[The effect of 3',5'-cyclic adenylic acid (cAMP) on the growth of bacteria].
The effect of intracellular cAMP level on the growth of bacteria was studied with E. coli AS 1.797, Corynebacterium pekinense AS 1.299 and Bacillus megaterium AS 1.217. The experimental results show that the growth of E. coli AS 1.797 was decreased with increasing cAMP level in cell. With glucose as the sole carbon source, intracellular cAMP is low, and growth of E. coli AS 1.797 was inhibited by exogenous cAMP, but the analog metabolite of cAMP-5'-AMP had no effect on growth. When E. coli AS 1.797 was grown in media containing lactose, maltose and glycerin respectively, intracellular cAMP level is high, and exogenous cAMP did not inhibited the cell growth. When Corynebacterium pekinense AS 1.299 took glucose as carbon source the growth of this bacterium was also inhibited by exogenous cAMP, but the inhibition of cAMP was not specific, its role can be exchanged by 5'-AMP. B. megaterium AS 1.217 cultivated in different carbon source (include glucose) do not contain cAMP in cell, and its growth was not inhibited by exogenous cAMP. 5'-AMP had also no effect on the growth of this bacterium. Thus, the conclusion seems that the cAMP is not essential for the growth of bacteria, and it is a regulator that act a negative regulation in cell growth, but this regulator is of no effect for the growth of B. megaterium AS 1.217.


Polymeric architecture as a tool for controlling the reactivity of palladium(II) loaded nanoreactors.
Self-assembled systems, like polymeric micelles, have become great facilitators for conducting organic reactions in aqueous media due to their broad potential applications in green chemistry and biomedical applications. Massive strides have been taken to improve the reaction scope of such systems, enabling them to perform bioorthogonal reactions for prodrug therapy. Considering these significant advancements, we sought to study the relationships between the architecture of the amphiphiles and the reactivity of their PdII loaded micellar nanoreactors in conducting depropargylation reactions. Towards this goal, we designed and synthesized a series of isomeric polyethylene glycol (PEG)-dendron amphiphiles with different dendritic architectures but with an identical degree of hydrophobicity and hydrophilic to lipophilic balance (HLB). We observed that the dendritic architecture, which serves as the main binding site for the PdII ions, has greater influence on the reactivity than the hydrophobicity of the dendron. These trends remained constant for two different propargyl caged substrates, validating the obtained results. Density functional theory (DFT) calculations of simplified models of the dendritic blocks revealed the different binding modes of the various dendritic architectures to PdII ions, which could explain the observed differences in the reactivity of the nanoreactors with different dendritic architectures. Our results demonstrate how tuning the internal architecture of the amphiphiles by changing the orientation of the chelating moieties can be used as a tool for controlling the reactivity of PdII loaded nanoreactors.


Autoerythrocyte sensitization worsened by a copper-containing IUD.
Autoerythrocyte sensitization (Gardner-Diamond syndrome) causes painful ecchymoses, and usually occurs in young women. It is rare and of unknown etiology. The young woman in this report probably had the condition beginning at age 14, but the diagnosis was not made until age 19, shortly after a copper-containing intrauterine device (IUD) exacerbated her condition. The ecchymoses disappeared when the IUD was removed, but recurred when replaced. A non-copper IUD caused no ecchymoses. Taping a copper penny to the skin caused a similar rash. It seems that in this woman, the Gardner-Diamond syndrome was markedly worsened by exposure to copper.


Graph-based open-ended survey on concerns related to COVID-19.
The COVID-19 pandemic is an unprecedented public health crisis with broad social and economic consequences. We conducted four surveys between April and August 2020 using the graph-based open-ended survey (GOS) framework, and investigated the most pressing concerns and issues for the general public in Japan. The GOS framework is a hybrid of the two traditional survey frameworks that allows respondents to post their opinions in a free-format style, which can subsequently serve as one of the choice items for other respondents, just as in a multiple-choice survey. As a result, this framework generates an opinion graph that relates opinions and respondents. We can also construct annotated opinion graphs to achieve a higher resolution. By clustering the annotated opinion graphs, we revealed the characteristic evolution of the response patterns as well as the interconnectedness and multi-faceted nature of opinions. Substantively, our notable finding is that "social pressure," not "infection risk," was one of the major concerns of our respondents. Social pressure refers to criticism and discrimination that they anticipate receiving from others should they contract COVID-19. It is possible that the collectivist nature of Japanese culture coupled with the government's policy of relying on personal responsibility to combat COVID-19 explains some of the above findings, as the latter has led to the emergence of vigilantes. The presence of mutual surveillance can contribute to growing skepticism toward others as well as fear of ostracism, which may have negative consequences at both the societal and individual levels.


