Effects of autologous sera on immediate and late skin reaction to the house dust mite in atopic individuals.
To evaluate the in vivo effect of autologous serum including antibodies to house dust mite in atopic individuals, we observed the immediate (15 mins) and late (6 hours) skin reactions (ISR, LSR) on intradermal (ID) test of serially diluted Dermatophagoides farinae antigens (DFa, Allergopharma, Germany) mixed with autologous sera (DFa-S) and diluent alone (DFa-D). We tested 34 DFa-skin reactive atopic individuals including 12 asthmatics (BA), 8 asthmatics on immunotherapy with DFa (IT), and 14 healthy atopic controls (AC). We observed complete inhibition of ISR in the lowest allergen dose of DFa-S in 7 (58.3%) of 12 BA, 3 (37.5%) of 8 IT, and 2 (14.3%) of 14 AC. In BA, the inhibition of ISR was more frequent than AC (p < 0.05). We observed larger late reactions in half of LSR positive cases on ID test by DFa-S than by DFa-D (> or = 1.5 X size; accentuation of LSR). Accentuation of LSR were shown more frequently by DFa mixed with larger amount of serum (25% in 1:1 mix; 80% in 1:3 mix, p < 0.05). But there were no differences of DFa-specific IgE and IgG subclass antibodies regardless of the inhibition of ISR or the accentuation of LSR. In conclusion, some autologous sera from DFa-sensitive individuals showed the inhibition of ISR and the accentuation of LSR on DFa-ID test.


Surfactant removal and silica condensation during the photochemical calcination of thin film silica mesophases.
The evolution of photochemical surfactant removal and silica condensation from organically templated thin film silica nanocomposites with mesoscopic ordering has been probed using a combined application of Fourier transform infrared (FT-IR) spectroscopy and single wavelength ellipsometry. Thin films of silica nanocomposites were prepared by a previously reported evaporation-induced self-assembly process. Specifically, oxidized silicon and gold substrates were withdrawn at 25 mm/min from a subcritical micelle concentration solution containing an ethylene oxide surfactant as a structure-directing agent and tetraethyl orthosilicate as a silica precursor. Real-time grazing incidence difference FT-IR spectra of the nanocomposite films on gold taken during exposure to short-wavelength ultraviolet light (184-257 nm) show that surfactant removal and silica condensation occur gradually and concomitantly. Surfactant removal and silica reconstructions were found to be nearly complete after 90 min of exposure. Further, a transient feature was observed in the FT-IR spectra around 1713 cm(-1) during the UV exposure process and was assigned to a carbonyl (C=O) stretching mode absorption, reflecting the transient formation of a partially oxidized surfactant intermediate. From these data we propose a stepwise model for surfactant removal from the nanocomposite films. Ellipsometrically determined index of refraction values collected as a function of UV exposure are also shown to support such a stepwise mechanism of surfactant removal from the ordered nanocomposite silica thin film mesophases studied here.


Clinical implications of inflammatory bowel disease genetics on phenotype.
The genetic revolution has been with us for over a decade now. We have yet to see this impacting the care of patients except in a few rare examples. However, progress has been made in the field of inflammatory bowel disease (IBD) that could soon be translated to the bedside, both in terms of predicting the disease course as well as in the response to therapy. IBD traditionally has been classified as ulcerative colitis and Crohn's disease, with 10% of patients classified as having indeterminate colitis on the basis of clinical, radiologic, endoscopic, and histologic findings. However, this traditional view is now being challenged. Developments in genetics and serological markers, as well as an appreciation of the disease course, have led to an understanding that IBD is a heterogeneous group of diseases with some common genetic and environmental factors but different clinical manifestations in terms of disease behavior, location, and response to treatment. Data are now emerging that may allow us to more objectively select the correct therapy for the correct patient, rather than the current approach, which is based on clinical experience backed up by a less-than-perfect evidence base. In this article, we will review the evidence for this.


Extrachromosomal element capture and the evolution of multiple replication origins in archaeal chromosomes.
In all three domains of life, DNA replication begins at specialized loci termed replication origins. In bacteria, replication initiates from a single, clearly defined site. In contrast, eukaryotic organisms exploit a multitude of replication origins, dividing their genomes into an array of short contiguous units. Recently, the multiple replication origin paradigm has also been demonstrated within the archaeal domain of life, with the discovery that the hyperthermophilic archaeon Sulfolobus has three replication origins. However, the evolutionary mechanism driving the progression from single to multiple origin usage remains unclear. Here, we demonstrate that Aeropyrum pernix, a distant relative of Sulfolobus, has two origins. Comparison with the Sulfolobus origins provides evidence for evolution of replicon complexity by capture of extrachromosomal genetic elements. We additionally identify a previously unrecognized candidate archaeal initiator protein that is distantly related to eukaryotic Cdt1. Our data thus provide evidence that horizontal gene transfer, in addition to its well-established role in contributing to the information content of chromosomes, may fundamentally alter the manner in which the host chromosome is replicated.


The impact of co-morbid mental and physical disorders on presenteeism.
This study sought to: (i) explore the impact of mood disorders (such as depression, bipolar disorder, mania, or dysthymia) and five age-related chronic physical conditions (arthritis, back pain, diabetes, heart disease, and hypertension) on presenteeism (as indicated by self-reported activity limitations at work), and (ii) examine how mood disorders interact with each physical condition to affect this work outcome. Using Canadian Community Health Survey (CCHS) data, we modeled the relationships between self-reported restrictions at work and each health condition. We then calculated synergy indices (SI) for the interaction between mood disorders and each of the five physical conditions. All six health conditions were associated with presenteeism. The strongest association was observed for back pain [prevalence ratio (PR) 2.70, 95% confidence interval (95% CI) 2.57-2.83] and the weakest for hypertension (PR 1.18, 95% CI 1.11-1.25). The unadjusted SI indicated no interactions between mood disorders and any of the physical conditions, while the adjusted SI indicated statistically significant interactions between mood disorders and each of the five physical conditions. The statistically significant adjusted interactions were in a negative direction, such that having a mood disorder concurrent with a chronic physical condition was associated with a lower burden of presenteeism than expected. Post-hoc analyses revealed that this unexpected finding was attributable to adjustment for other co-morbid health conditions, particularly arthritis and back pain. Our results suggest that targeting chronic physical conditions or mood disorders may be productive in reducing presenteeism. The combined effect on presenteeism when the two types of conditions occur simultaneously is similar to the additive effect of these conditions when each occurs in isolation.


Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors.
Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors. We evaluated 352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor. The patients received a bolus of andexanet, followed by a 2-hour infusion. The coprimary outcomes were the percent change in anti-factor Xa activity after andexanet treatment and the percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion, with hemostatic efficacy adjudicated on the basis of prespecified criteria. Efficacy was assessed in the subgroup of patients with confirmed major bleeding and baseline anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.25 IU per milliliter for those receiving enoxaparin). Patients had a mean age of 77 years, and most had substantial cardiovascular disease. Bleeding was predominantly intracranial (in 227 patients [64%]) or gastrointestinal (in 90 patients [26%]). In patients who had received apixaban, the median anti-factor Xa activity decreased from 149.7 ng per milliliter at baseline to 11.1 ng per milliliter after the andexanet bolus (92% reduction; 95% confidence interval [CI], 91 to 93); in patients who had received rivaroxaban, the median value decreased from 211.8 ng per milliliter to 14.2 ng per milliliter (92% reduction; 95% CI, 88 to 94). Excellent or good hemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). Reduction in anti-factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage. In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti-factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327.).


Rituximab, ofatumumab and other monoclonal anti-CD20 antibodies for chronic lymphocytic leukaemia.
Chronic lymphocytic leukaemia (CLL) accounts for 25% of all leukaemias and is the most common lymphoid malignancy in western countries. Standard treatments include mono- or polychemotherapies, usually combined with monoclonal antibodies such as rituximab or alemtuzumab. However, the impact of these agents remains unclear, as there are hints for increased risk of severe infections. The objectives of this review are to provide an evidence-based answer regarding the clinical benefits and harms of monoclonal anti-CD20 antibodies (such as rituximab, ofatumumab, GA101) compared to no further therapy or to other anti-leukaemic therapies in patients with CLL, irrespective of disease status. We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 12, 2011), MEDLINE (from January 1990 to 4 January 2012), and EMBASE (from 1990 to 20 March 2009) as well as conference proceedings (American Society of Hematology, American Society of Clinical Oncology, European Hematology Association and European Society of Medical Oncology) for randomised controlled trials (RCTs). We included RCTs examining monoclonal anti-CD20 antibodies compared to no further therapy or to anti-leukaemic therapy such as chemotherapy or monoclonal antibodies in patients with newly diagnosed or relapsed CLL. We used hazard ratios (HR) as effect measures for overall survival (OS), progression-free survival (PFS) and time to next treatment, and risk ratios (RR) for response rates, treatment-related mortality (TRM) and adverse events (AEs). Two review authors independently extracted data and assessed quality of trials. We screened a total of 1150 records. Seven RCTs involving 1763 patients were identified, but only five could be included in the two separate meta-analyses we performed. We judged the overall the quality of these trials as moderate to high. All trials were randomised and open-label studies. However, two trials were published as abstracts only, therefore we were unable to assess the potential risk of bias for these trials in detail.Three RCTs (N = 1421) assessed the efficacy of monoclonal anti-CD20 antibodies (i.e. rituximab) plus chemotherapy compared to chemotherapy alone. The meta-analyses showed a statistically significant OS (HR 0.78, 95% confidence interval (CI) 0.62 to 0.98, P = 0.03, the number needed to treat for an additional beneficial effect (NNTB) was 12) and PFS (HR 0.64, 95% CI 0.55 to 0.74, P < 0.00001) advantage for patients receiving rituximab. In the rituximab-arm occurred more AEs, World Health Organization (WHO) grade 3 or 4 (3 trials, N = 1398, RR 1.15, 95% CI 1.08 to 1.23, P < 0.0001; the number needed to harm for an additional harmful outcome (NNTH) was 9), but that did not lead to a statistically significant difference regarding TRM (3 trials, N = 1415, RR 1.19, 95% CI 0.70 to 2.01, P = 0.52).Two trials (N = 177) evaluated rituximab versus alemtuzumab. Neither study reported OS or PFS. There was no statistically significant difference between arms regarding complete response rate (CRR) (RR 1.21, 95% CI 0.94 to 1.58, P = 0.14) or TRM (RR 0.31, 95% CI 0.06 to 1.51, P = 0.15). However, the CLL2007FMP trial was stopped early owing to an increase in mortality in the alemtuzumab arm. More serious AEs occurred in this arm (43% with alemtuzumab versus 22% with rituximab; P = 0.006).Two trials assessed different dosages or time schedules of monoclonal anti-CD20 antibodies. One trial (N = 104) evaluated two different rituximab schedules (concurrent arm: fludarabine plus rituximab (Flu-R) plus rituximab consolidation versus sequential arm: fludarabine alone plus rituximab consolidation). The comparison of the concurrent versus sequential regimen of rituximab showed a statistically significant difference of the CRR with 33% in the concurrent-arm and 15% in the sequential-arm (P = 0.04), that did not lead to statistically significant differences regarding OS (HR 1.14, 95% CI 0.20 to 6.65, P = 0.30) or PFS (HR 0.96, 95% CI 0.43 to 2.15, P = 0.11). Furthermore results showed no differences in occurring AEs, except for neutropenia, which was more often observed in patients of the concurrent arm. The other trial (N = 61) investigated two different dosages (500 mg and 1000 mg) of ofatumumab in addition to FluC. The arm investigating ofatumumab did not assess OS and a median PFS had not been reached owing to the short median follow-up of eight months. It showed no statistically significant differences between arms regarding CRR (32% in the FCO500 arm versus 50% in the FCO1000 arm; P = 0.10) or AEs (anaemia, neutropenia, thrombocytopenia). This meta-analysis showed that patients receiving chemotherapy plus rituximab benefit in terms of OS as well as PFS compared to those with chemotherapy alone. Therefore, it supports the recommendation of rituximab in combination with FluC as an option for the first-line treatment as well as for the people with relapsed or refractory CLL. The available evidence regarding the other assessed comparisons was not sufficient to deduct final conclusions.


Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2.
Vitamin K allows for gamma-carboxylation of glutamyl residues, a conversion that activates clotting factors and bone proteins. Vitamin K antagonists such as warfarin inhibit this process. Our goal was to quantify the association between warfarin and osteoporotic fractures in patients with atrial fibrillation. This was a retrospective cohort study of Medicare beneficiaries with atrial fibrillation who were hospitalized between March 1998 and April 1999 in all 50 US states. The study outcome was osteoporotic fractures, identified by an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for a fracture of the hip, spine, or wrist. Compared with 7587 patients who were not prescribed warfarin, the adjusted odds ratio (OR) of fracture was 1.25 (95% confidence interval [CI], 1.06-1.48) in 4461 patients prescribed long-term warfarin therapy (> or = 1 year). The association between osteoporotic fracture and long-term warfarin use was significant in men (OR, 1.63; 95% CI, 1.26-2.10) but nonsignificant in women (OR, 1.05; 95% CI, 0.88-1.26). In 1833 patients prescribed warfarin for less than a year, the risk of osteoporotic fracture was not increased significantly (OR, 1.03). Odds ratios (95% CIs) of independent predictors of osteoporotic fractures were as follows: increasing age, 1.63 (1.47-1.80) per decade; high fall risk, 1.78 (1.42-2.21); hyperthyroidism, 1.77 (1.16-2.70); neuropsychiatric disease, 1.51 (1.28-1.78); and alcoholism, 1.50 (1.01-2.24). Factors with a reduced OR (95% CI) included African American race, 0.30 (0.18-0.51); male sex, 0.54 (0.46-0.62); and use of beta-adrenergic antagonists, 0.84 (0.70-1.00). Long-term use of warfarin was associated with osteoporotic fractures, at least in men with atrial fibrillation. Beta-adrenergic antagonists may protect against osteoporotic fractures.


Dengue Virus Targets Nrf2 for NS2B3-Mediated Degradation Leading to Enhanced Oxidative Stress and Viral Replication.
Dengue virus (DENV) is a mosquito-borne virus that infects upward of 300 million people annually and has the potential to cause fatal hemorrhagic fever and shock. While the parameters contributing to dengue immunopathogenesis remain unclear, the collapse of redox homeostasis and the damage induced by oxidative stress have been correlated with the development of inflammation and progression toward the more severe forms of disease. In the present study, we demonstrate that the accumulation of reactive oxygen species (ROS) late after DENV infection (>24 hpi) resulted from a disruption in the balance between oxidative stress and the nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant response. The DENV NS2B3 protease complex strategically targeted Nrf2 for degradation in a proteolysis-independent manner; NS2B3 licensed Nrf2 for lysosomal degradation. Impairment of the Nrf2 regulator by the NS2B3 complex inhibited the antioxidant gene network and contributed to the progressive increase in ROS levels, along with increased virus replication and inflammatory or apoptotic gene expression. By 24 hpi, when increased levels of ROS and antiviral proteins were observed, it appeared that the proviral effect of ROS overcame the antiviral effects of the interferon (IFN) response. Overall, these studies demonstrate that DENV infection disrupts the regulatory interplay between DENV-induced stress responses, Nrf2 antioxidant signaling, and the host antiviral immune response, thus exacerbating oxidative stress and inflammation in DENV infection.IMPORTANCE Dengue virus (DENV) is a mosquito-borne pathogen that threatens 2.5 billion people in more than 100 countries annually. Dengue infection induces a spectrum of clinical symptoms, ranging from classical dengue fever to severe dengue hemorrhagic fever or dengue shock syndrome; however, the complexities of DENV immunopathogenesis remain controversial. Previous studies have reported the importance of the transcription factor Nrf2 in the control of redox homeostasis and antiviral/inflammatory or death responses to DENV. Importantly, the production of reactive oxygen species and the subsequent stress response have been linked to the development of inflammation and progression toward the more severe forms of the disease. Here, we demonstrate that DENV uses the NS2B3 protease complex to strategically target Nrf2 for degradation, leading to a progressive increase in oxidative stress, inflammation, and cell death in infected cells. This study underlines the pivotal role of the Nrf2 regulatory network in the context of DENV infection.


Bacillus cereus Adhesion to Simulated Intestinal Mucus Is Determined by Its Growth on Mucin, Rather Than Intestinal Environmental Parameters.
Adhesion of pathogenic bacteria to intestinal mucus, the protective layer of the gastrointestinal epithelium, is often considered a virulence factor. The ability of food-poisoning Bacillus cereus strains to attach to mucus and the factors affecting this interaction have not yet been investigated. Therefore, the role of adhesion in pathogenesis of B. cereus still remains unknown. In the present study, an in vitro assay based on mucin agar was used to simulate adhesion of B. cereus to mucus. Bacterial-associated factors (e.g., strain specificity and microbial competition) known to influence adhesion to different surfaces and a variety of environmental conditions (e.g., pH and oxygen) encountered in the gastrointestinal tract were investigated. The effect of these parameters on B. cereus NVH 0500/00 mucin adhesion was generally limited even in the presence of microbial competition. This suggests that B. cereus NVH 0500/00 is a versatile pathogen. Inoculation of 4 to 5 log colony-forming units (CFU) per milliliter. B. cereus NVH 0500/00 resulted in 5-6 log CFU/mL mucin-associated bacteria after a short incubation period. This indicates that this pathogenic strain could grow in the presence of mucin agar. This growth may potentially mask the effect of the studied conditions. Yet, extensive attachment of B. cereus to mucin is not necessarily a prerequisite for virulence, because other pathogenic strains do not adhere with the same efficiency to mucin. Nevertheless, adhesion may contribute to the disease by providing close contact to nutrient sources, such as mucin, which would not only result in bacterial proliferation, but also in disruption of the protective host mucus surface.


ATP-induced morphological changes in supporting cells of the developing cochlea.
The developing cochlea of mammals contains a large group of columnar-shaped cells, which together form a structure known as Kölliker's organ. Prior to the onset of hearing, these inner supporting cells periodically release adenosine 5'-triphosphate (ATP), which activates purinergic receptors in surrounding supporting cells, inner hair cells and the dendrites of primary auditory neurons. Recent studies indicate that purinergic signaling between inner supporting cells and inner hair cells initiates bursts of action potentials in auditory nerve fibers before the onset of hearing. ATP also induces prominent effects in inner supporting cells, including an increase in membrane conductance, a rise in intracellular Ca(2+), and dramatic changes in cell shape, although the importance of ATP signaling in non-sensory cells of the developing cochlea remains unknown. Here, we review current knowledge pertaining to purinergic signaling in supporting cells of Kölliker's organ and focus on the mechanisms by which ATP induces changes in their morphology. We show that these changes in cell shape are preceded by increases in cytoplasmic Ca(2+), and provide new evidence indicating that elevation of intracellular Ca(2+) and IP(3) are sufficient to initiate shape changes. In addition, we discuss the possibility that these ATP-mediated morphological changes reflect crenation following the activation of Ca(2+)-activated Cl(-) channels, and speculate about the possible functions of these changes in cell morphology for maturation of the cochlea.


Association of major dietary patterns and blood pressure longitudinal change in Bangladesh.
Observational studies and clinical trials have shown associations of diet and high blood pressure (BP). However, prospective studies on the association between dietary patterns and longitudinal BP change are lacking, especially in low-income populations. We evaluated the association of dietary patterns and food groups with longitudinal change of BP in 10 389 participants in the Health Effects of Arsenic Longitudinal Study, with a median of 6.7 years of follow-up. Dietary information was obtained through a previously validated food-frequency questionnaire. BP was measured at baseline and at each biennial follow-up using the same method. Each standard deviation (SD) increase for the 'gourd vegetable' dietary pattern score was related to a slower annual change of 0.08, 0.04, and 0.05 mmHg in SBP, DBP, or pulse pressure, respectively. Each SD increase in the 'balanced' dietary pattern score was related to a decreasing annual change of 0.06 mmHg (P = 0.012) and 0.08 mmHg in SBP and pulse pressure (P < 0.001). On the contrary, one SD increase in 'western' dietary pattern score was related to a greater annual increase of 0.07 (P = 0.005) and 0.05 mmHg in SBP and pulse pressure (P = 0.013). Higher intake of fruits and vegetables was associated with a slower rate of change in annual SBP and pulse pressure, whereas higher meat intake was related to a more rapid increase in annual pulse pressure. The findings suggest that dietary patterns play a significant role in the rate of BP change over time in a low-income population.


