parts of Latin America and Africa. Reductions in plant diversity by increased atmospheric N deposition may be more widespread than first thought, and more targeted studies are required in low background areas, especially in the G200 ecoregions.


Methylation markers of malignant potential in meningiomas.
Although most meningiomas are benign, about 20% are atypical (Grade II or III) and have increased mortality and morbidity. Identifying tumors with greater malignant potential can have significant clinical value. This validated genome-wide methylation study comparing Grade I with Grade II and III meningiomas aims to discover genes that are aberrantly methylated in atypical meningiomas. Patients with newly diagnosed meningioma were identified as part of the Ohio Brain Tumor Study. The Infinium HumanMethylation27 BeadChip (Illumina, Inc.) was used to interrogate 27,578 CpG sites in 14,000 genes per sample for a discovery set of 33 samples (3 atypical). To verify the results, the Infinium HumanMethylation450 BeadChip (Illumina, Inc.) was used to interrogate 450,000 cytosines at CpG loci throughout the genome for a verification set containing 7 replicates (3 atypical), as well as 12 independent samples (6 atypical). A nonparametric Wilcoxon exact test was used to test for difference in methylation between benign and atypical meningiomas in both sets. Heat maps were generated for each set. Methylation results were validated for the 2 probes with the largest difference in methylation intensity by performing Western blot analysis on a set of 20 (10 atypical) samples, including 11 replicates. The discovery array identified 95 probes with differential methylation between benign and atypical meningiomas, creating 2 distinguishable groups corresponding to tumor grade when visually examined on a heat map. The validation array evaluated 87 different probes and showed that 9 probes were differentially methylated. On heat map examination the results of this array also suggested the existence of 2 major groups that corresponded to histological grade. IGF2BP1 and PDCD1, 2 proteins that can increase the malignant potential of tumors, were the 2 probes with the largest difference in intensity, and for both of these the atypical meningiomas had a decreased median production of protein, though this was not statistically significant (p = 0.970 for IGF2BP1 and p = 1 for PDCD1). A genome-wide methylation analysis of benign and atypical meningiomas identified 9 genes that were reliably differentially methylated, with the strongest difference in IGF2BP1 and PDCD1. The mechanism why increased methylation of these sites is associated with an aggressive phenotype is not evident. Future research may investigate this mechanism, as well as the utility of IGF2BP1 as a marker for pathogenicity in otherwise benign-appearing meningiomas.


Conserved and specific functions of axoneme components in trypanosome motility.
The Trypanosoma brucei flagellum is unusual as it is attached along the cell body and contains, in addition to an apparently conventional axoneme, a structure called the paraflagellar rod, which is essential for cell motility. Here, we investigated flagellum behaviour in normal and mutant trypanosome cell lines where expression of genes encoding various axoneme proteins (PF16, PF20, DNAI1, LC2) had been silenced by RNAi. First, we show that the propulsive wave (normally used for forward motility) is abolished in the absence of outer dynein arms, whereas the reverse wave (normally used for changing direction) still occurs. Second, in contrast to Chlamydomonas--but like metazoa, the central pair adopts a fixed orientation during flagellum beating. This orientation becomes highly variable in central-pair- and outer-dynein-arm-mutants. Third, the paraflagellar rod contributes to motility by facilitating three-dimensional wave propagation and controlling cell shape. Fourth, motility is required to complete the last stage of cell division in both insect and bloodstream stages of the parasite. Finally, our study also reveals the conservation of molecular components of the trypanosome flagellum. Coupled to the ease of reverse genetics, it raises the interest of trypanosomes as model organisms to study cilia and flagella.


Group 6 metal pentacarbonyl complexes of air-stable primary, secondary, and tertiary ferrocenylethylphosphines.
The synthesis and characterization of a series of Group 6 metal pentacarbonyl complexes of air stable primary, secondary, and tertiary phosphines containing ferrocenylethyl substituents are reported [M(CO)5L: M = Cr, Mo, W; L = PH2(CH2CH2Fc), PH(CH2CH2Fc)2, P(CH2CH2Fc)3]. The structure and composition of the complexes were confirmed by multinuclear NMR spectroscopy, IR and UV-Vis absorption spectroscopy, mass spectrometry, X-ray crystallography, and elemental analysis. The solid-state structural data reported revealed trends in M-C and M-P bond lengths that mirrored those of the atomic radii of the Group 6 metals involved. UV-Vis absorption spectroscopy and cyclic voltammetry highlighted characteristics consistent with electronically isolated ferrocene units including wavelengths of maximum absorption between 435 and 441 nm and reversible one-electron (per ferrocene unit) oxidation waves between 10 and -5 mV relative to the ferrocene/ferrocenium redox couple. IR spectroscopy confirmed that the σ donating ability of the phosphines increased as ferrocenylethyl substituents were introduced and that the tertiary phosphine ligand described is a stronger σ donor than PPh3 and a weaker σ donor than PEt3, respectively.


Opening- and Closing-Wedge Distal Femoral Osteotomy: A Systematic Review of Outcomes for Isolated Lateral Compartment Osteoarthritis.
Lateral compartment osteoarthritis of the knee can be a challenging pathology in the younger, active population due to limited treatment options and high patient expectations. Distal femoral osteotomy (DFO) has been reported to be a potential treatment option. To perform a systematic review on the survival, outcomes, and complications of DFO for treatment of genu valgum with concomitant lateral compartment osteoarthritis of the knee. Systematic review; Level of evidence, 4. A systematic review of the literature was performed using the Cochrane Database of Systematic Reviews, the Cochrane Central Registry of Controlled Trials, PubMed, and MEDLINE from 1980 to present. Inclusion criteria were as follows: outcomes of opening- and closing-wedge DFOs performed for treatment of genu valgum with concomitant lateral compartment osteoarthritis of the knee, English language, minimum 2-year follow-up, and human studies. Data abstracted from the selected studies included type of osteotomy (opening vs closing), survival rate, patient-reported and radiographic outcomes, and complications. Fourteen studies met the inclusion criteria and were considered for the review. A total of 9 closing-wedge and 5 opening-wedge DFO studies were included. All were retrospective studies and reported good to excellent patient-reported outcomes after DFO. Survival decreased with increasing time from surgery, with 1 study reporting a 100% survival rate at 6.5 years, compared with 21.5% at 20 years in another study. A low rate of complications was reported throughout the review. Highly heterogeneous literature exists for both opening- and closing-wedge DFOs for the treatment of isolated lateral compartment osteoarthritis with valgus malalignment. A mean survival rate of 80% at 10-year follow-up was reported, supporting that this procedure can be a viable treatment option to delay or reduce the need for joint arthroplasty. A low complication rate was observed, with symptomatic hardware being the most prevalent postoperative complication.