Dapagliflozin Improves Heart Failure Symptoms and Physical Limitations Across the Full Range of Ejection Fraction: Pooled Patient-Level Analysis From DEFINE-HF and PRESERVED-HF Trials.
Patients with heart failure (HF) have a high burden of symptoms and physical limitations, regardless of ejection fraction (EF). Whether the benefits of SGLT2 (sodium-glucose cotransporter-2) inhibitors on these outcomes vary across the full range of EF remains unclear. Patient-level data were pooled from the DEFINE-HF trial (Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction) of 263 participants with reduced EF (≤40%), and PRESERVED-HF trial (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure) of 324 participants with preserved EF (≥45%). Both were randomized, double-blind 12-week trials of dapagliflozin versus placebo, recruiting participants with New York Heart Association class II or higher and elevated natriuretic peptides. The effect of dapagliflozin on the change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at 12 weeks was tested with ANCOVA adjusted for sex, baseline KCCQ, EF, atrial fibrillation, estimated glomerular filtration rate, and type 2 diabetes. Interaction of dapagliflozin effects on KCCQ-CSS by EF was assessed using EF both categorically and continuously with restricted cubic spline. Responder analyses, examining proportions of patients with deterioration, and clinically meaningful improvements in KCCQ-CSS were conducted using logistic regression. Of 587 patients randomized (293 dapagliflozin, 294 placebo), EF was ≤40, >40-≤60, and >60% in 262 (45%), 199 (34%), and 126 (21%), respectively. Dapagliflozin improved KCCQ-CSS at 12 weeks (placebo-adjusted difference 5.0 points [95% CI, 2.6-7.5]; P<0.001). This was consistent in participants with EF≤40 (4.6 points [95% CI, 1.0-8.1]; P=0.01), >40 to ≤60 (4.9 points [95% CI, 0.8-9.0]; P=0.02) and >60% (6.8 points [95% CI, 1.5-12.1]; P=0.01; Pinteraction=0.79). Benefits of dapagliflozin on KCCQ-CSS were also consistent when analyzing EF continuously (Pinteraction=0.94). In responder analyses, fewer dapagliflozin-treated patients had deterioration and more had small, moderate, and large KCCQ-CSS improvements versus placebo; these results were also consistent regardless of EF (all Pinteractionvalues nonsignificant). In patients with HF, dapagliflozin significantly improves symptoms and physical limitations after 12 weeks of treatment, with consistent and clinically meaningful benefits across the full range of EF. URL: https://www. gov; Unique identifiers: NCT02653482 and NCT03030235.


Changes in population HIV RNA levels in Mbarara, Uganda, during scale-up of HIV antiretroviral therapy access.
In a rural Ugandan community scaling up antiretroviral therapy (ART), we sought to determine if population-based HIV RNA levels [population viral load (VL)] decreased from 2011 to 2012. Serial cross-sectional analyses (May 2011 and May 2012) of a defined study community of 6300 persons in a district with HIV prevalence of 8%. We measured HIV-1 RNA (VL) levels on all individuals testing positive for HIV during a 5-day high-throughput multidisease community health campaign in May 2012 that recruited two-thirds of the population. We aggregated individual-level VL results into population VL metrics including the proportion of individuals with an undetectable VL and compared these VL metrics to those we previously reported for this geographic region in 2011. In 2012, 223 of 2179 adults were HIV-seropositive adults (10%). Overall, among 208 of 223 HIV-seropositive adults in whom VL was tested, 53% had an undetectable VL [95% confidence interval (CI): 46 to 60], up from 37% (95% CI: 30 to 45; P = 0.02) in 2011. Seven (3%) individuals had a VL of >100,000 copies/mL in 2012, down from 21 (13%) in 2011 (P = 0.0007). Mean log (VL) (geometric mean) was 3.18 log (95% CI: 3.06 to 3.29 log) in 2012, down from 3.62 log (95% CI: 3.46 to 3.78 log) in 2011 (P < 0.0001). Similar reductions in population VL were seen among men and women. Reductions in population VL metrics and a substantial increase in the proportion of persons with an undetectable VL were observed in a rural Ugandan community from 2011 to 2012. These findings from a resource-limited setting experiencing rapid ART scale-up may reflect a population-level effectiveness of expanding ART access.