Multi-wavelength generation by self-seeded four-wave mixing.
A cost effective method of generating multi-wavelength based on the cascaded four wave mixing effect is experimentally demonstrated. The proposed scheme is free from external tunable laser sources and pump modulators, resulting from the use of a broadened linewidth tunable dual wavelength erbium-doped fiber laser as intracavity pump. In this configuration, the number of four wave mixing cascades becomes larger in tandem with the increment of erbium-doped fiber amplifier output power. When its output power is set at 20.57 dBm, six waves having optical signal to noise ratio larger than 10 dB are generated. The six waves are stable with peak power fluctuations less than 1 dB within 30 minutes period and tunable with wavelength spacing ranging from 1.03 nm to 11.31 nm.


The effects of gender, flow and video game experience on combat identification training.
The present study examined the effects of gender, video game experience (VGE), and flow state on multiple indices of combat identification (CID) performance. Individuals were trained on six combat vehicles in a simulation, presented through either a stereoscopic or non-stereoscopic display. Participants then reported flow state, VGE and were tested on their ability to discriminate friend vs. foe and identify both pictures and videos of the trained vehicles. The effect of stereoscopy was not significant. There was an effect of gender across three dependent measures. For the two picture-based measures, the effect of gender was mediated by VGE. Additionally, the effect of gender was moderated by flow state on the identification measures. Overall, the study suggests that gender differences may be overcome by VGE and by achieving flow state. Selection based on these individual differences may be useful for future military simulation. Practitioner Summary: This work investigates the effect of gender, VGE and flow state on CID performance. For three measures of performance, there was a main effect of gender. Gender was mediated by previous VGE on two measures, and gender was moderated by flow state on two measures.


Global diversity and biogeography of deep-sea pelagic prokaryotes.
The deep-sea is the largest biome of the biosphere, and contains more than half of the whole ocean's microbes. Uncovering their general patterns of diversity and community structure at a global scale remains a great challenge, as only fragmentary information of deep-sea microbial diversity exists based on regional-scale studies. Here we report the first globally comprehensive survey of the prokaryotic communities inhabiting the bathypelagic ocean using high-throughput sequencing of the 16S rRNA gene. This work identifies the dominant prokaryotes in the pelagic deep ocean and reveals that 50% of the operational taxonomic units (OTUs) belong to previously unknown prokaryotic taxa, most of which are rare and appear in just a few samples. We show that whereas the local richness of communities is comparable to that observed in previous regional studies, the global pool of prokaryotic taxa detected is modest (~3600 OTUs), as a high proportion of OTUs are shared among samples. The water masses appear to act as clear drivers of the geographical distribution of both particle-attached and free-living prokaryotes. In addition, we show that the deep-oceanic basins in which the bathypelagic realm is divided contain different particle-attached (but not free-living) microbial communities. The combination of the aging of the water masses and a lack of complete dispersal are identified as the main drivers for this biogeographical pattern. All together, we identify the potential of the deep ocean as a reservoir of still unknown biological diversity with a higher degree of spatial complexity than hitherto considered.


Ethanol Reversal of Tolerance to the Respiratory Depressant Effects of Morphine.
Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO2 in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths.


Proteomic analysis of the eyespot of Chlamydomonas reinhardtii provides novel insights into its components and tactic movements.
Flagellate green algae have developed a visual system, the eyespot apparatus, which allows the cell to phototax. To further understand the molecular organization of the eyespot apparatus and the phototactic movement that is controlled by light and the circadian clock, a detailed understanding of all components of the eyespot apparatus is needed. We developed a procedure to purify the eyespot apparatus from the green model alga Chlamydomonas reinhardtii. Its proteomic analysis resulted in the identification of 202 different proteins with at least two different peptides (984 in total). These data provide new insights into structural components of the eyespot apparatus, photoreceptors, retina(l)-related proteins, members of putative signaling pathways for phototaxis and chemotaxis, and metabolic pathways within an algal visual system. In addition, we have performed a functional analysis of one of the identified putative components of the phototactic signaling pathway, casein kinase 1 (CK1). CK1 is also present in the flagella and thus is a promising candidate for controlling behavioral responses to light. We demonstrate that silencing CK1 by RNA interference reduces its level in both flagella and eyespot. In addition, we show that silencing of CK1 results in severe disturbances in hatching, flagellum formation, and circadian control of phototaxis.


Features of the formate dehydrogenase mRNA necessary for decoding of the UGA codon as selenocysteine.
The fdhF gene encoding the 80-kDa selenopolypeptide subunit of formate dehydrogenase H from Escherichia coli contains an in-frame TGA codon at amino acid position 140, which encodes selenocysteine. We have analyzed how this UGA "sense codon" is discriminated from a UGA codon signaling polypeptide chain termination. Deletions were introduced from the 3' side into the fdhF gene and the truncated 5' segments were fused in-frame to the lacZ reporter gene. Efficient read-through of the UGA codon, as measured by beta-galactosidase activity and incorporation of selenium, was dependent on the presence of at least 40 bases of fdhF mRNA downstream of the UGA codon. There was excellent correlation between the results of the deletion studies and the existence of a putative stem-loop structure lying immediately downstream of the UGA in that deletions extending into the helix drastically reduced UGA translation. Similar secondary structures can be formed in the mRNAs coding for other selenoproteins. Selenocysteine insertion cartridges were synthesized that contained this hairpin structure and variable portions of the fdhF gene upstream of the UGA codon and inserted into the lacZ gene. Expression studies showed that upstream sequences were not required for selenocysteine insertion but that they may be involved in modulating the efficiency of read-through. Translation of the UGA codon was found to occur with high fidelity since it was refractory to ribosomal mutations affecting proofreading and to suppression by the sup-9 gene product.


A model for a nurse-led programme of bedside placement of peripherally inserted central catheters in neonates and infants with congenital cardiac disease.
Neonates and infants with congenital and acquired cardiac disease often require placement of central venous lines for extended intravenous therapy. It may be advantageous to avoid the larger venous vessels of the head and neck and lower extremities in order to preserve these for future interventions and therapies. We evaluated the results of a nursing led peripherally inserted central catheter team in our congenital cardiac centre. Bedside peripherally inserted central catheter the insertion procedures were evaluated for success, complications, and completion of therapy. A total of 125 peripherally inserted central catheters were successfully placed in 105 patients. The mean age at the time of placement was 13.5 plus or minus 19.1 days; median age was 7 days; mean weight was 3.5 plus or minus 1.1 kilogram. Cyanotic cardiac disease accounted for 76% of the diagnoses. Central placement of these lines was successful in 78% of patients. Complications during insertions were limited to inadvertent arterial access in five (3%) infants and oxygen desaturations during sedation for the procedure in two (1%) patients. None of the infants suffered long-term compromise from arterial access; none required intubation for the desaturations. The team was able to respond to 90% of their requests within 24 hours. Median catheter dwell time was 14 days. In a population of infants with cardiac disease, a nursing staffed peripherally inserted central catheter team achieved an insertion rate of 78% with few complications and a rapid response time. Reliance on bedside insertion permits continuous critical care monitoring and may eliminate the need for fluoroscopy.


[The simple swallowing provocation test as a means of screening for swallowing disorders: a comparison with the water swallowing test].
The sensitivity and specificity of the simple swallowing provocation test (S-SPT) were evaluated in a group of patients who were being examined for aspiration pneumonia (ASP) (ASP group: 72.5 +/- 3.9 years old) and in a group of age-matched control subjects (CTRL group: 69.5 +/- 2.9 years old). The S-SPT was evaluated in terms of the swallowing response and latent time (LT) for swallowing after a bolus injection of 0.4 ml of distilled water at the suprapharynx. Responses to the S-SPT were classified as normal or abnormal, dependent on induction of the swallowing reflex within 3 seconds after bolus injection. The sensitivity and specificity of the S-SPT in detecting ASP were calculated. Of the 40 patients in the ASP group, 18 were given a diagnosis of ASP on the basis of clinical findings and laboratory examinations. The sensitivity and specificity of the S-SPT were 94.4% and 86.4%, respectively, compared to 77.8% and 68.1%, respectively, for the water swallowing test. Because the S-SPT can be performed without any need for special patient effort or cooperation, it should be effective in diagnosing ASP in a wide variety of patients, including those who are bedridden.


Prevascularization of 3D printed bone scaffolds by bioactive hydrogels and cell co-culture.
Vascularization is a fundamental prerequisite for large bone construct development and remains one of the main challenges of bone tissue engineering. Our current study presents the combination of 3D printing technique with a hydrogel-based prevascularization strategy to generate prevascularized bone constructs. Human adipose derived mesenchymal stem cells (ADMSC) and human umbilical vein endothelial cells (HUVEC) were encapsulated within our bioactive hydrogels, and the effects of culture conditions on in vitro vascularization were determined. We further generated composite constructs by forming 3D printed polycaprolactone/hydroxyapatite scaffolds coated with cell-laden hydrogels and determined how the co-culture affected vascularization and osteogenesis. It was demonstrated that 3D co-cultured ADMSC-HUVEC generated capillary-like networks within the porous 3D printed scaffold. The co-culture systems promoted in vitro vascularization, but had no significant effects on osteogenesis. The prevascularized constructs were subcutaneously implanted into nude mice to evaluate the in vivo vascularization capacity and the functionality of engineered vessels. The hydrogel systems facilitated microvessel and lumen formation and promoted anastomosis of vascular networks of human origin with host murine vasculature. These findings demonstrate the potential of prevascularized 3D printed scaffolds with anatomical shape for the healing of larger bone defects. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1788-1798, 2018.


Epidemiology of stillbirth and strategies for its prevention in Vietnam.
To describe major epidemiologic and placental findings regarding stillbirth in Vietnam. A cross-sectional study of all stillbirths in a tertiary referral facility in Ho Chi Minh City, Vietnam, was performed. Detailed examination of each infant, placental pathology, and semi-structured maternal interviews were conducted according to the Perinatal Society of Australia and New Zealand Perinatal Death Classification guidelines. Maternal, fetal, and placental characteristics were examined. Between December 8, 2008, and January 9, 2009, there were 4694 live births and 122 stillbirths at the facility. In total, 107 (87.7%) cases were included in the study. Low education level was associated with a lack of prenatal care; induced abortion accounted for 34.6% of fetal deaths (gender selection was not the reason); 35.5% of infants were born at 22-28 weeks of gestation; 31.8% of stillbirths were small for gestational age; histologic evidence of chorioamnionitis was present in 40.2% of cases. Calcium supplements were less likely to have been taken in cases in which death from hypertension occurred. alpha-Thalassemia was the main cause of fetal hydrops (6.2%). Improving access to prenatal care and prenatal calcium and iron supplementation, and screening for congenital abnormalities and alpha-thalassemia may help to reduce rates of perinatal death in Vietnam.