National trends in bariatric surgery, 1996-2002.
Surgical therapy for the long-term treatment of obesity ("bariatric surgery") in individuals whose body mass index (calculated as weight in kilograms divided by the square of height in meters) is 40 or higher or in those who have significant obesity-related comorbidities and a body mass index of 35 or higher is one of few interventions shown to be effective. Many aspects of recent national bariatric surgery trends are unclear, including the ages of individuals undergoing such procedures and the economic burden borne by public vs private payers. Population-adjusted rates of bariatric surgery are rapidly increasing and have economic implications that differ for private vs public payers. We examined hospitalization and charge data from the Nationwide Inpatient Sample from 1996 through 2002, representative of national patterns for children and adults. We derived nationally weighted estimates of population-adjusted hospitalization rates and inflation-adjusted charges for bariatric surgery. We also examined the relative economic burden for public vs private payers for bariatric surgery discharges. Population-adjusted rates of bariatric surgery in the overall sample increased more than 7-fold in the study period, from 3.5 per 100 000 US population in 1996 to 24.0 per 100 000 in 2002. During this period, among youth (<20 years old), rates increased from 0.23 per 100 000 to 0.73 per 100 000; and among elderly persons (>65 years old), rates increased from 0.30 per 100 000 to 1.69 per 100 000. The rate increased most dramatically among those aged 20 to 65 years, who composed 97% or more of bariatric surgery discharges annually. Increases in bariatric surgical volume corresponded with increasing economic consequences overall, exceeding USD $2 billion in annual charges by 2002 (mean, USD $29,107 per discharge). Since 2000, private payers have been charged for more than 80% of the national total; annual charges to Medicare and Medicaid have been comparatively modest, but each exceeded USD $100 million by 2002. National rates of bariatric surgery have increased markedly among children and adults, with attendant economic consequences, principally for private insurers. This trend may reflect the dearth of effective primary care and preventive interventions to address the obesity epidemic.


Structural basis of nucleoside and nucleoside drug selectivity by concentrative nucleoside transporters.
Concentrative nucleoside transporters (CNTs) are responsible for cellular entry of nucleosides, which serve as precursors to nucleic acids and act as signaling molecules. CNTs also play a crucial role in the uptake of nucleoside-derived drugs, including anticancer and antiviral agents. Understanding how CNTs recognize and import their substrates could not only lead to a better understanding of nucleoside-related biological processes but also the design of nucleoside-derived drugs that can better reach their targets. Here, we present a combination of X-ray crystallographic and equilibrium-binding studies probing the molecular origins of nucleoside and nucleoside drug selectivity of a CNT from Vibrio cholerae. We then used this information in chemically modifying an anticancer drug so that it is better transported by and selective for a single human CNT subtype. This work provides proof of principle for utilizing transporter structural and functional information for the design of compounds that enter cells more efficiently and selectively.


Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.
A locus segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21, close to the amyloid precursor protein (APP) gene. Recombinants between the APP gene and the AD locus have been reported which seemed to exclude it as the site of the mutation causing familial AD. But recent genetic analysis of a large number of AD families has demonstrated that the disease is heterogeneous. Families with late-onset AD do not show linkage to chromosome 21 markers. Some families with early-onset AD show linkage to chromosome 21 markers, but some do not. This has led to the suggestion that there is non-allelic genetic heterogeneity even within early onset familial AD. To avoid the problems that heterogeneity poses for genetic analysis, we have examined the cosegregation of AD and markers along the long arm of chromosome 21 in a single family with AD confirmed by autopsy. Here we demonstrate that in this kindred, which shows linkage to chromosome 21 markers, there is a point mutation in the APP gene. This mutation causes an amino-acid substitution (Val----Ile) close to the carboxy terminus of the beta-amyloid peptide. Screening other cases of familial AD revealed a second unrelated family in which this variant occurs. This suggests that some cases of AD could be caused by mutations in the APP gene.


Extraordinary optical transmission based on subwavelength metallic grating with ellipse walls.
This paper presents a nanometer-sized metallic film periodically pierced by narrow slits with ellipse walls deposited on a substrate that demonstrates special optical properties of broadband extraordinary optical transmission (BEOT). Compared to slits with straight walls, the metal slits with nonlinearly tapered ellipse walls can collect more light on the upper surface, which is coupled into a gap plasmon polariton propagating along the ellipse walls, then delivers the light at the smaller exit slit opening. In the visible spectral region, BEOT of TM-polarized light is achieved with up to 80% transmission at resonance, which is resulted from the simultaneous enhancement of zero-order slit resonance and higher-order slit resonances excited due to the existence of the substrate. The spectral range of BEOT is limited by Wood-Rayleigh anomalies and surface plasmon polariton resonances (SPPs). The BEOT spectrum of oblique incidence with small incident angle that is divided into two separate bands are also presented and analyzed theoretically. This metallic grating overcomes the low optical transmission limit of the structures with wavelength-sized grating period in visible and near-IR regions. It can be used to design nanostructured BEOT polarizer, which is an important component in novel biomimetic-based optoelectronic systems especially those in skylight polarized environment.


Better Understanding and Recognition of the Disconnects, Experiences, and Needs of Patients with Irritable Bowel Syndrome with Constipation (BURDEN IBS-C) Study: Results of an Online Questionnaire.
The BURDEN IBS-C study was conducted to better understand the experiences, attitudes, and unmet needs of sufferers of irritable bowel syndrome with constipation (IBS-C) in comparison to the perceptions and challenges of healthcare providers (HCPs) who treat IBS-C patients. This was an author-developed, online questionnaire using KnowledgePanel® to survey individuals with IBS-C (N = 1311). HCPs participated in a complementary online questionnaire and were recruited separately (N = 331). The study was fielded from June 29, 2016, to January 30, 2017. Most patients had used (86%) and/or were using (76%) over-the-counter treatments for their IBS-C, with 12% currently on prescription therapy. At the time this study was conducted, 66% and 63% were not satisfied/completely satisfied with over-the-counter or prescription treatment, respectively, citing inadequate efficacy (55%) and side effects (39%), most commonly diarrhea, as common reasons for dissatisfaction. IBS-C respondents most commonly reported feeling frustrated (43%) and stressed (28%) regarding IBS-C, though 39% were accepting of IBS-C as part of daily life. HCPs were aligned with patients in thinking that patients were frustrated (76%) and stressed (65%) but HCPs were less likely to recognize that patients had become accepting of their IBS-C (13%). Most HCPs (79%) were not satisfied/completely satisfied with the prescription treatments available at the time this study was conducted. Inadequate response rates to current therapies (55%) and treatment adherence/compliance issues (58%) were the most frequent challenges encountered by HCPs. IBS-C respondents reported that their symptoms impacted productivity and personal activity, on average, 4 and 3 days/month, respectively. These results suggest that current management pathways may not be adequately addressing the symptoms and needs of individuals with IBS-C, most notably side effects and lack of efficacy. Patients and HCPs expressed dissatisfaction with over-the-counter and prescription treatments available at the time this study was conducted. Additional treatment options and improved dialogue would be beneficial to HCPs and patients. Synergy Pharmaceuticals Inc.