Neoadjuvant Chemotherapy Followed by Delayed Surgery: Is it Necessary for All Patients With Nonmetastatic High-Grade Pelvic Osteosarcoma?
Neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy is the most-frequently employed strategy for patients with high-grade osteosarcoma. However, the contribution of neoadjuvant chemotherapy compared with postoperative adjuvant chemotherapy has not been tested rigorously in patients with nonmetastatic high-grade pelvic osteosarcoma. (1) Does neoadjuvant chemotherapy followed by delayed surgery offer a survival benefit to patients with nonmetastatic high-grade pelvic osteosarcoma compared with immediate surgery and adjuvant chemotherapy? (2) Is the timing of chemotherapy and surgery associated with a difference in the survivorship free from local recurrence and the risk of complications? (3) Is the threshold of 90% necrosis after neoadjuvant chemotherapy appropriate to distinguish responders from nonresponders in patients with pelvic osteosarcoma? Between 2000 and 2015, our center treated 112 patients with nonmetastatic high-grade primary pelvic osteosarcoma, of whom 93 underwent tumor resection with chemotherapy. Four patients (4%) were lost to followup before 24 months but were not known to have died; the remaining 89 patients were included in this retrospective study. Based on the timing of surgery and chemotherapy, patients were analyzed in two groups: (1) neoadjuvant chemotherapy followed by delayed surgery and adjuvant chemotherapy (n = 56; mean followup of 61 months, range 27-137 months), and (2) immediate surgery followed by adjuvant chemotherapy (n = 33; mean followup of 77 months, range 25-193 months). The total duration and intensity of chemotherapy was similar in both groups. During the period in question, we generally used neoadjuvant therapy followed by delayed surgery and adjuvant chemotherapy when patients received their biopsies in our center. We typically used immediate surgery with adjuvant chemotherapy when patients initially refused chemotherapy or when they had severe pain or poor walking function. Patients in the neoadjuvant chemotherapy group had a higher proportion of sacral infiltration; other factors such as sex, age and tumor size were well balanced between groups. We compared overall survival and local recurrence-free survival rates between the two groups. We completed univariate log-rank tests and multivariate Cox analyses in all patients to identify factors associated with survival and local recurrence using the Kaplan-Meier method. No survival benefit was found in the patients treated with neoadjuvant chemotherapy followed by delayed surgery compared with the group treated with immediate surgery and adjuvant chemotherapy. At 5 years, the overall survival (OS) was 42% (95% CI, 33-52) for all patients in this study, 43% (95% CI, 30-56) for the neoadjuvant group, and 40% (95% CI, 25-55) for the immediate surgery group; p = 0.709. With the numbers available, there was no difference in the likelihood of successful limb salvage (five of 56 patients [89%] in the neoadjuvant chemotherapy group versus three of 33 patients [91%] in the immediate surgery group; p = 0.557). The 5-year local recurrence-free survival was 67% (95% CI, 59-76) with no difference between the two groups (68%; 95% CI, 57-78% versus 67%; 95% CI, 52-81; p = 0.595). With the numbers available, there was no difference in survival between patients whose tumors demonstrated more than 90% necrosis; however, only four of 56 patients in the neoadjuvant chemotherapy group demonstrated 90% necrosis. We found no survival advantage with chemotherapy before surgery compared with immediate surgery in patients with nonmetastatic high-grade pelvic osteosarcoma. The decision on chemotherapy timing should be made for reasons other than survival. A prospective trial is needed to confirm this conclusion. Level III, therapeutic study.