Heteromeric Kv1 potassium channel expression: amino acid determinants involved in processing and trafficking to the cell surface.
Kv1.4 and Kv1.1 potassium channels are expressed in brain as mature glycoproteins that are trans-Golgi glycosylated. When expressed in cell lines these homomers had very different trans-Golgi glycosylation efficiencies and cell surface expression levels with Kv1.4 > Kv1.1 for both parameters (Zhu, J., Watanabe, I., Gomez, B., and Thornhill, W. B. (2001) J. Biol. Chem. 276, 39419-39427). This previous study identified determinants in the outer pore region of Kv1.4 and Kv1.1 that positively and negatively, respectively, affected these events when expressed as homomers. Here we investigated which subunit exhibited positive or negative effects on these processes when expressed as heteromers. Kv1.4/Kv1.1 heteromers, by coexpression or expression as tandem-linked heteromers, were expressed on the cell surface at approximately 20-fold lower levels versus Kv1.4 homomers but they were trans-Golgi glycosylated. The lower Kv1.4/Kv1.1 expression level was not rescued by Kvbeta 2.1 subunits. Thus Kv1.1 inhibited high cell surface expression and partially retained the heteromer in the endoplasmic reticulum, whereas Kv1.4 stimulated trans-Golgi glycosylation. The subunit determinants and cellular events responsible for these differences were investigated. In a Kv1.4/Kv1.1 heteromer, the Kv1.1 pore was a major negative determinant, and it inhibited high cell surface expression because it induced high partial endoplasmic reticulum retention and it decreased protein stability. Other Kv1.1 regions also inhibited high surface expression of heteromers. The Kv1.1 C terminus induced partial Golgi retention and contributed to a decreased protein stability, whereas the Kv1.1 N terminus contributed to only a decreased protein stability. Thus a neuron may regulate its cell surface K+ channel protein levels by different Kv1 subfamily homomeric and heteromeric combinations that affect intracellular retention characteristics and protein stability.


Three-Year Impacts Of The Affordable Care Act: Improved Medical Care And Health Among Low-Income Adults.
Major policy uncertainty continues to surround the Affordable Care Act (ACA) at both the state and federal levels. We assessed changes in health care use and self-reported health after three years of the ACA's coverage expansion, using survey data collected from low-income adults through the end of 2016 in three states: Kentucky, which expanded Medicaid; Arkansas, which expanded private insurance to low-income adults using the federal Marketplace; and Texas, which did not expand coverage. We used a difference-in-differences model with a control group and an instrumental variables model to provide individual-level estimates of the effects of gaining insurance. By the end of 2016 the uninsurance rate in the two expansion states had dropped by more than 20 percentage points relative to the nonexpansion state. For uninsured people gaining coverage, this change was associated with a 41-percentage-point increase in having a usual source of care, a $337 reduction in annual out-of-pocket spending, significant increases in preventive health visits and glucose testing, and a 23-percentage-point increase in "excellent" self-reported health. Among adults with chronic conditions, we found improvements in affordability of care, regular care for those conditions, medication adherence, and self-reported health.


Regulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation.
The loss of regulation of cell proliferation is a key event in leukemic transformation, and the oncogene tribbles (Trib)2 is emerging as a pivotal target of transcription factors in acute leukemias. Deregulation of the transcription factor E2F1, normally repressed by CCAAT enhancer-binding protein α (C/EBPα)-p42, occurs in acute myeloid leukemia (AML), resulting in the perturbation of cell cycle and apoptosis, emphasizing its importance in the molecular pathogenesis of AML. Here we show that E2F family members directly regulate Trib2 in leukemic cells and identify a feedback regulatory loop for E2F1, C/EBPα, and Trib2 in AML cell proliferation and survival. Further analyses revealed that E2F1-mediated Trib2 expression was repressed by C/EBPα-p42, and in normal granulocyte/macrophage progenitor cells, we detect C/EBPα bound to the Trib2 promoter. Pharmacological inhibition of the cell cycle or Trib2 knockdown resulted in a block in AML cell proliferation. Our work proposes a novel paradigm whereby E2F1 plays a key role in the regulation of Trib2 expression important for AML cell proliferation control. Importantly, we identify the contribution of dysregulated C/EBPα and E2F1 to elevated Trib2 expression and leukemic cell survival, which likely contributes to the initiation and maintenance of AML and may have significant implications for normal and malignant hematopoiesis.


Identification of differential expression of genes in hepatocellular carcinoma by suppression subtractive hybridization combined cDNA microarray.
The genetic background of hepatocellular carcinoma (HCC) has yet to be completely understood. Here, we describe the application of suppression subtractive hybridization (SSH) coupled with cDNA microarray analysis for the isolation and identification of differential expression of genes in HCC. Twenty-six known genes were validated as up-regulated and 19 known genes as down-regulated in HCC. The known genes identified were found to have diverse functions. In addition to the overexpression of AFP, these genes (increased in the presence of HCC) are involved in many processes, such as transcription and protein biosynthesis (HNRPDL, PABPC1, POLR2K, SRP9, SNRPA, and six ribosomal protein genes including RPL8, RPL14, RPL41, RPS5, RPS17, RPS24), the metabolism of lipids and proteins (FADS1, ApoA-II, ApoM, FTL), cell proliferation (Syndecan-2, and Annexin A2), and signal transduction (LRRC28 and FMR1). Additionally, a glutathione-binding protein involved in the detoxification of methylglyoxal known as GLO1 and an enzyme which increases the formation of prostaglandin E(2) known as PLA2G10 were up-regulated in HCC. Among the underexpressed genes discovered in HCC, most were responsible for liver-synthesized proteins (fibrinogen, complement species, amyloid, albumin, haptoglobin, hemopexin and orosomucoid). The enzyme implicated in the biotransformation of CYP family members (LOC644587) was decreased. The genes coding enzymes ADH1C, ALDH6A1, ALDOB, Arginase and CES1 were also found. Additionally, we isolated a zinc transporter (Zip14) and a function-unknown gene named ZBTB11 (Zinc finger and BTB domain containing 11) which were underexpressed, and seven expression sequence tags deregulated in HCC without significant homology reported in the public database. Essentially, by using SSH combined with a cDNA microarray we have identified a number of genes associated with HCC, most of which have not been previously reported. Further characterization of these differentially expressed genes will provide information useful in understanding the genes responsible for the development of HCC.


Irukandji jellyfish polyps exhibit tolerance to interacting climate change stressors.
Increasing ocean temperatures and strengthening boundary currents have caused the poleward migration of many marine species. Cubozoan jellyfish known to cause Irukandji syndrome have historically been confined to tropical waters but may be expanding into subtropical regions. Here, we examine the interactive effects of warming and acidification on the population dynamics of polyps of an Irukandji jellyfish, Alatina nr mordens, and the formation of statoliths in newly metamorphosed medusae, to determine if this jellyfish could tolerate future conditions predicted for southeast Queensland (SEQ), Australia. Two experiments, examining the orthogonal factors of temperature and pH, were undertaken. Experiment 1 mimicked the current, ca. 2050 and ca. 2100 summer temperature and pH conditions predicted for SEQ using A1F1 scenarios (temperature: 25, 27, 29 °C; pH: 7.9, 7.8, 7.6) and Experiment 2 mimicked current and future winter conditions (18 and 22 °C, pH 7.9, 7.8, 7.6). All polyps in Experiment 1 survived and budded. Fewer polyps budded in the lower pH treatments; however, patterns varied slightly among temperature treatments. Statoliths at pH 7.6 were 24% narrower than those at pH 7.8 and 7.9. Most polyps survived the winter conditions mimicked by Experiment 2 but only polyps in the 22 °C, pH 7.9 treatment increased significantly. The current absence of A. nr mordens medusae in SEQ, despite the polyps' ability to tolerate the current temperature and pH conditions, suggests that ecological, rather than abiotic factors currently limit their distribution. Observations that budding was lower under low pH treatments suggest that rates of asexual reproduction will likely be much slower in the future. We consider that A. nr mordens polyps are likely to tolerate future conditions but are unlikely to thrive in the long term. However, if polyps can overcome potential ecological boundaries and acidification proceeds slowly A. nr mordens could expand polewards in the short term.


Involvement of cyclic GMP in nitric-oxide-induced gastric relaxation Comparison of the actions of cyclic GMP and cyclic AMP.
Smooth muscle relaxation induced by various agents that increase the cellular levels of cyclic nucleotides (cAMP and cGMP) is accompanied by a decrease in intracellular Ca2+ concentration. However, little is known about the differences between the inhibitory effects of cAMP and cGMP on the contraction of smooth muscle. To compare the effects and underlying mechanisms of cAMP and cGMP on the inhibition of gastric smooth muscle contraction, cyclic nucleotide promoting agents, as well as cell membrane permeable cyclic nucleotides were used. Isometric contraction was measured from circular muscle strips prepared from the fundus of cat stomach in a cylinder-shaped chamber filled with Krebs-Ringer solution (pH 7.4, temperature 36 degrees C) bubbled with 5% CO2 in O2. The level of inositol phosphates (IPs) was measured. Forskolin and sodium nitroprusside significantly inhibited acetylcholine (ACh)-induced gastric smooth muscle contraction and increased the cellular levels of cAMP and cGMP, respectively. Direct application of 8-Br-cAMP and 8-Br-cGMP also significantly inhibited ACh-induced contraction. Both verapamil and TMB-8 inhibited ACh-induced contraction. The combined inhibitory effect of verapamil and TMB-8 was significantly greater than the effect of either one, separately. Forskolin or sodium nitroprusside similarly augmented the effect of verapamil. However, the inhibitory effect of TMB-8 was augmented only by 8-Br-cGMP or sodium nitroprusside but not by 8-BrcAMP or forskolin. Forskolin and 8-Br-cAMP significantly inhibited the formation of inositol phosphates stimulated by ACh. cAMP inhibits the contraction mechanism associated with intracellular Ca2+ mobilization as well as extracellular Ca2+ influx, while cGMP inhibits contraction by inhibiting the mechanism associated with extracellular Ca2+ influx.