Cellular reprogramming: recent advances in modeling neurological diseases.
The remarkable advances in cellular reprogramming have made it possible to generate a renewable source of human neurons from fibroblasts obtained from skin samples of neonates and adults. As a result, we can now investigate the etiology of neurological diseases at the cellular level using neuronal populations derived from patients, which harbor the same genetic mutations thought to be relevant to the risk for pathology. Therapeutic implications include the ability to establish new humanized disease models for understanding mechanisms, conduct high-throughput screening for novel biogenic compounds to reverse or prevent the disease phenotype, identify and engineer genetic rescue of causal mutations, and develop patient-specific cellular replacement strategies. Although this field offers enormous potential for understanding and treating neurological disease, there are still many issues that must be addressed before we can fully exploit this technology. Here we summarize several recent studies presented at a symposium at the 2011 annual meeting of the Society for Neuroscience, which highlight innovative approaches to cellular reprogramming and how this revolutionary technique is being refined to model neurodevelopmental and neurodegenerative diseases, such as autism spectrum disorders, schizophrenia, familial dysautonomia, and Alzheimer's disease.


Stem-cell homeostasis and growth dynamics can be uncoupled in the Arabidopsis shoot apex.
The shoot apical meristem (SAM) is a collection of stem cells that resides at the tip of each shoot and provides the cells of the shoot. It is divided into functional regions. The central zone (CZ) at the tip of the meristem is the domain of expression of the CLAVATA3 (CLV3) gene, encoding a putative ligand for a transmembrane receptor kinase, CLAVATA1, active in cells of the rib meristem (RM), located just below the CZ. We show here that CLV3 restricts its own domain of expression (the CZ) by preventing differentiation of peripheral zone cells (PZ), which surround the CZ, into CZ cells and restricts overall SAM size by a separate, long-range effect on cell division rate.


Defective synthesis of vasodilator prostaglandins in the spontaneously hypertensive rat.
Results of in vitro studies performed in different laboratories have led to the hypothesis that in spontaneously hypertensive rats (SHR), the biosynthesis of the vasodilator prostaglandins (PG) I2 and E2 increases secondarily to the rise in the arterial pressure, as a protective mechanism for reducing the severity of hypertension. In this study, this hypothesis was tested in vivo in SHR and control Wistar-Kyoto (WKY) rats under normal and high sodium diets. The 24-hour urinary excretion of 2,3-dinor-6-oxo-PGF1 alpha, an endogenous metabolite of PGI2, was used as an index of the total production of PGI2 in the rats, whereas the urinary levels of PGE2 were used as an index of the renal production of this prostaglandin. Urinary levels of PGE2, obtained at 10 and 12 weeks of age, were always lower in SHR than in WKY rats and were not influenced by dietary sodium. In WKY and SHR on normal diets, the urinary levels of 2,3-dinor-6-oxo-PGF1 alpha did not differ significantly. However, the chronic administration of a high sodium diet (5.9% NaCl) was accompanied by a significant and sustained rise in the urinary excretion of 2,3-dinor-6-oxo-PGF1 alpha in the order of 30% to 50% in WKY but not in SHR, a finding similar to that in Dahl rats. These results point to the existence of an impaired capacity in SHR to synthesize vasodilator prostaglandins in vivo, contrary to the situation prevailing in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)


An event-driven approach for studying gene block evolution in bacteria.
Gene blocks are genes co-located on the chromosome. In many cases, gene blocks are conserved between bacterial species, sometimes as operons, when genes are co-transcribed. The conservation is rarely absolute: gene loss, gain, duplication, block splitting and block fusion are frequently observed. An open question in bacterial molecular evolution is that of the formation and breakup of gene blocks, for which several models have been proposed. These models, however, are not generally applicable to all types of gene blocks, and consequently cannot be used to broadly compare and study gene block evolution. To address this problem, we introduce an event-based method for tracking gene block evolution in bacteria. We show here that the evolution of gene blocks in proteobacteria can be described by a small set of events. Those include the insertion of genes into, or the splitting of genes out of a gene block, gene loss, and gene duplication. We show how the event-based method of gene block evolution allows us to determine the evolutionary rateand may be used to trace the ancestral states of their formation. We conclude that the event-based method can be used to help us understand the formation of these important bacterial genomic structures. The software is available under GPLv3 license on http://github.com/reamdc1/gene_block_evolution.git. Supplementary online material: http://iddo-friedberg.net/operon-evolution


Focusing the HIV response through estimating the major modes of HIV transmission: a multi-country analysis.
An increasing number of countries have been estimating the distribution of new adult HIV infections by modes of transmission (MOT) to help prioritise prevention efforts. We compare results from studies conducted between 2008 and 2012 and discuss their use for planning and responding to the HIV epidemic. The UNAIDS recommended MOT model helps countries to estimate the proportion of new HIV infections that occur through key transmission modes including sex work, injecting drug use (IDU), men having sex with men (MSM), multiple sexual partnerships, stable relationships and medical interventions. The model typically forms part of a country-led process that includes a comprehensive review of epidemiological data. Recent revisions to the model are described. Modelling results from 25 countries show large variation between and within regions. In sub-Saharan Africa, new infections occur largely in the general heterosexual population because of multiple partnerships or in stable discordant relationships, while sex work contributes significantly to new infections in West Africa. IDU and sex work are the main contributors to new infections in the Middle East and North Africa, with MSM the main contributor in Latin America. Patterns vary substantially between countries in Eastern Europe and Asia in terms of the relative contribution of sex work, MSM, IDU and spousal transmission. The MOT modelling results, comprehensive review and critical assessment of data in a country can contribute to a more strategically focused HIV response. To strengthen this type of research, improved epidemiological and behavioural data by risk population are needed.


Canadian emergency medicine and critical care physician perspectives on pandemic triage in COVID-19.
Local and regional policies to guide the allocation of scarce critical care resources have been developed, but the views of prospective users are not understood. We sought to investigate the perspectives of Canadian acute care physicians toward triaging scarce critical care resources in the COVID-19 pandemic. We rapidly deployed a brief survey to Canadian emergency and critical care physicians in April 2020 to investigate current attitudes toward triaging scarce critical care resources and identify subsequent areas for improvement. Descriptive and between-group analyses along with thematic coding were used. The survey was completed by 261 acute care physicians. Feelings of anxiety related to the pandemic were common (65 percent), as well as fears of psychological distress if required to triage scarce resources (77 percent). Only 49 percent of respondents felt confident in making resource allocation decisions. Both critical care and emergency physicians favored multidisciplinary teams over single physicians to allocate scarce critical care resources. Critical care physicians were supportive of decision making by teams not involved in patient care (3.4/5 versus 2.9/5 p = 0.04), whereas emergency physicians preferred to maintain their involvement in such decisions (3.4/5 versus 4.0/5 p = 0.007). Free text responses identified five themes for subsequent action including the need for further guidance on existing triage policies, ethical support in decision making, medicolegal protection, additional tools for therapeutic communications, and healthcare provider psychological support. There is an urgent need for collaboration between policymakers and frontline physicians to develop critical care resource triage policies that wholly consider the diversity of provider perspectives across practice environments.