Transport of antibiotics and metabolite analogs by systems under cyclic AMP control: positive selection of Salmonella typhimurium cya and crp mutants.
Mutants in the cyclic AMP (cAMP) control system in Salmonella typhimurium (cya = adenyl cyclase, crp = cAMP receptor protein) were partially resistant to growth inhibition by 22 antibiotics (including fosfomycin, nalidixic acid, and streptomycin) and 29 inhibitory analogs of normal bacterial fuel/carbon sources. This resistance was used as the basis for an efficient positive selection of cya and crp mutants. We propose that these antibiotics and analogs enter the bacteria through transport systems normally used for transporting fuel/carbon sources and that this is accomplished because of a structural similarity between the antibiotic and the natural substrate of the particular transport system involved. We propose that these transport systems are all under positive control by cAMP and that cAMP acts as a signal molecule (alarmone) for fuel/carbon deprivation. Evidence is provided for a hierarchy within operons controlled by cAMP. The methodology is shown to be useful for analyzing both antibiotic transport systems and the cAMP super-control system.


A randomized, double-blind, placebo-controlled trial of low-dose oral prednisolone for treating painful hand osteoarthritis.
Anti-inflammatory therapies are effective analgesics for OA. This study determined whether low-dose oral prednisolone (PNL) was an effective analgesic for hand OA. This was a randomized, double-blind, placebo-controlled trial of people with ACR criteria hand OA and baseline hand pain visual analogue scale (VAS) of >40/100 mm. Participants received 5 mg PNL or placebo daily for 4 weeks. Pain VAS, disease activity VAS, Australian/Canadian Hand Osteoarthritis Index and joint counts were performed at baseline, 4 and 12 weeks. Primary outcome was the change in hand pain VAS at 4 weeks. Analysis of covariance was used for analysis, controlling for baseline values. To explore potential mechanism of action of PNL, non-contrast 0.2 Tesla MRI was performed on the most painful hand at baseline and 4 weeks. A total of 70 participants were recruited (57 women, mean age 61 years, mean baseline pain VAS 61.5 mm); 75% had more than one joint with definite MRI synovitis/effusion. At 4 weeks the adjusted mean reduction in pain VAS was 19.9 mm (PNL group) and 16.8 mm (placebo group) (P = 0.54). There were no statistically significant differences in VAS, Australian/Canadian Hand Osteoarthritis Index or joint counts between placebo and PNL groups at 4 or 12 weeks. A total of 20 participants in each group achieved an Outcome Measures in Rheumatology-Osteoarthritis Research Society International response. Baseline synovitis/effusion did not predict response to treatment. This is the first randomized controlled trial of low-dose corticosteroid alone for painful hand OA, which demonstrated that short-term low-dose oral PNL is not an effective analgesic treatment for hand OA. International Standard Randomised Controlled Trial Number Register, www.isrctn.org, Trial number 99697616.


DNA synthesis in excised tobacco leaves after bromodeoxyuridine incorporation: immunohistochemical detection in semi-thin spurr sections.
We describe a method for localizing replicating cells in detached tobacco leaves allowed to root. The proposed protocol has shown that formalin fixation and Spurr embedding of petiole bases can be used for demonstrating DNA synthesis after bromodeoxyuridine (BrdU) incorporation. The incorporated BrdU was immunologically visualized. After resin removal, different procedures of DNA denaturation and protease digestion were tested. Combined hydrolysis with 4 N HCl for 10 min at room temperature and digestion with 0.4% pepsin for 15 min at 37 degrees C led to the best reproducible results, with either the peroxidase or the gold detection system. The method is rapid and sensitive, with precise resolution. It can be used at the light and electron microscopic levels. Its potential application is to elucidate in the same organ the role of cytokinins, a class of plant growth regulators, in dividing cells and to define the chronology of their biosynthesis in roots in relation to DNA synthesis.