Asphyxial suicides using plastic bags.
Fifty-three suicides using plastic bags were identified in a review of cases within the jurisdiction of the King County Medical Examiner's Office, Seattle, Washington from 1984 to 1993. We found that this method was used at a greater frequency by individuals older than 50 in comparison with other methods. The most commonly identified stressor leading to the suicide in this population was failing health. The use of this method as a means of "self deliverance," as advocated by the Hemlock Society, could be inferred in only a small minority of cases where terminal illnesses were identified. This method may be preferred by those older than 50 years because of the ready availability of plastic bags and the relative nonviolence of the death. Analysis of the autopsy findings showed no specific features for this method of suicide. In particular, petechiae, which are often considered a marker of asphyxia, were present in only a small minority of cases (3%). Furthermore, the scene investigation rarely revealed specific features, other than the plastic bag in place. Thus, if the plastic bag were removed after death, the cause and manner of death would be obscure.


Innominate vein stenosis in breast cancer patients after totally implantable venous access port placement.
To evaluate the risk factors for central vein stenosis after placement of the totally implantable venous access ports (TIVPs) and the clinical relevance of this condition in breast cancer patients. TIVPs were placed in 191 women with breast cancer via the internal jugular vein (IJV) from January 2009 to December 2012 (mean age, 51.42 years) by left-side (n = 102) and right-side (n = 89) approaches. Medical records were retrospectively reviewed. The presence of significant central vein stenosis, tip location of the catheter and retrosternal space were evaluated on chest computed tomography images. Statistical analysis was performed. Central vein stenosis developed in 1 and 14 patients after placement via the right and left IJV, respectively. Differences in the cumulative incidence of central vein stenosis were statistically significant between left- and right-side approach groups (log rank test p-value: 0.009). In Cox regression analysis, the hazard ratio for central vein stenosis was 9.441 (p = 0.031) in the left-side approach. The distance between the sternum and the left innominate vein was found to be significantly and independently related to the development of central vein stenosis (p = 0.026). The hazard ratio of distances between the sternum and left innominate vein lt;16 mm was 10.133 (1.319-77.841). The incidence of central vein stenosis in breast cancer patients was higher after placement of TIVPs via the left IJV. When left-side TIVP placement is required in a patient with right-side breast cancer, the possibilities of left innominate vein stenosis should be considered.


Artificial selection on male genitalia length alters female brain size.
Male harassment is a classic example of how sexual conflict over mating leads to sex-specific behavioural adaptations. Females often suffer significant costs from males attempting forced copulations, and the sexes can be in an arms race over male coercion. Yet, despite recent recognition that divergent sex-specific interests in reproduction can affect brain evolution, sexual conflict has not been addressed in this context. Here, we investigate whether artificial selection on a correlate of male success at coercion, genital length, affects brain anatomy in males and females. We analysed the brains of eastern mosquitofish (Gambusia holbrooki), which had been artificially selected for long or short gonopodium, thereby mimicking selection arising from differing levels of male harassment. By analogy to how prey species often have relatively larger brains than their predators, we found that female, but not male, brain size was greater following selection for a longer gonopodium. Brain subregion volumes remained unchanged. These results suggest that there is a positive genetic correlation between male gonopodium length and female brain size, which is possibly linked to increased female cognitive ability to avoid male coercion. We propose that sexual conflict is an important factor in the evolution of brain anatomy and cognitive ability.


Long-term efficacy follow-up on two cryolipolysis case studies: 6 and 9 years post-treatment.
Cryolipolysis is a noninvasive esthetic procedure that utilizes controlled cooling to reduce subcutaneous fat. Clinical studies have established its safety, efficacy, and tolerability for fat reduction in a variety of areas including the abdomen, flanks, thighs, submental area, arms, back, and chest. Because of obvious esthetic concerns, long-term unilateral studies leaving an untreated flank, thigh, or arm are not performed, but serve as ideal controls for weight gain or loss or re-distribution of fat for other reasons. This article follows two patients previously documented in a case report to demonstrate their ongoing treatment efficacy at 6 and 9 years after treatment. Clinical photographs of the treated flanks and untreated contralateral controls demonstrate long-term durability in these two subjects.


Hemotoxicity of carbon nanotubes.
Carbon nanotubes may enter into the bloodstream and interact with blood components indirectly via translocation following unintended exposure or directly after an intended administration for biomedical purposes. Once introduced into systemic circulation, nanotubes will encounter various proteins, biomolecules or cells which have specific roles in the homeostasis of the circulatory system. It is therefore essential to determine whether those interactions will lead to adverse effects or not. Advances in the understanding of how carbon nanotubes interact with blood proteins, the complement system, red blood cells and the hemostatic system are reviewed in this article. While many studies on carbon nanotube health risk assessment and their biomedical applications have appeared in the last few years, reports on the hemocompatibility of these nanomaterials remain surprisingly limited. Yet, defining the hemotoxicological profile is a mandatory step toward the development of clinically-relevant medications or contrast agents based on carbon nanotubes.


Idiopathic scoliosis in Korean schoolchildren: a prospective screening study of over 1 million children.
Cross-sectional epidemiologic scoliosis screening was carried out to determine the current prevalence of scoliosis in the Korean population and to compare with the results of previous studies. Between 2000 and 2008, 1,134,890 schoolchildren underwent scoliosis screening. The children were divided into two age groups, 10-12-year-olds (elementary school) and 13-14-year-olds (middle school), to calculate age- and sex-specific prevalence rates. Children with a scoliometer reading ≥5° were referred for radiograms. Two surgeons independently measured curve types, magnitudes, and Risser scores (inter-observer r = 0.964, intra-observer r = 0.978). Yearly and overall prevalence rates of scoliosis were calculated. There were 584,554 boys and 550,336 girls in the sample, with a male to female ratio of 1.1:1. There were 77,910 (6.2%) children (26,824 boys and 51,086 girls) with scoliometer readings >5°, and 37,339 of them had positive results with Cobb angles ≥10° (positive predictive value, 46.4%). The overall scoliosis prevalence rate was 3.26%; girls had a higher prevalence (4.65%) than boys (1.97%). Prevalence rates increased progressively from 1.66 to 6.17% between 2000 and 2008, with the exception of 2002. According to age and gender, 10-12-year-old girls had the highest scoliosis prevalence rates (5.57%), followed by 13-14-year-old girls (3.90%), 10-12-year-old boys (2.37%), and 13-14-year-old boys (1.42%). In girls and boys, prevalence rates dropped by 64.53 and 60.65% among 10-12-year-olds and 13-14-year-olds, respectively (P = 0.00). The proportion of 10°-19° curves was 95.25 and 84.45% in boys and girls, respectively; and the proportion of 20°-29° curves was 3.91 and 11.28%, which was a significant difference (P = 0.00). Thoracic curves were the most common (47.59%) followed by thoracolumbar/lumbar (40.10%), double (9.09%), and double thoracic (3.22%) curves. A comparison of the curve patterns revealed significant differences between genders (P = 0.00). We present this report as a guide for studying the prevalence of idiopathic scoliosis in a large population, and the increasing trend in the prevalence of idiopathic scoliosis emphasizes the need for awareness.


Characterization and preliminary assessment of a sorbent produced by accelerated mineral carbonation.
This study shows that calcium silicate/aluminate-based materials can be carbonated to produce sorbents for metal removal. The material chosen for investigation, cement clinker, was accelerated carbonated, and its structural properties were investigated using X-ray diffraction (XRD), scanning electron microscopy, thermal gravimetric and differential thermal analysis, nuclear magnetic resonance spectroscopy, and nitrogen gas adsorption techniques. The principal carbonation reactions involved the transformation of dicalcium silicate, tricalcium silicate, and tricalcium aluminate into a Ca/Al-modified amorphous silica and calcium carbonate. It was found that carbonated cement had high acid buffering capacity, and maintained its structural integrity within a wide pH range. The uptake of Pb(II), Cd(II), Zn(II), Ni(II), Cr(II), Sr(II), Mo(VI), Cs(II), Co(II), and Cu(II) from concentrated (1000 mg L(-1)) single-metal solutions varied from 35 to 170 mg g(-1) of the carbonate cement. The removal of metals was hardly effected by the initial solution pH due to the buffering capability of the carbonated material. The kinetics of Pb, Cd, Cr, Sr, Cs, and Co removal followed a pseudo-second-order kinetic model, whereas the equilibrium batch data for Cu fitted the pseudo-first-order rate equation. PHREEQC simulation supported by XRD analysis suggested the formation of metal carbonates and silicates, calcium molybdate, and chromium (hydro)oxide. Cesium was likely to be adsorbed by Ca/Al-modified amorphous silica.


Thrombin-cleaved fragments of osteopontin are overexpressed in malignant glial tumors and provide a molecular niche with survival advantage.
Osteopontin (OPN), which is highly expressed in malignant glioblastoma (GBM), possesses inflammatory activity modulated by proteolytic cleavage by thrombin and plasma carboxypeptidase B2 (CPB2) at a highly conserved cleavage site. Full-length OPN (OPN-FL) was elevated in cerebrospinal fluid (CSF) samples from all cancer patients compared with noncancer patients. However, thrombin-cleaved OPN (OPN-R) and thrombin/CPB2-double-cleaved OPN (OPN-L) levels were markedly increased in GBM and non-GBM gliomas compared with systemic cancer and noncancer patients. Cleaved OPN constituted ∼23 and ∼31% of the total OPN in the GBM and non-GBM CSF samples, respectively. OPN-R was also elevated in GBM tissues. Thrombin-antithrombin levels were highly correlated with cleaved OPN, but not OPN-FL, suggesting that the cleaved OPN fragments resulted from increased thrombin and CPB2 in this extracellular compartment. Levels of VEGF and CCL4 were increased in CSF of GBM and correlated with the levels of cleaved OPN. GBM cell lines were more adherent to OPN-R and OPN-L than OPN-FL. Adhesion to OPN altered gene expression, in particular genes involved with cellular processes, cell cycle regulation, death, and inflammation. OPN and its cleaved forms promoted motility of U-87 MG cells and conferred resistance to apoptosis. Although functional mutation of the RGD motif in OPN largely abolished these functions, OPN(RAA)-R regained significant cell binding and signaling function, suggesting that the SVVYGLR motif in OPN-R may substitute for the RGD motif if the latter becomes inaccessible. OPN cleavage contributes to GBM development by allowing more cells to bind in niches where they acquire anti-apoptotic properties.