Intestinal anti-inflammatory effects of artichoke pectin and modified pectin fractions in the dextran sulfate sodium model of mice colitis. Artificial neural network modelling of inflammatory markers.
Anti-inflammatory properties of artichoke pectin and modified fractions (arabinose- and galactose-free) used at two doses (40 and 80 mg kg-1) in mice with colitis induced by dextran sulfate sodium have been investigated. Expression of pro-inflammatory markers TNF-α and ICAM-I decreased in groups of mice treated with original and arabinose-free artichoke pectin while IL-1β and IL-6 liberation was reduced only in mice groups treated with original artichoke pectin. A decrease in iNOS and TLR-4 expression was observed for most treatments. Intestinal barrier gene expression was also determined. MUC-1 and Occludin increased in groups treated with original artichoke pectin while MUC-3 expression also increased in arabinose-free pectin treatment. Galactose elimination led to a loss of pectin bioactivity. Characteristic expression profiles were established for each treatment through artificial neural networks showing high accuracy rates (≥90%). These results highlight the potential amelioration of inflammatory bowel disease on mice model colitis through artichoke pectin administration.


Color demosaicking via directional linear minimum mean square-error estimation.
Digital cameras sample scenes using a color filter array of mosaic pattern (e.g., the Bayer pattern). The demosaicking of the color samples is critical to the image quality. This paper presents a new color demosaicking technique of optimal directional filtering of the green-red and green-blue difference signals. Under the assumption that the primary difference signals (PDS) between the green and red/blue channels are low pass, the missing green samples are adaptively estimated in both horizontal and vertical directions by the linear minimum mean square-error estimation (LMMSE) technique. These directional estimates are then optimally fused to further improve the green estimates. Finally, guided by the demosaicked full-resolution green channel, the other two color channels are reconstructed from the LMMSE filtered and fused PDS. The experimental results show that the presented color demosaicking technique outperforms the existing methods both in PSNR measure and visual perception.


Scientists' statement regarding data on the sodium-hypertension relationship and sodium health claims on food labeling.
Nutrition Reviews has had a continuing interest in the scientific basis of arguments for and against health claims on foods. Such claims were first authorized by the Food and Drug Administration (FDA) in 1993 under the terms of the Nutrition Labelling and Education Act of the U.S. Congress, passed in 1990. Since then there have been petitions that have resulted in a newly authorized claim for oats and other petitions directed toward modification or deletion of the originally approved claims. The Salt Institute, an industry-supported organization, has actively participated in the discussions regarding the sodium and hypertension health claim. The scientists signing this statement are familiar with the evolving understanding of the relationship between sodium and hypertension. The statement reviews more recent studies and critiques the arguments for a sodium health claim. We invite our readers to respond to the discussion in this controversial area of nutrition science and policy.


Risk of preterm delivery with increasing depth of excision for cervical intraepithelial neoplasia in England: nested case-control study.
To determine the association between depth of excision of cervical intraepithelial neoplasia and risk of preterm birth. Case-control study nested in record linkage cohort study. 12 hospitals in England. From a cohort of 11 471 women with at least one histological sample taken at colposcopy and a live singleton birth (before or after colposcopy), 1313 women with a preterm birth (20-36 weeks) were identified and frequency matched on maternal age at delivery, parity, and study site to 1313 women with term births (38-42 weeks). Risk of preterm birth and very/extreme preterm birth by depth of excisional treatment of the cervical transformation zone. After exclusions, 768 preterm births (cases) and 830 term births after colposcopy remained. The risk of preterm birth was no greater in women with a previous small (<10 mm) excision (absolute risk 7.5%, 95% confidence interval 6.0% to 8.9%) than in women with a diagnostic punch biopsy (7.2%, 5.9% to 8.5%). Women with a medium (10-14 mm) (absolute risk 9.6%; relative risk 1.28, 0.98 to 1.68), large (15-19 mm) (15.3%; 2.04, 1.41 to 2.96), or very large (≥ 20 mm) excision (18.0%; 2.40, 1.53 to 3.75) had a higher risk of preterm delivery than those with small excision. The same pattern was seen in 161 women with very/extremely preterm births (20-31 weeks) and with increasing volume excised. Most births were conceived more than three years after colposcopy, and the risk of preterm delivery did not seem to depend on time from excision to conception. The risk of preterm birth is at most minimally affected by a small excision. Larger excisions, particularly over 15 mm or 2.66 cm(3), are associated with a doubling of the risk of both preterm and very preterm births. The risk does not decrease with increasing time from excision to conception. Efforts should be made to excise the entire lesion while preserving as much healthy cervical tissue as possible. Close obstetric monitoring is warranted for women who have large excisions of the cervical transformation zone.


The human core of the shared socioeconomic pathways: Population scenarios by age, sex and level of education for all countries to 2100.
This paper applies the methods of multi-dimensional mathematical demography to project national populations based on alternative assumptions on future, fertility, mortality, migration and educational transitions that correspond to the five shared socioeconomic pathways (SSP) storylines. In doing so it goes a significant step beyond past population scenarios in the IPCC context which considered only total population size. By differentiating the human population not only by age and sex-as is conventionally done in demographic projections-but also by different levels of educational attainment the most fundamental aspects of human development and social change are being explicitly addressed through modeling the changing composition of populations by these three important individual characteristics. The scenarios have been defined in a collaborative effort of the international Integrated Assessment Modeling community with the medium scenario following that of a major new effort by the Wittgenstein Centre for Demography and Global Human Capital (IIASA, OEAW, WU) involving over 550 experts from around the world. As a result, in terms of total world population size the trajectories resulting from the five SSPs stay very close to each other until around 2030 and by the middle of the century already a visible differentiation appears with the range between the highest (SSP3) and the lowest (SSP1) trajectories spanning 1.5 billion. The range opens up much more with the SSP3 reaching 12.6 billion in 2100 and SSP1 falling to 6.9 billion which is lower than today's world population.


High-provitamin A carotenoid (Orange) maize increases hepatic vitamin A reserves of offspring in a vitamin A-depleted sow-piglet model during lactation.
The relationship of dietary vitamin A transfer from mother to fetus is not well understood. The difference in swine offspring liver reserves was investigated between single-dose vitamin A provided to the mother post-conception compared with continuous provitamin A carotenoid dietary intake from biofortified (enhanced provitamin A) orange maize (OM) fed during gestation and lactation. Vitamin A-depleted sows were fed OM (n = 5) or white maize (WM) + 1.05 mmol retinyl palmitate administered at the beginning of gestation (n = 6). Piglets (n = 102) were killed at 0, 10, 20, and 28 d after birth. Piglets from sows fed OM had higher liver retinol reserves (P < 0.0001) and a combined mean concentration from d 10 to 28 of 0.11 ± 0.030 μmol/g. Piglets from sows fed WM had higher serum retinol concentrations (0.56 ± 0.25 μmol/L; P = 0.0098) despite lower liver retinol concentrations of 0.068 ± 0.026 μmol/g from d 10 to 28. Milk was collected at 0, 5, 10, 20, and 28 d. Sows fed OM had a higher milk retinol concentration (1.36 ± 1.30 μmol/L; P = 0.038), than those fed WM (0.93 ±1.03 μmol/L). Sow livers were collected at the end of the study (n = 3/group) and had identical retinol concentrations (0.22 ± 0.05 μmol/g). Consumption of daily provitamin A carotenoids by sows during gestation and lactation increased liver retinol status in weanling piglets, illustrating the potential for provitamin A carotenoid consumption from biofortified staple foods to improve vitamin A reserves. Biofortified OM could have a measurable impact on vitamin A status in deficient populations if widely adopted.