Alteration of gut microbiota with a broad-spectrum antibiotic does not impair maternal care in the European earwig.
The microbes residing within the gut of an animal host often increase their own fitness by modifying their host's physiological, reproductive and behavioural functions. Whereas recent studies suggest that they may also shape host sociality and therefore have critical effects on animal social evolution, the impact of the gut microbiota on maternal care remains unexplored. This is surprising, as this behaviour is widespread among animals, often determines the fitness of both juveniles and parents, and is essential in the evolution of complex animal societies. Here, we tested whether life-long alterations of the gut microbiota with rifampicin-a broad-spectrum antibiotic-impair pre- and post-hatching maternal care in the European earwig. Our results first confirm that rifampicin altered the mothers' gut microbial communities and indicate that the composition of the gut microbiota differs before and after egg care. Contrary to our predictions, however, the rifampicin-induced alterations of the gut microbiota did not modify pre- or post-hatching care. Independent of maternal care, rifampicin increased the females' faeces production and resulted in lighter eggs and juveniles. By contrast, rifampicin altered none of the other 21 physiological, reproductive and longevity traits measured over the 300 days of a female's lifetime. Overall, these findings reveal that altering the gut microbiota with a large spectrum antibiotic such as rifampicin does not necessarily affect host sociality. They also emphasize that not all animals have evolved a co-dependence with their microbiota and call for caution when generalizing the central role of gut microbes in host biology.


Pea protein hydrolysate reduces blood glucose in high-fat diet and streptozotocin-induced diabetic mice.
Food proteins have been recognized as an ideal source to release bioactive peptides with the potential to intervene nutrition related chronic diseases, such as cardiovascular diseases, obesity and diabetes. Our previous studies showed that pea protein hydrolysate (PPH) could suppress hepatic glucose production in hepatic cells via inhibiting the gluconeogenic signaling. Thus, we hypothesized that PPH could play the hypoglycemic role in vivo. In the present study, the mice model with type 2 diabetic mellitus (T2DM) was developed by high-fat diet and low dose of streptozotocin injections. PPH was administered orally with a dosage of 1000 mg/kg body weight for 9 weeks, followed by the downstream biomedical analyses. The results showed that the 9-week treatment of PPH could reduce fasting blood glucose by 29.6% and improve glucose tolerance in the T2DM mice. The associated mechanisms included suppression of the gluconeogenic pathway, activation of the insulin signaling and modulation of the renin angiotensin system in the liver of the diabetic mice. In addition, the levels of pro-inflammatory markers in both liver and serum were reduced by the PPH treatment. The hypoglycemic effect of PPH in T2DM mice was demonstrated in the present study. Findings from this study could provide rationale to incorporate PPH into functional foods or nutraceuticals for glycemic control.


Vagal afferent fibres determine the oxytocin-induced modulation of gastric tone.
Oxytocin (OXT) inputs to the dorsal vagal complex (DVC; nucleus of the tractus solitarius (NTS) dorsal motor nucleus of the vagus (DMV) and area postrema) decrease gastric tone and motility. Our first aim was to investigate the mechanism(s) of OXT-induced gastric relaxation. We demonstrated recently that vagal afferent inputs modulate NTS-DMV synapses involved in gastric and pancreatic reflexes via group II metabotropic glutamate receptors (mGluRs). Our second aim was to investigate whether group II mGluRs similarly influence the response of vagal motoneurons to OXT. Microinjection of OXT in the DVC decreased gastric tone in a dose-dependent manner. The OXT-induced gastric relaxation was enhanced following bethanechol and reduced by l-NAME administration, suggesting a nitrergic mechanism of gastroinhibition. DVC application of the group II mGluR antagonist EGLU induced a gastroinhibition that was not dose dependent and shifted the gastric effects of OXT to a cholinergic-mediated mechanism. Evoked and miniature GABAergic synaptic currents between NTS and identified gastric-projecting DMV neurones were not affected by OXT in any neurones tested, unless the brainstem slice was (a) pretreated with EGLU or (b) derived from rats that had earlier received a surgical vagal deafferentation. Conversely, OXT inhibited glutamatergic currents even in naive slices, but their responses were unaffected by EGLU pretreatment. These results suggest that the OXT-induced gastroinhibition is mediated by activation of the NANC pathway. Inhibition of brainstem group II mGluRs, however, uncovers the ability of OXT to modulate GABAergic transmission between the NTS and DMV, resulting in the engagement of an otherwise silent cholinergic vagal neurocircuit.