Big brains, meat, tuberculosis, and the nicotinamide switches: co-evolutionary relationships with modern repercussions?
Meat-eating was a game changer for human evolution. We suggest that the limiting factors for expanding brains earlier were scarcities of nicotinamide and tryptophan. In humans and some other omnivores, lack of meat causes these deficiencies. Nicotinamide adenine dinucleotide (NADH) is necessary to synthesize adenosine triphosphate (ATP) via either glycolysis or via the mitochondrial respiratory chain. NAD consumption is also necessary for developmental and repair circuits. Inadequate supplies result in "de-evolutionary" brain atrophy, as seen with pellagra. If trophic nicotinamide/tryptophan was a "prime mover" in building bigger brains, back-up mechanisms should have evolved. One strategy may be to recruit extra gut symbionts that produce NADH precursors or export nicotinamide (though this may cause diarrhea). We propose a novel supplier TB that co-evolved early, which did not originally and does not now inevitably cause disease. TB has highly paradoxical immunology for a pathogen, and secretes and is inhibited by nicotinamide and its analogue, isoniazid. Sharp declines in TB and diarrhea correlated with increased meat intake in the past, suggesting that dietary vitamin B3 and tryptophan deficiencies (also associated with poor cognition and decreased lifespans) are still common where meat is unaffordable.


Collaborative quality improvement for neonatal intensive care. NIC/Q Project Investigators of the Vermont Oxford Network.
To make measurable improvements in the quality and cost of neonatal intensive care using a multidisciplinary collaborative quality improvement model. Interventional study. Patient demographic and clinical information for infants with birth weight 501 to 1500 g was collected using the Vermont Oxford Network Database for January 1, 1994 to December 31, 1997. Ten self-selected neonatal intensive care units (NICUs) received the intervention. They formed 2 subgroups (6 NICUs working on infection, 4 NICUs working on chronic lung disease). Sixty-six other NICUs served as a contemporaneous comparison group. Infants with birth weight 501 to 1500 g born at or admitted within 28 days of birth between 1994 and 1997 to the 6 study NICUs in the infection group (n = 3063) and the 66 comparison NICUs (n = 21 509); infants with birth weight 501 to 1000 g at the 4 study NICUs in the chronic lung disease group (n = 738). NICUs formed multidisciplinary teams that worked together under the direction of a trained facilitator over a 3-year period beginning in January 1995. They received instruction in quality improvement, reviewed performance data, identified common improvement goals, and implemented "potentially better practices" developed through analysis of the processes of care, literature review, and site visits. The rates of infection after the third day of life with coagulase-negative staphylococcal or other bacterial pathogens for infants with birth weight 501 to 1500 g, and the rates of oxygen supplementation or death at 36 weeks' adjusted gestational age for infants with birth weight 501 to 1000 g. Between 1994 and 1996, the rate of infection with coagulase-negative staphylococcus decreased from 22.0% to 16.6% at the 6 project NICUs in the infection group; the rate of supplemental oxygen at 36 weeks' adjusted gestational age decreased from 43.5% to 31.5% at the 4 NICUs in the chronic lung disease group. There was heterogeneity in the effects among the NICUs in both project groups. The changes observed at the project NICUs for these outcomes were significantly larger than those observed at the 66 comparison NICUs over the 4-year period from 1994 to 1997. We conclude that multidisciplinary collaborative quality improvement has the potential to improve the outcomes of neonatal intensive care.


The relationship between depressive symptoms and walking among Hispanic older adults: a longitudinal, cross-lagged panel analysis.
This study examines the relationship between depressive symptoms and walking behavior across 30 months in a prospective study of 217 community-dwelling, Hispanic older adults in Miami, Florida (ages 70-100 years). Analyses examine the direction of the relationship between depressive symptoms and physical activity (i.e., walking) over time, as well as test for a potential bi-directional or reciprocal relationship between these two variables. Structural equation modeling (SEM) with a cross-lagged panel design revealed that walking was unrelated to subsequent depressive symptoms. However, depressive symptoms were related to subsequent walking behavior at every time-point, such that higher levels of depressive symptoms were predictive of less walking in the future. Older adults who had clinically-relevant depressive symptoms at the initial assessment had 1.34 times the risk of not walking 30 months later, compared to older adults without clinically-relevant depressive symptoms. Results support the need for primary care providers to evaluate and address depressive symptoms among older adults, as a means of reducing sedentary behavior and potentially improving health. Further research on the prevention and management of depressive symptoms and sedentary behavior is needed, given the morbidity related to both of these health risks, particularly for minority and low-socio-economic status (SES) older adults.


Electrophysiological and behavioral responses of the whitestriped longhorned beetle, Batocera lineolata, to the diurnal rhythm of host plant volatiles of holly, Viburnum awabuki.
The adsorption method of Tenax-TA absorbent with GC-MS was used to analyze diurnal rhythms of volatiles from undamaged holly plants, Viburnum awabuki Kock (Dipsacales: Adoxaceae) holly infested by the white-striped longhorned beetle, Batocera lineolata Chevrolat (Coleoptera: Cerambycidae). Electroantennography and a Y-tube olfactometer were used to compare and analyze electroantennogram and behavioral responses of unmated male and female adults to the volatiles from V. awabuki (both undamaged and infested plants). The results of the GC-MS analysis showed that phytosterol and alkane are major volatiles for V. awabuki. The relative content of V. awabuki volatiles changed during the day. Electroantennogram and behavioral responses of unmated male and female adults to the volatiles from both undamaged and infested plants of V. awabuki were stronger between 08:00 and 10:00 and 16:00 and 18:00, which is consistent with early morning and evening feeding behaviors of adults in the field.


High-speed properties of a phase-modulation scheme based on electromagnetically induced transparency.
Recently a cross-phase modulation scheme that yields giant Kerr nonlinearities by use of an electromagnetically induced transparency (EIT) was proposed [Schmidt and Imamoglu, Opt. Lett. 21, 1936 (1996)]. We analyze the high-speed properties of this scheme for short-pulse propagation. We discuss the relevant losses in this system and show that for short pulses one-photon losses are dominant. We demonstrate that over the entire bandwidth the attainable phase shift in an EIT scheme with a quasi-cw coupling field is orders of magnitude higher than in a conventional three-level scheme or in EIT schemes, in which matched pulses are used to create the transparency.


Human papillomavirus messenger RNA assay for cervical cancer screening: the Shenzhen Cervical Cancer Screening Trial I.
Testing for high-risk types of human papillomavirus (HPV) has been consistently more sensitive than cervical cytology for high-grade precancers and cancers of the cervix (cervical intraepithelial neoplasia grade 2 or higher) but less specific. New assays are being developed to improve on the overall accuracy of molecular testing. The Gen-Probe APTIMA HPV assay (AHPV) is a multiplex assay that qualitatively detects 14 HPV types in a single tube. Because the AHPV targets HPV-E6/E7 messenger RNA transcripts, it should theoretically have a greater specificity than HPV assays that detect HPV DNA. The objective of this study was to compare the sensitivity and the specificity of the Gen-Probe AHPV with those of the Qiagen Hybrid Capture 2 assay (HC2) and liquid-based cytologic examination for cervical cancer screening. A total of 2098 unscreened or poorly screened women 25 to 59 years of age were recruited in the city of Shenzhen, China. Two cervical specimens were collected: 1 in SurePath liquid for cytologic examination and 1 in PreservCyt for HPV testing by HC2 and the AHPV. The testing was performed by blinded technicians according to the manufacturer's instructions. Women who had atypical squamous cells of undetermined significance or worse cytologic diagnosis and/or were HPV positive by either assay were asked to return for colposcopy and biopsy. Overall, 2095 women had complete data. Overall, 16.5% of the women were positive on HC2, 10.1% were positive on the AHPV, 5.45% had atypical squamous cells of undetermined significance or greater on cytologic examination, and 1.4% had histologically confirmed cervical disease: cervical intraepithelial neoplasia grade 2 or higher. The sensitivity values of liquid-based cytologic examination, HC2, and the AHPV were 66.7%, 88.9%, and 100%, respectively. The specificity values were 95.5%, 84.5%, and 91.2%, respectively. The AHPV was significantly more accurate by receiver operating characteristic curve comparison (P = 0.005). The low false-positive rate (high specificity) and the high sensitivity of the AHPV makes this assay suitable for use as a primary assay for detecting cervical disease in a screening setting.


Factors Influencing Cyst Infection in Autosomal Dominant Polycystic Kidney Disease.
Cyst infection is a frequent and serious complication of autosomal dominant polycystic kidney disease (ADPKD) that is often difficult to treat. However, the factors influencing cyst infection are still unknown. Therefore, we investigated clinical factors related to the duration of hospitalization and death due to cyst infection. All ADPKD patients undergoing cyst drainage or nephrectomy or partial hepatectomy at Toranomon Hospital from January 2004 to March 2016, in whom cyst fluid analysis showed bacteria or neutrophils indicating definite cyst infection, were reviewed retrospectively. Factors influencing the duration of hospitalization and death due to cyst infection were analyzed. A total of 243 patients with cyst infection were enrolled, including 104 men and 139 women (mean age: 62.6 ± 10.0 years). Seventeen patients died of cyst infection. Multivariate logistic regression analysis revealed that hepatomegaly, positive cyst contents culture, and the maximum white blood cell (WBC) count were significantly associated with death from cyst infection. Death was significantly more likely if patients had massive hepatomegaly (≥5,113.2 mL) compared with mild hepatomegaly (< 1,898.7 mL; odds ratio 38.1; 95% CI 2.9-492.6, p = 0.0004). Multivariate Cox proportional hazards analysis revealed that older age, dialysis duration, hepatic transcatheter arterial embolization, maximum WBC count, and hepatomegaly were significantly associated with longer hospital stay for cyst infection, while female sex, nephrectomy, serum albumin, and serum cholinesterase were significantly associated with shorter hospital stay. Discharge alive from hospital was significantly associated with massive hepatomegaly versus mild hepatomegaly (hazard ratio 0.0072; 95% CI 0.0008-0.0659, p < 0.0001). Hepatomegaly was strongly associated with both death and longer hospital stay due to cyst infection.