Efficient vacuum-free-processed quantum dot light-emitting diodes with printable liquid metal cathodes.
Colloidal quantum dot light-emitting diodes (QLEDs) are recognized as promising candidates for next generation displays. QLEDs can be fabricated by low-cost solution processing except for the metal electrodes, which, in general, are deposited by costly vacuum evaporation. To be fully compatible with the low-cost solution process, we herein demonstrate vacuum-free and solvent-free fabrication of electrodes using a printable liquid metal. With eutectic gallium-indium (EGaIn) based liquid metal cathodes, vacuum-free-processed QLEDs are demonstrated with superior external quantum efficiencies of 11.51%, 12.85% and 5.03% for red, green and blue devices, respectively, which are about 2-, 1.5- and 1.1-fold higher than those of the devices with thermally evaporated Al cathodes. The improved performance is attributable to the reduction of electron injection by the native oxide of EGaIn, which serves as an electron-blocking layer for the devices and thus improves the balance of carrier injection. Also, the T50 half-lifetime of the vacuum-free-processed QLEDs is about 2-fold longer than that of the devices with Al cathodes. Our results demonstrate that EGaIn-based solvent-free liquid metals are promising printable electrodes for realizing efficient, low-cost and vacuum-free-processed QLEDs. The elimination of vacuum and high-temperature processes significantly reduces the production cost and paves the way for industrial roll-to-roll manufacturing of large area displays.


Increased Risk of Revision, Reoperation, and Implant Constraint in TKA After Multiligament Knee Surgery.
The risk of major complications and revision arthroplasty after TKA in patients who previously underwent multiligament knee surgery have been poorly characterized. Is multiligament knee surgery before TKA associated with (1) worse implant survival, (2) increased use of TKA design constraint, (3) a greater risk for major complications, and (4) poorer scores for pain and function compared with similar patients receiving TKA for primary osteoarthritis? Fifty-nine TKAs were performed at our institution between 1985 and 2014 in 59 patients (36 men, 23 women; mean age, 53 years) with a history of previous multiligament knee surgery (≥ two ligaments). Of those, we had followup for 39 (66%), 18 (31%), and six (10%) patients at 5, 10, and 15 years, respectively; mean followup was 5.4 years (range, 1-25 years). A two-to-one matched control group consisting of patients undergoing primary TKA for the diagnosis of osteoarthritis was selected for comparison. Patients were matched based on gender, age at primary TKA (within 5 years), and date of the TKA (within 5 years). Medical records were reviewed for survivorship, TKA design, complications (reoperation, revision, infection, manipulation under anesthesia, and periprosthetic joint infection), TKA design, and clinical outcomes (Knee Society Scores [KSS], Knee Society Function Score [KSS-F]). The overall 15-year revision-free survival in patients with prior multiligament knee surgery was decreased in comparison to the matched controls (42% [95% CI, 16%-73%] vs 94% [95% CI, 81%-99%]; p < 0.001). Varus-valgus constraint implant design was used for more patients in the multiligament cohort at index TKA than in the matched control group (9/59 [15%] vs 0/110 [0%], respectively; odds ratio [OR], 45; 95% CI, 3-781; p = 0.009). Patients with a history of multiligament knee surgery also were at increased risk of reoperation for any cause (14/59 [24%] vs 7/118 [6%]; OR, 5; 95% CI, 2-14; p = 0.001). With the numbers available, there was no difference in the frequency of manipulation under anesthesia after TKA (10% [6/59] versus 3% [4/118]; p = 0.08) A higher proportion of patients in the multiligament cohort had infections develop compared with the matched controls (4/59 [7%] vs 1/118 [< 1%)], respectively; p = 0.04). There was no difference in the KSS improvement after TKA between the multiligament group and the control group (34 ± 18 vs 28 ± 15; p = 0.088). The final KSS and KSS-F scores likewise showed no difference between those groups (88 ± 13 vs 85 ± 10; p = 0.232) (85 ± 17 vs 84 ± 14; p = 0.75). A history of multiligament surgery is associated with lower long-term survivorship, higher use of constrained TKA designs, and higher risk of major complications, including reoperation and infection. Further research is necessary to determine if a particular multiligamentous surgical technique can prevent posttraumatic arthritis and TKA complications. Level III, therapeutic study.


Development of oligonucleotide probes and PCR primers for detecting phylogenetic subgroups of sulfate-reducing bacteria.
PCR primer sets for the 16S rRNA gene of six phylogenetic groups of sulfate-reducing bacteria (SRB) were designed. Their application in conjunction with group-specific internal oligonucleotide probes was used to detect SRB DNA in samples of landfill leachate. Six generic/suprageneric groups could be differentiated: DESULFOTOMACULUM:; DESULFOBULBUS:; DESULFOBACTERIUM:; DESULFOBACTER:; DESULFOCOCCUS:-DESULFONEMA:-DESULFOSARCINA:; DESULFOVIBRIO:-DESULFOMICROBIUM: The predicted specificities of the PCR primer and oligonucleotide probe combinations were confirmed with DNA from reference strains. In all cases, the PCR primers and probes were specific, the only exception being that the Desulfococcus-Desulfonema-Desulfosarcina (group 5) PCR primers were able to amplify DNA from DESULFOBACTERIUM: (group 3) reference strains but these groups could nevertheless be differentiated with the internal oligonucleotide probes. The proliferation of SRB in landfill sites interferes with methanogenesis and waste stabilization, but relatively little is known about the composition of SRB populations in this environment. DNA was extracted from samples of landfill leachate from several municipal waste landfill sites and used as template in PCR reactions with SRB group-specific primer sets. Group-specific oligonucleotide probes were then used to confirm that the PCR products obtained contained the target SRB 16S rDNA. Both 'direct' and 'nested' PCR protocols were used to amplify SRB 16S rDNA from landfill leachates. Three of the six SRB groups could be detected using the 'direct' PCR approach (DESULFOTOMACULUM:, DESULFOBACTER: and Desulfococcus-Desulfonema-Desulfosarcina). When 'nested' PCR was applied, an additional two groups could be detected (DESULFOBULBUS: and DESULFOVIBRIO:-DESULFOMICROBIUM:). Only DESULFOBACTERIUM: could not be detected in any leachate samples using either direct or nested PCR. The SRB-specific 16S rDNA primers and probes described here can be applied to investigations of SRB molecular ecology in general, and can be further developed for examining SRB population composition in relation to landfill site performance.