Beyond clines: lineages and haplotype blocks in hybrid zones.
Hybrid zones formed between recently diverged populations offer an opportunity to study the mechanisms underlying reproductive isolation and the process of speciation. Here, we use a combination of analytical theory and explicit forward simulations to describe how selection against hybrid genotypes impacts patterns of introgression across genomic and geographic space. By describing how lineages move across the hybrid zone, in a model without coalescence, we add to modern understanding of how clines form and how parental haplotypes are broken up during introgression. Working with lineages makes it easy to see that clines form in about 1/s generations, where s is the strength of selection against hybrids, and linked clines persist over a genomic scale of 1/T, where T is the age, in generations, of the hybrid zone. Locally disadvantageous alleles tend to exist as small families, whose lineages trace back to the side from which they originated at speed s dispersal distances per generation. The lengths of continuous tracts of ancestry provide an additional source of information: blocks of ancestry surrounding incompatibilities can be substantially longer than the genomewide average block length at the same spatial location, an observation that might be used to identify candidate targets of selection.


Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis.
The effects of pregnancy were studied in a multiple sclerosis incidence cohort. In order to eliminate interaction bias between the disease and pregnancy, analysis of the risk of relapse during pregnancy and the puerperium was limited to the onset bout, using fecundity figures for Sweden. The risk of onset bout was significantly reduced during pregnancy while the risk of onset bout in the post-partum period did not differ significantly from the risk during non-pregnancy periods. We also found a decreased risk of multiple sclerosis onset in parous compared with nulliparous women. The association between nulliparity and multiple sclerosis tended to increase with age. Furthermore, the effect of pregnancy on the long-term prognosis in established multiple sclerosis was analysed by comparing the risk of change from a relapsing-remitting to a chronic progressive course and the risk of reaching level 6 of the Disability Status Scale in women with pregnancy after multiple sclerosis onset with that in non-pregnant control patients, matched for neurological deficit, disease duration and age. There was a significantly decreased risk of a progressive course in women who were pregnant after multiple sclerosis onset.


Missense mutations in the sodium borate cotransporter SLC4A11 cause late-onset Fuchs corneal dystrophy.
Homozygous mutations in the Borate Cotransporter SLC4A11 cause two early-onset corneal dystrophies: congenital hereditary endothelial dystrophy (CHED) and Harboyan syndrome. More recently, four sporadic patients with late-onset Fuchs corneal dystrophy (FCD), a common age-related disorder, were also reported to harbor heterozygous mutations at this locus. We therefore tested the hypothesis that SLC4A11 contributes to FCD and asked whether mutations in SLC4A11 are responsible for familial cases of late-onset FCD. We sequenced SLC4A11 in 192 sporadic and small nuclear late-onset FCD families and found seven heterozygous missense novel variations that were absent from ethnically matched controls. Familial data available for one of these mutations showed segregation under a dominant model in a three-generational family. In silico analyses suggested that most of these substitutions are intolerant, whereas biochemical studies of the mutant protein indicated that these alleles impact the localization and/or posttranslational modification of the protein. These results suggest that heterozygous mutations in SLC4A11 are modest contributors to the pathogenesis of adult FCD, suggesting a causality continuum between FCD and CHED. Taken together with a recent model between FCD and yet another early onset corneal dystrophy, PPCD, our data suggest a shared pathomechanism and genetic overlap across several corneal dystrophies.


The economic impact of the utilization of liver allografts with high donor risk index.
The disparity between the organ supply and the demand for liver transplantation (LT) has resulted in the growing utilization of 'marginal donor' organs. While economic outcomes for subsets of 'marginal' organs have been described for renal transplantation, similar analyses have not been performed for LT. Using UNOS data for 17 710 LTs performed between 2002 and 2005, we assessed the relationship between recipient model for end-stage liver disease (MELD) score, organ quality as defined by donor risk index (DRI, Feng et al. 2005) and hospital length of stay (LOS). Single-center cost-accounting data for 338 liver transplants were then analyzed with a multivariate linear regression model to determine the estimated cost associated with a day of LOS. Overall, 8.4% of donor organs were classified as high risk (DRI > 2-2.5) and 1.9% as very high risk (DRI > 2.5). In the lowest MELD group (0-10), the LOS difference between 'ideal' donors (DRI < 1.0) and very high risk (DRI > 2.5) was 10.6 days which was associated with an estimated incremental cost of $47 986. For patients with MELD >35, the average LOS increased from 23.2 to 41.8 days when very high DRI donors were used, resulting in an estimated increase in cost of nearly $84 000. We conclude that the use of marginal liver grafts results in increased hospital costs independent of recipient risk factors.