High-throughput quantification of root growth using a novel image-analysis tool.
Measuring the dynamics of plant growth is fundamental to the understanding of plant development processes. This paper describes a high-throughput, automatic method to trace Arabidopsis (Arabidopsis thaliana) seedling roots grown on agarose plates. From the trace, additional software can quantify length, curvature, and stimulus response parameters such as onset of gravitropism. The method combines a particle-filtering algorithm with a graph-based method to trace the center line of a root. This top-down approach is robust to a variety of noise effects and is reasonably flexible across different image sets. The resulting tool requires minimal interaction from the user and is able to process long time-lapse sequences with user interaction only required on the first frame. The tool is described first, followed by its use on two sample data sets, one measuring root length and the other additionally analyzing the gravitropic response and curvature. The tool, RootTrace, is open source; both the program and source code will be available online.


Transcription and Beyond: Delineating FOXG1 Function in Cortical Development and Disorders.
Forkhead Box G1 (FOXG1) is a member of the Forkhead family of genes with non-redundant roles in brain development, where alteration of this gene's expression significantly affects the formation and function of the mammalian cerebral cortex. FOXG1 haploinsufficiency in humans is associated with prominent differences in brain size and impaired intellectual development noticeable in early childhood, while homozygous mutations are typically fatal. As such, FOXG1 has been implicated in a wide spectrum of congenital brain disorders, including the congenital variant of Rett syndrome, infantile spasms, microcephaly, autism spectrum disorder (ASD) and schizophrenia. Recent technological advances have yielded greater insight into phenotypic variations observed in FOXG1 syndrome, molecular mechanisms underlying pathogenesis of the disease, and multifaceted roles of FOXG1 expression. In this review, we explore the emerging mechanisms of FOXG1 in a range of transcriptional to posttranscriptional events in order to evolve our current view of how a single transcription factor governs the assembly of an elaborate cortical circuit responsible for higher cognitive functions and neurological disorders.


Defining the syndromes of parathyroid failure after total thyroidectomy.
Acute and chronic parathyroid insufficiency syndromes are the most common complication after total thyroidectomy. Permanent hypoparathyroidism imposes an important medical burden on patient lifestyle due to the need for lifetime medication, regular visits and significant long-term costs. Its true prevalence has been underestimated due to lack of clear definitions, inadequate follow-up and conflicts of interest when reporting individual patient series. The aim of this review is to propose precise definitions for the different syndromes associated to parathyroid failure based on the follow-up and management of patients developing hypocalcemia (<8 mg/dL at 24 hours) after first-time total thyroidectomy for cancer or goiter at our unit. Short and long-term post-thyroidectomy parathyroid failure presents as three different metabolic syndromes: (I) postoperative hypocalcemia is defined as a s-Ca <8 mg/dL (<2 mmol/L) within 24 hours after surgery requiring calcium/vit D replacement therapy at the time of hospital discharge; (II) protracted hypoparathyroidism as a subnormal iPTH concentration (<13 pg/mL) and/or need for calcium/vit D replacement at 4-6 weeks; and (III) permanent hypoparathyroidism as a subnormal iPTH concentration (<13 pg/mL) and/or need for calcium/vit D replacement 1 year after total thyroidectomy. Each of these syndromes has its own pattern of recovery and should be approached with different therapeutic strategies.


Stroke Prevention Worldwide--What Could Make It Work?
The global burden of stroke is of continual major importance for global health. The present report addresses some of the core principles that could make stroke prevention work. The prevention of stroke shares many common features with other non-communicable diseases (NCDs); stroke prevention should therefore be part of the joint actions on NCD led by the WHO and member states. Stroke prevention is an integral part of both the 2011 UN declaration on actions on NCDs and the UN Post-2015 Sustainable Developmental Goals. Stroke prevention requires an intersectoral approach, with important responsibilities on the part of governmental bodies, non-government organizations and the health sector as well as communities, industries and individuals. Although official development assistance will need to be provided for the lowest income countries, financing will need to be raised for most countries by reallocation of resources within the country. Stroke is a prototype NCD in that there is overwhelming scientific evidence that with actions taken to reduce risk factors, the risk of stroke can be substantially reduced. Prevention of stroke will also have beneficial effects on cognitive decline and dementia. As most strokes do not lead to death, stroke statistics should not only focus on mortality, but also on disability and quality of life. All preventive actions should start early in life and continue during the life cycle. Prevention of stroke is a complex medical and a political issue with many challenges. Upscaling of efforts to prevent stroke are urgently needed in all regions, and the opportunity to act is now.


Linker chemistry dictates the delivery of a phototoxic organometallic rhenium(i) complex to human cervical cancer cells from core crosslinked star polymer nanoparticles.
We have investigated core-crosslinked star polymer nanoparticles designed with tunable release chemistries as potential nanocarriers for a photoactive Re(i) organometallic complex. The nanoparticles consisted of a brush poly(oligo-ethylene glycol)methyl ether acrylate (POEGA) corona and a cross-linked core of non-biodegradable N,N'-methylenebis(acrylamide) (MBAA) and either pentafluorophenyl acrylate (PFPA), 3-vinyl benzaldehyde (VBA) or diacetone acrylamide (DAAM). Each star was modified with an amine functionalized photodynamic agent (i.e. a rhenium(i) organometallic complex) resulting in the formation of either a stable amide bond (POEGA-star-PFPA), or hydrolytically labile aldimine (POEGA-star-VBA) or ketimine bonds (POEGA-star-DAAM). These materials revealed linker dependent photo- and cytotoxicity when tested in vitro against non-cancerous lung fibroblast MRC-5 cells and HeLa human cervical cancer cells: the toxicity results correlated with final intracellular Re concentrations.


Dual effects of a homeopathic mineral complex on carrageenan-induced oedema in rats.
Carrageenan oedema, a classical experimental model commonly used to test activity of anti-inflammatory drugs, was used to evaluate the therapeutic activity of a low-potency mineral complex (MC). The MC was administered in the right plantar surface of albino rats 60 min before, simultaneously and 30 min after injection of carrageenan, an irritant which causes a local, transitory increase of fluid volume. The administration of the MC 60 min before the injection of carrageenan primed the animal to enhanced inflammatory response to the irritant. The administration of MC contemporarily to carrageenan did not modify the kinetic and the extent of the oedema, while the administration of the MC 30 min after the induction of the oedema significantly reduced the early phase of the inflammatory reaction. This indicated that the therapeutic action of this MC is not due to conventional anti-inflammatory effect but to activation of endogenous regulatory mechanisms, a phenomenon which may be regarded as a simple application of the 'similia rule'.


Phagolysosomal Survival Enables Non-lytic Hyphal Escape and Ramification Through Lung Epithelium During Aspergillus fumigatus Infection.
Aspergillus fumigatus is the most important mould pathogen in immunosuppressed patients. Suboptimal clearance of inhaled spores results in the colonisation of the lung airways by invasive hyphae. The first point of contact between A. fumigatus and the host is the lung epithelium. In vitro and ex vivo studies have characterised critical aspects of the interaction of invasive hyphae on the surface of epithelial cells. However, the cellular interplay between internalised A. fumigatus and the lung epithelium remains largely unexplored. Here, we use high-resolution live-cell confocal microscopy, 3D rendered imaging and transmission electron microscopy to define the development of A. fumigatus after lung epithelium internalisation in vitro. Germination, morphology and growth of A. fumigatus were significantly impaired upon internalisation by alveolar (A549) and bronchial (16HBE) lung epithelial cells compared to those growing on the host surface. Internalised spores and germlings were surrounded by the host phagolysosome membrane. Sixty per cent of the phagosomes containing germlings were not acidified at 24 h post infection allowing hyphal development. During escape, the phagolysosomal membrane was not ruptured but likely fused to host plasma membrane allowing hyphal exit from the intact host cell in an non-lytic Manner. Subsequently, escaping hyphae elongated between or through adjacent epithelial lung cells without penetration of the host cytoplasm. Hyphal tips penetrating new epithelial cells were surrounded by the recipient cell plasma membrane. Altogether, our results suggest cells of lung epithelium survive fungal penetration because the phagolysosomal and plasma membranes are never breached and that conversely, fungal spores survive due to phagosome maturation failure. Consequently, fungal hyphae can grow through the epithelial cell layer without directly damaging the host. These processes likely prevent the activation of downstream immune responses alongside limiting the access of professional phagocytes to the invading fungal hypha. Further research is needed to investigate if these events also occur during penetration of fungi in endothelial cells, fibroblasts and other cell types.


Genomes of the Mouse Collaborative Cross.
The Collaborative Cross (CC) is a multiparent panel of recombinant inbred (RI) mouse strains derived from eight founder laboratory strains. RI panels are popular because of their long-term genetic stability, which enhances reproducibility and integration of data collected across time and conditions. Characterization of their genomes can be a community effort, reducing the burden on individual users. Here we present the genomes of the CC strains using two complementary approaches as a resource to improve power and interpretation of genetic experiments. Our study also provides a cautionary tale regarding the limitations imposed by such basic biological processes as mutation and selection. A distinct advantage of inbred panels is that genotyping only needs to be performed on the panel, not on each individual mouse. The initial CC genome data were haplotype reconstructions based on dense genotyping of the most recent common ancestors (MRCAs) of each strain followed by imputation from the genome sequence of the corresponding founder inbred strain. The MRCA resource captured segregating regions in strains that were not fully inbred, but it had limited resolution in the transition regions between founder haplotypes, and there was uncertainty about founder assignment in regions of limited diversity. Here we report the whole genome sequence of 69 CC strains generated by paired-end short reads at 30× coverage of a single male per strain. Sequencing leads to a substantial improvement in the fine structure and completeness of the genomes of the CC. Both MRCAs and sequenced samples show a significant reduction in the genome-wide haplotype frequencies from two wild-derived strains, CAST/EiJ and PWK/PhJ. In addition, analysis of the evolution of the patterns of heterozygosity indicates that selection against three wild-derived founder strains played a significant role in shaping the genomes of the CC. The sequencing resource provides the first description of tens of thousands of new genetic variants introduced by mutation and drift in the CC genomes. We estimate that new SNP mutations are accumulating in each CC strain at a rate of 2.4 ± 0.4 per gigabase per generation. The fixation of new mutations by genetic drift has introduced thousands of new variants into the CC strains. The majority of these mutations are novel compared to currently sequenced laboratory stocks and wild mice, and some are predicted to alter gene function. Approximately one-third of the CC inbred strains have acquired large deletions (>10 kb) many of which overlap known coding genes and functional elements. The sequence of these mice is a critical resource to CC users, increases threefold the number of mouse inbred strain genomes available publicly, and provides insight into the effect of mutation and drift on common resources.