Ubx2 links the Cdc48 complex to ER-associated protein degradation.
Endoplasmic reticulum (ER)-associated protein degradation requires the dislocation of selected substrates from the ER to the cytosol for proteolysis via the ubiquitin-proteasome system. The AAA ATPase Cdc48 (known as p97 or VCP in mammals) has a crucial, but poorly understood role in this transport step. Here, we show that Ubx2 (Sel1) mediates interaction of the Cdc48 complex with the ER membrane-bound ubiquitin ligases Hrd1 (Der3) and Doa10. The membrane protein Ubx2 contains a UBX domain that interacts with Cdc48 and an additional UBA domain. Absence of Ubx2 abrogates breakdown of ER proteins but also that of a cytosolic protein, which is ubiquitinated by Doa10. Intriguingly, our results suggest that recruitment of Cdc48 by Ubx2 is essential for turnover of both ER and non-ER substrates, whereas the UBA domain of Ubx2 is specifically required for ER proteins only. Thus, a complex comprising the AAA ATPase, a ubiquitin ligase and the recruitment factor Ubx2 has a central role in ER-associated proteolysis.


Rural Veterans' dental utilization, Behavioral Risk Factor Surveillance Survey, 2014.
Rural residents are overrepresented in the military; however, access to Veteran services is limited in rural areas. There is a need to identify rural Veteran healthcare utilization. This study addresses that need and has two purposes: a) to determine if there is an association between rural dwelling and Veteran utilization of dental services; and b) to determine if there is an association between rural dwelling and the oral health outcome of missing teeth. Data from the 2014 Behavioral Risk Factor Surveillance Survey were used in this study. Chi square and logistic regression analyses were conducted. Rural Veterans were less likely to have a dental visit during the previous year as compared with metropolitan Veterans in unadjusted analysis (Odds ratio = 0.71, 95% Confidence Interval, 0.64, 0.77) and in adjusted analysis [0.87 (95% Confidence Interval, 0.78, 0.96)]. In cases in which all teeth were missing, rural Veterans had an unadjusted odds ratio of 1.79 [95% Confidence Interval, 1.55, 2.08] and an adjusted odds ratio of 1.37 [95% Confidence Interval, 1.17, 1.62] as compared with metropolitan Veterans. The Veterans Health Administration develops policies for establishing centers for care for Veterans. The policy development should take into consideration that rural Veterans have not been as likely as urban Veterans to utilize dental services and have poorer oral health outcomes.


Elevated plasma vitamin B12 levels as a marker for cancer: a population-based cohort study.
A substantial proportion of patients referred for plasma vitamin B12 (cobalamin [Cbl]) measurement present with high Cbl levels, which have been reported in patients with different cancer types. However, the cancer risk among patients with newly diagnosed high Cbl levels has not been adequately examined. We conducted this cohort study using population-based Danish medical registries. Patients referred for Cbl measurement with levels greater than the lower reference limit (≥200 pmol/L) were identified from the population of Northern Denmark during the period of 1998 to 2009 using a database of laboratory test results covering the entire population. Data on cancer incidence (follow-up 1998-2010), Cbl treatment, and prior diagnoses were obtained from medical registries. Patients receiving Cbl treatment were excluded. Cancer risks were calculated as standardized incidence ratios (SIRs) with 95% confidence intervals (CIs), stratified by plasma Cbl levels. All statistical tests were two-sided. We identified 333 667 persons without prevalent cancer and not receiving Cbl treatment. Six percent had Cbl levels greater than the upper reference limit (≥601 pmol/L). Cancer risk increased with higher Cbl levels and was highest during the first year of follow-up (Cbl 601-800 pmol/L: SIR = 3.44, 95% CI = 3.14 to 3.76; Cbl >800 pmol/L: SIR = 6.27, 95% CI = 5.70 to 6.88; both P < .001). The risks were particularly elevated for hematological and smoking- and alcohol-related cancers for persons with high Cbl levels. High Cbl levels were associated with the risk of subsequently diagnosed cancer, mostly within the first year of follow-up. This may have clinical implications for the interpretation of high Cbl levels.


EEG-fMRI fusion of paradigm-free activity using Kalman filtering.
We address here the use of EEG and fMRI, and their combination, in order to estimate the full spatiotemporal patterns of activity on the cortical surface in the absence of any particular assumptions on this activity such as stimulation times. For handling such a high-dimension inverse problem, we propose the use of (1) a global forward model of how these measures are functions of the "neural activity" of a large number of sources distributed on the cortical surface, formalized as a dynamical system, and (2) adaptive filters, as a natural solution to solve this inverse problem iteratively along the temporal dimension. This estimation framework relies on realistic physiological models, uses EEG and fMRI in a symmetric manner, and takes into account both their temporal and spatial information. We use the Kalman filter and smoother to perform such an estimation on realistic artificial data and demonstrate that the algorithm can handle the high dimensionality of these data and that it succeeds in solving this inverse problem, combining efficiently the information provided by the two modalities (this information being naturally predominantly temporal for EEG and spatial for fMRI). It performs particularly well in reconstructing a random temporally and spatially smooth activity spread over the cortex. The Kalman filter and smoother show some limitations, however, which call for the development of more specific adaptive filters. First, they do not cope well with the strong nonlinearity in the model that is necessary for an adequate description of the relation between cortical electric activities and the metabolic demand responsible for fMRI signals. Second, they fail to estimate a sparse activity (i.e., presenting sharp peaks at specific locations and times). Finally their computational cost remains high. We use schematic examples to explain these limitations and propose further developments of our method to overcome them.


Combination Antiplatelet and Oral Anticoagulant Therapy in Patients With Coronary and Peripheral Artery Disease.
Antiplatelet therapy is the mainstay for the treatment of acute and chronic arterial disease involving the coronary and peripheral beds. However, questions remain about optimal antithrombotic therapy for long-term treatment of chronic vascular disease. The observation that dual antiplatelet therapy with acetylsalicylic acid and clopidogrel was associated with lower thrombotic event rates than acetylsalicylic acid monotherapy in patients with acute coronary syndromes and those undergoing percutaneous coronary intervention changed the treatment paradigm. Moreover, the demonstration that more pharmacodynamically potent P2Y12 inhibitors than clopidogrel were associated with fewer thrombotic event occurrences further solidified the dual antiplatelet therapy approach. However, recurrent thrombotic events occur in ≈1 in 10 patients in the first year following an acute coronary syndrome event, despite treatment with the most potent P2Y12 inhibitors, a limitation that has stimulated interest in exploring the efficacy and safety of approaches using anticoagulants on top of antiplatelet therapy. These investigations have included treatment with very-low-dose oral anticoagulation, and even its replacement of acetylsalicylic acid in the presence of a P2Y12 inhibitor, in patients stabilized after an acute coronary syndrome event. Recent basic and translational studies have suggested noncanonical effects of coagulation factor inhibition that may further modulate clinical benefits. This in-depth review will discuss developments in our understanding of the roles that platelets and coagulation factors play in atherothrombosis and review the rationale and clinical evidence for combining antiplatelet and oral anticoagulant therapy in patients with coronary and peripheral artery disease.


Survival experience among patients with AIDS receiving zidovudine. Follow-up of patients in a compassionate plea program.
Through a compassionate plea program (Treatment Investigational New Drug), 4805 patients with acquired immunodeficiency syndrome who previously had experienced Pneumocystis carinii pneumonia (PCP) received zidovudine (Retrovir, formerly azidothymidine). Overall survival at 44 weeks after initiation of therapy was 73% (+/- 2.1%). A positive association was found between survival and pretherapy clinical status as defined by hemoglobin level, functional ability, and stage of disease as measured by time since diagnosis of PCP. For patients with baseline hemoglobin levels of 120 g/L or greater, Karnofsky scores of 90 or greater, and PCP diagnosis within 90 days prior to initiation of therapy, 44-week survival was 88%. Adverse clinical experiences associated with zidovudine therapy were consistent with those from a double-blind, placebo-controlled trial. Survival experience of this large and diverse cohort is consistent with, and extends data from, this clinical trial. Comparison with available natural history data suggests that zidovudine therapy is associated with increased 44-week survival of post-PCP patients with acquired immunodeficiency syndrome.


MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline.
Small RNAs associate with Argonaute proteins and serve as sequence-specific guides for regulation of mRNA stability, productive translation, chromatin organization, and genome structure. In animals, the Argonaute superfamily segregates into two clades. The Argonaute clade acts in RNAi and in microRNA-mediated gene regulation in partnership with 21-22 nt RNAs. The Piwi clade, and their 26-30 nt piRNA partners, have yet to be assigned definitive functions. In mice, two Piwi-family members have been demonstrated to have essential roles in spermatogenesis. Here, we examine the effects of disrupting the gene encoding the third family member, MIWI2. Miwi2-deficient mice display a meiotic-progression defect in early prophase of meiosis I and a marked and progressive loss of germ cells with age. These phenotypes may be linked to an inappropriate activation of transposable elements detected in Miwi2 mutants. Our observations suggest a conserved function for Piwi-clade proteins in the control of transposons in the germline.


Neuroblastoma screening data. An epidemiologic analysis.
Neuroblastoma is one of the most common malignant neoplasms in children under age 5 years. Little progress has been made in the prognosis of advanced stage disease in the past three decades. Since the development in the 1960s of a simple urine test to detect neuroblastoma metabolites, there has been hope that mortality from this disease could be reduced by early detection via mass screening of young infants. Encouraging reports from Japan on mass screening programs instituted in the 1970s have been appearing in the medical literature since 1982, resulting in widespread interest in screening. This article applies standard epidemiologic criteria for screening evaluations to the Japanese reports. We find that the data needed to definitively assess the value of screening were not a part of those reports and that the benefits claimed from the reported data could be due to overdiagnosis. In addition, the most recent Japanese data, combined with recent advances in biologic understanding of neuroblastoma, show that screening at age 6 months may not detect tumors with poor prognoses. Even if it could, it is uncertain whether those outcomes could be substantially altered by earlier diagnosis. Although a final verdict on the value of neuroblastoma screening is not yet possible, these neuroblastoma studies are an excellent example of how screening results must be viewed with extreme caution in the absence of age-specific, population-based incidence and mortality rates.


The neonicotinoid thiamethoxam impairs male fertility in solitary bees, Osmia cornuta.
The ongoing loss of global biodiversity is endangering ecosystem functioning and human food security. While environmental pollutants are well known to reduce fertility, the potential effects of common neonicotinoid insecticides on insect fertility remain poorly understood. Here, we show that field-realistic neonicotinoid exposure can drastically impact male insect fertility. In the laboratory, male and female solitary bees Osmia cornuta were exposed to four concentrations of the neonicotinoid thiamethoxam to measure survival, food consumption, and sperm traits. Despite males being exposed to higher dosages of thiamethoxam, females revealed an overall increased hazard rate for survival; suggesting sex-specific differences in toxicological sensitivity. All tested sublethal concentrations (i.e., 1.5, 4.5 and 10 ng g-1) reduced sperm quantity by 57% and viability by 42% on average, with the lowest tested concentration leading to a reduction in total living sperm by 90%. As the tested sublethal concentrations match estimates of global neonicotinoid pollution, this reveals a plausible mechanism for population declines, thereby reflecting a realistic concern. An immediate reduction in environmental pollutants is required to decelerate the ongoing loss of biodiversity.


Copper Supplementation in Watering Solution Reaches the Xylem But Does Not Protect Tobacco Plants Against Xylella fastidiosa Infection.
Xylella fastidiosa is a xylem-limited plant pathogenic bacterium that causes disease in many crops worldwide. Copper (Cu) is an antimicrobial agent widely used on X. fastidiosa hosts to control other diseases. Although the effects of Cu for control of foliar pathogens are well known, it is less studied on xylem-colonizing pathogens. Previous results from our group showed that low concentrations of CuSO4 increased biofilm formation, whereas high concentrations inhibited biofilm formation and growth in vitro. In this study, we conducted in planta experiments to determine the influence of Cu in X. fastidiosa infection using tobacco as a model. X. fastidiosa-infected and noninfected plants were watered with tap water or with water supplemented with 4 mM or 8 mM of CuSO4. Symptom progression was assessed, and sap and leaf ionome analysis was performed by inductively coupled plasma with optical emission spectroscopy. Cu uptake was confirmed by increased concentrations of Cu in the sap of plants treated with CuSO4-amended water. Leaf scorch symptoms in Cu-supplemented plants showed a trend toward more severe at later time points. Quantification of total and viable X. fastidiosa in planta indicated that CuSO4-amended treatments did not inhibit but slightly increased the growth of X. fastidiosa. Cu in sap was in the range of concentrations that promote X. fastidiosa biofilm formation according to our previous in vitro study. Based on these results, we proposed that the plant Cu homeostasis machinery controls the level of Cu in the xylem, preventing it from becoming elevated to a level that would lead to bacterial inhibition.


Intravenous immunoglobulin replacement induces an in vivo reduction of inflammatory monocytes and retains the monocyte ability to respond to bacterial stimulation in patients with common variable immunodeficiencies.
Intravenous IgG administration induces significant modifications in the innate and adaptive compartment of the immune system including the monocyte/macrophage system. We analyzed the in vivo effect of IgG administered at replacement dosages on the frequency of monocytes subsets, on the modulation of CD11b and sialic acid-binding immunoglobulin-like lectin receptor (Siglec 9) expression and on monocytes production of reactive oxygen species. We showed that patients with Common Variable Immune Deficiency have an increased frequency pro-inflammatory intermediate CD14(++)CD16(+) monocytes and an increased expression of CD11b and Siglec 9 on monocytes. IgG administered at replacement dosages exerted an in vivo anti-inflammatory effect as shown by a reduction of circulating monocytes, of intermediate pro-inflammatory monocytes, of CD11b and Siglec 9 expression and of ex vivo monocytes oxidative burst. Nevertheless, intravenous IgG administration did not affect the monocyte functional ability to respond to a bacterial stimulation in terms of CD11b and Siglec 9 expression and reactive oxygen species production.