Comparative results between two groups of track-and-field athletes with or without the use of Master Amino acid Pattern as protein substitute.
Comparative results of this study have shown that athletes, by taking the Master Amino acid Pattern (MAP) as a dietary protein substitute and performing physical activity, have had (1) increased body muscle mass, strength, and endurance; (2) decreased fat mass; (3) increased basal metabolism rate; (4) greater improvement in performance of the nonprevailing muscles compared to the prevailing ones; and (5) improved muscular and hematologic lactate clearance, which allows for better muscle performance and faster muscle recovery after physical activity. It was concluded that the use of MAP as a dietary protein substitute in conjunction with physical activity can provide a safe and unprecedented way to optimize the body's protein synthesis, thereby improving anthropometric characteristics and physical and physiologic performance.


Identification of comatose patients at high risk for death or severe disability. SUPPORT Investigators. Understand Prognoses and Preferences for Outcomes and Risks of Treatments.
To develop and validate a simple prognostic scoring system to identify patients in nontraumatic coma at high risk for poor outcomes using data available early in the hospital course. Prospective cohort study. Five geographically diverse academic medical centers. A total of 596 patients in nontraumatic coma enrolled in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT), including 247 in the model derivation set and 349 in the model validation set. Death and severe disability by 2 months. For the 596 patients studied (median age, 67 years; 52% female), the primary cause of coma was cardiac arrest in 31% and cerebral infarction or intracerebral hemorrhage in 36%. At 2 months 69% had died, 20% had survived with known severe disability, 8% were known to have survived without severe disability, and 3% survived with unknown functional status. Five clinical variables available on day 3 after enrollment were associated independently with 2-month mortality: abnormal brain stem response (adjusted odds ratio [OR] = 3.2; 95% confidence interval [CI], 1.3 to 8.1), absent verbal response (OR = 4.6; 95% CI, 1.8 to 11.7), absent withdrawal response to pain (OR = 4.3; 95% CI, 1.7 to 10.8), creatinine level greater than or equal to 132.6 mumol/L (1.5 mg/dL) (OR = 4.5; 95% CI, 1.8 to 11.0), and age of 70 years or older (OR = 5.1; 95% CI, 2.2 to 12.2). Mortality at 2 months for patients with four or five of these risk factors was 97% (58/60; 95% CI, 88% to 100%) in the validation set. Brain stem and motor responses best predicted death or severe disability by 2 months. For patients with either an abnormal brain stem response or absent motor response to pain, the rate of death or severe disability at 2 months was 96% (185/193; 95% CI, 92% to 98%) in the validation set. Five readily available clinical variables identify a large subgroup of patients in nontraumatic coma at high risk for poor outcomes. This risk stratification approach offers physicians, patients, and patients' families information that may prove useful in patient care decisions and resource allocation.


Phosphorus and Nitrogen Dual-Doped Hollow Carbon Dot as a Nanocarrier for Doxorubicin Delivery and Biological Imaging.
Innovative phosphorus and nitrogen dual-doped hollow carbon dots (PNHCDs) have been fabricated for anticancer drug delivery and biological imaging. The functional groups of PNHCDs are introduced by simply mixing glucose, 1,2-ethylenediamine, and concentrated phosphoric acid. This is an automatic method without external heat treatment to rapidly produce large quantities of PNHCDs, which avoid high temperature, complicated operations, and long reaction times. The as-prepared PNHCDs possess small particle size, hollow structure, and abundant phosphate/hydroxyl/pyridinic/pyrrolic-like N groups, endowing PNHCDs with fluorescent properties, improving the accuracy of PNHCDs as an optical monitoring code both in vitro and in vivo. The investigation of PNHCDs as an anticancer drug nanocarrier for doxorubicin (DOX) indicates a better antitumor efficacy than free DOX owing to its enhanced nuclear delivery in vitro and tumor accumulation in vivo, which results in highly effective tumor growth inhibition and improved targeted therapy for cancer in clinical medicine.


Expression of perilipins in human skeletal muscle in vitro and in vivo in relation to diet, exercise and energy balance.
The perilipin proteins enclose intracellular lipid droplets. We describe the mRNA expression of the five perilipins in human skeletal muscle in relation to fatty acid supply, exercise and energy balance. We observed that all perilipins were expressed in skeletal muscle biopsies with the highest mRNA levels of perilipin 2, 4 and 5. Cultured myotubes predominantly expressed perilipin 2 and 3. In vitro, incubation of myotubes with fatty acids enhanced mRNA expression of perilipin 1, 2 and 4. In vivo, low fat diet increased mRNA levels of perilipin 3 and 4. Endurance training, but not strength training, enhanced the expression of perilipin 2 and 3. Perilipin 1 mRNA correlated positively with body fat mass, whereas none of the perilipins were associated with insulin sensitivity. In conclusion, all perilipins mRNAs were expressed in human skeletal muscle. Diet as well as endurance exercise modulated the expression of perilipins.


Validity of premature ejaculation diagnostic tool and its association with International Index of Erectile Function-15 in Chinese men with evidence-based-defined premature ejaculation.
The premature ejaculation diagnostic tool (PEDT) is a brief diagnostic measure to assess premature ejaculation (PE). However, there is insufficient evidence regarding its validity in the new evidence-based-defined PE. This study was performed to evaluate the validity of PEDT and its association with IIEF-15 in different types of evidence-based-defined PE. From June 2015 to January 2016, a total of 260 men complaining of PE and defined as lifelong PE (LPE)/acquired PE (APE) according to the evidence-based definition from Andrology Clinic of the First Affiliated Hospital of Anhui Medical University, along with 104 male healthy controls without PE from a medical examination center, were enrolled in this study. All individuals completed questionnaires including demographics, medical and sexual history, as well as PEDT and IIEF-15. After statistical analysis, it was found that men with PE reported higher PEDT scores (14.28 ± 3.05) and lower IIEF-15 (41.26 ± 8.20) than men without PE (PEDT: 5.32 ± 3.42, IIEF-15: 52.66 ± 6.86, P < 0.001 for both). It was suggested that a score of ≥9 indicated PE in both LPE and APE by sensitivity and specificity analyses (sensitivity: 0.875, 0.913; specificity: 0.865, 0.865, respectively). In addition, IIEF-15 were higher in men with LPE (42.64 ± 8.11) than APE (39.43 ± 7.84, P < 0.001). After adjusting for age, IIEF-15 was negatively related to PEDT in men with LPE (adjust r = -0.225, P < 0.001) and APE (adjust r = -0.378, P < 0.001). In this study, we concluded that PEDT was valid in the diagnosis of evidenced-based-defined PE. Furthermore, IIEF-15 was negatively related to PEDT in men with different types of PE.


The time to measure positional information: maternal hunchback is required for the synchrony of the Bicoid transcriptional response at the onset of zygotic transcription.
It is widely accepted that morphogenetic gradients determine cell identity by concentration-dependent activation of target genes. How precise is each step in the gene expression process that acts downstream of morphogens, however, remains unclear. The Bicoid morphogen is a transcription factor directly activating its target genes and provides thus a simple system to address this issue in a quantitative manner. Recent studies indicate that the Bicoid gradient is precisely established in Drosophila embryos after eight nuclear divisions (cycle 9) and that target protein expression is specified five divisions later (cycle 14), with a precision that corresponds to a relative difference of Bicoid concentration of 10%. To understand how such precision was achieved, we directly analyzed nascent transcripts of the hunchback target gene at their site of synthesis. Most anterior nuclei in cycle 11 interphasic embryos exhibit efficient biallelic transcription of hunchback and this synchronous expression is specified within a 10% difference of Bicoid concentration. The fast diffusion of Bcd-EGFP (7.7 mum(2)/s) that we captured by fluorescent correlation spectroscopy in the nucleus is consistent with this robust expression at cycle 11. However, given the interruption of transcription during mitosis, it remains too slow to be consistent with precise de novo reading of Bicoid concentration at each interphase, suggesting the existence of a memorization process that recalls this information from earlier cycles. The two anterior maternal morphogens, Bicoid and Hunchback, contribute differently to this early response: whereas Bicoid provides dose-dependent positional information along the axis, maternal Hunchback is required for the synchrony of the response and is therefore likely to be involved in this memorization process.


State-of-the-Art Deep Learning in Cardiovascular Image Analysis.
Cardiovascular imaging is going to change substantially in the next decade, fueled by the deep learning revolution. For medical professionals, it is important to keep track of these developments to ensure that deep learning can have meaningful impact on clinical practice. This review aims to be a stepping stone in this process. The general concepts underlying most successful deep learning algorithms are explained, and an overview of the state-of-the-art deep learning in cardiovascular imaging is provided. This review discusses >80 papers, covering modalities ranging from cardiac magnetic resonance, computed tomography, and single-photon emission computed tomography, to intravascular optical coherence tomography and echocardiography. Many different machines learning algorithms were used throughout these papers, with the most common being convolutional neural networks. Recent algorithms such as generative adversarial models were also used. The potential implications of deep learning algorithms on clinical practice, now and in the near future, are discussed.


Stereodirection of an α-ketoester at sub-molecular sites on chirally modified Pt(111): heterogeneous asymmetric catalysis.
Chirally modified Pt catalysts are used in the heterogeneous asymmetric hydrogenation of α-ketoesters. Stereoinduction is believed to occur through the formation of chemisorbed modifier-substrate complexes. In this study, the formation of diastereomeric complexes by coadsorbed methyl 3,3,3-trifluoropyruvate, MTFP, and (R)-(+)-1-(1-naphthyl)ethylamine, (R)-NEA, on Pt(111) was studied using scanning tunneling microscopy and density functional theory methods. Individual complexes were imaged with sub-molecular resolution at 260 K and at room temperature. The calculations find that the most stable complex isolated in room-temperature experiments is formed by the minority rotamer of (R)-NEA and pro-S MTFP. The stereodirecting forces in this complex are identified as a combination of site-specific chemisorption of MTFP and multiple non-covalent attractive interactions between the carbonyl groups of MTFP and the amine and aromatic groups of (R)-NEA.