The metabolic outcomes of growth hormone treatment in children are gender specific.
To evaluate the impact of gender on the clinical and metabolic parameters in prepubertal growth hormone deficiency (GHD) children at diagnosis and during GH treatment (GHT). The data of 105 prepubertal children (61 males, 44 females, mean age 6.8 ± 0.7 years) affected by idiopathic GHD were retrospectively evaluated. Body height, BMI, waist circumference (WC), IGF-I, HbA1c, lipid profile, fasting and after-OGTT glucose and insulin levels, insulin sensitivity and secretion indices were evaluated at baseline and after 24 months of GHT. At baseline, no significant difference was found in all clinical, hormonal and metabolic parameters between males and females. After 24 months of GHT, both males and females showed a significant increase in height (both P < 0.001), BMI (both P < 0.001), WC (P < 0.001 and P = 0.004, respectively), IGF-I (both P < 0.001), fasting glucose (P < 0.001 and P = 0.001, respectively), fasting insulin (both P < 0.001) and Homa-IR (both P < 0.001), with a concomitant significant decrease in insulin sensitivity index (ISI) (both P < 0.001) and oral disposition index (DIo) (P = 0.001 and P < 0.001, respectively). At 24 months of GHT, females showed significantly higher BMI (P = 0.027), lower ISI (P < 0.001) and DIo (P < 0.001), in concomitance with a significant greater change from baseline to 24 months of BMI (P = 0.013), WC (P < 0.001), ISI (P = 0.002) and DIo (P = 0.072), although the latter does not reach statistical significance. Twenty-four months of GHT in prepubertal children leads to different metabolic outcomes according to gender, with a greater reduction in insulin sensitivity in females, regardless of auxological and hormonal parameters. Therefore, prepubertal GHD females should probably need a more proper monitoring in clinical practice.


[Inequalities in health: definitions, concepts, and theories].
Individuals from different backgrounds, social groups, and countries enjoy different levels of health. This article defines and distinguishes between unavoidable health inequalities and unjust and preventable health inequities. We describe the dimensions along which health inequalities are commonly examined, including across the global population, between countries or states, and within geographies, by socially relevant groupings such as race/ethnicity, gender, education, caste, income, occupation, and more. Different theories attempt to explain group-level differences in health, including psychosocial, material deprivation, health behavior, environmental, and selection explanations. Concepts of relative versus absolute; dose response versus threshold; composition versus context; place versus space; the life course perspective on health; causal pathways to health; conditional health effects; and group-level versus individual differences are vital in understanding health inequalities. We close by reflecting on what conditions make health inequalities unjust, and to consider the merits of policies that prioritize the elimination of health disparities versus those that focus on raising the overall standard of health in a population.


Phytobezoar-induced small bowel obstruction associated with a concomitant gastric phytobezoar and ulcer in an elderly woman.
Bezoars are aggregates of indigested foreign material that accumulate in the gastroenteric tract, expecially in the stomach and in the narrowest points of the small bowel. They often occur in subjects who follow a diet rich in fruit and vegetables and in those one who previously underwent gastric resective surgery for peptic ulcer. Bezoar formation has even been observed in case of reduced gastric motility and secretion due to diabetes, hypothyroidism, pernicious anemia, myotonic syndromes, and Guillain-Barré syndrome. As they are an uncommon cause of small bowel obstruction, phytobezoars are often not considered in the differential diagnosis of occlusive intestinal syndromes and so frequently come as an intraoperative finding. A consequence of this missed diagnosis in the preoperative period is an unnecessary diagnostic delay that can significantly increase morbidity and mortality. This case report illustrates the need to include phytobezoars in the preoperative diagnostic workout of intestinal obstruction in order to rule out the presence of multiple bezoars and prevent recurrent obstruction. Now that phytobezoars are becoming a less infrequent cause of small bowel obstruction than previously thought, such a diagnostic possibility should always be considered.


Introgression at differentially aged hybrid zones in red-tailed chipmunks.
Hybrid zones allow us to investigate the maintenance and the break down of reproductive isolation; they are a window into the speciation process. Tamias ruficaudus (red-tailed chipmunk) has a roughly ring-like distribution in the Inland Northwest and includes two morphologically well-differentiated subspecies, T. r. ruficaudus (in the eastern portion of its range) and T. r. simulans (in the western portion). These taxa meet at two contact zones: the Lochsa River in Idaho and 200 km to the north, near Whitefish, Montana. The Lochsa Zone is encompassed within the Clearwater River Drainage, which has been proposed as a glacial refugium for many taxa throughout the Pleistocene, whereas the Whitefish Zone was under the Cordilleran ice sheet during the most recent glacial maxima approximately 10,000 years ago. Mitochondrial DNA introgression has been documented at both contact zones, yet the subspecies remain significantly distinct with respect to bacular morphology and no intermediate morphologies have ever been reported. Here, we elucidate differentiation and introgression of the nuclear genome using ten microsatellite loci and compare findings to previously described mitochondrial DNA haplotype distribution and introgression. We found significant substructure in the nuclear data; each subspecies is divided into at least two genetically distinct demes. At the Lochsa contact zone, individuals restricted to the mtDNA zone of introgression form a distinct deme at microsatellite loci whereas in the younger, Whitefish contact zone, there is no hybrid-zone specific group. The genetic distances of the demes within these two subspecies indicate recent northward expansion.


Phenotypic characterization and anti-tumor effects of cytokine-induced killer cells derived from cord blood.
Cytokine-induced killer (CIK) cell therapy represents a feasible immunotherapeutic option for treating malignancies. However, the number of anti-tumor lymphocytes cannot be easily obtained from the cancer patients with poor immunity status, and older patients cannot tolerate repeated collection of blood. Cord blood-derived CIK (CB-CIK) cells have shown efficacy in treating the patients with cancer in several clinical trials. This study was conducted to evaluate the biological characteristics and anti-tumor function of CB-CIK cells. The immunogenicity, chemokine receptors and proliferation of CB-CIK cells were analyzed by flow cytometry. The CIK cells on day 13 were treated with cisplatin and the anti-apoptosis capacity was analyzed. The function of CB-CIK cells against the human cancer was evaluated both in vitro and in vivo. Compared with peripheral blood-derived CIK (PB-CIK) cells, CB-CIK cells demonstrated lower immunogenicity and increased proliferation rates. CB-CIK cells also had a higher percentage of main functional fraction CD3(+)CD56(+). The anti-apoptosis ability of CB-CIK cells after treatment with cisplatin was higher than that of PB-CIK cells. Furthermore, CB-CIK cells were effective for secreting interleukin-2 and interferon-γ and a higher percentage of chemokine receptors CCR6 and CCR7. In addition, tumor growth was greatly inhibited by CB-CIK treatment in a nude mouse xenograft model. CB-CIK cells exhibit more efficient anti-tumor activity in in vitro analysis and in the preclinical model and may serve as a potential therapeutic approach for the treatment of cancer.