Nuclear beta-catenin expression at the invasive front and in the vessels predicts liver metastasis in colorectal carcinoma.
Beta-catenin is a component of the Wingless/Wnt signaling pathway and can activate target genes associated with proliferation and invasion, linking with the APC gene. The purpose of this study was to investigate whether nuclear expression of beta-catenin in cells at the invasive front or in the vessels was associated with liver metastasis in human colon cancer. One hundred and eighteen patients with colorectal carcinoma who underwent surgical resection (45 patients with liver metastasis and 73 patients without liver metastasis at least 5 years after surgery) were included in the study. Proliferative activity was determined in several areas (tumor center, invasive front and in the vessels) by immunohistochemistry and whether it was correlated with liver metastasis was examined. In 73.1% of primary tumors, positive staining for beta-catenin was detected in the membranes at the tumor center and in the nuclei at the invasive front. In 32 patients (26.9% of all cases), beta-catenin was expressed exclusively in the nuclei of the carcinoma cells throughout the tumors. Significant differences in expression of nuclear beta-catenin in the primary tumors were detected between the liver metastasis and non-liver metastasis groups at the tumor center (p=0.004), invasive front (p=0.021) and in the vessels (p<0.0001). Nuclear accumulation of beta-catenin in cellular cells at the invasive front and in the vessels was the most powerful predictor of liver metastasis in colorectal cancer. This may be an important marker in the selection of patients for adjuvant therapy or other treatment modalities.


Leading by example: Development of a maternal modelling of positive body image scale and relationships to body image attitudes.
The aims of this study were to develop a measure, the Role Modelling of Body Image (Attitudes and Behaviors) Questionnaire (RMBI-Q), to determine maternal perceptions of their body image role modelling in front of their children, and to evaluate how role modelling differs with demographic characteristics to identify characteristics of mothers who may require assistance in being a positive role model. Participants were a community-based sample of 887 mothers who provided demographic information and completed the RMBI-Q, Body Appreciation Scale (BAS-2), and a measure of dietary restraint (DEBQ) in an online questionnaire. Exploratory factor analysis revealed one 7-item factor for the RMBI-Q. Confirmatory factor analysis revealed that removal of an item was necessary for model fit, and thus, a 6-item version of the RMBI-Q was evaluated. Good internal consistency, test-retest reliability, content validity, and convergent validity were found. Higher scores on the RMBI-Q correlated with greater maternal body appreciation and lower dietary restraint. More positive role modelling was reported by mothers with lower body mass index and younger children. The RMBI-Q is useful for assessing maternal modelling of positive behaviors that may improve children's body image. Findings highlight avenues for body image interventions for mothers.


Significance of thrombocytopenia in patients with primary and postessential thrombocythemia/polycythemia vera myelofibrosis.
Severe thrombocytopenia (platelets <50 × 109 /L) is associated with very poor outcome of patients with myelofibrosis (MF). As patients with primary myelofibrosis (PMF) differ from patients with postessential thrombocythemia (PET-MF) and postpolycythemia vera myelofibrosis (PPV-MF), we aimed to evaluate the significance of low platelets among these patients. We present clinical characteristics and outcome of patients with either PMF, PPV-MF, or PET-MF, and thrombocytopenia who presented to our institution between 1984 and 2015. Of 1269 patients (877 PMF, 212 PPV-MF, 180 PET-MF), 11% and 14% had platelets either <50 × 109 /L or between 50-100 × 109 /L, respectively. Patients with platelets <50 × 109 /L were most anemic and transfusion dependent, had highest blast count and unfavorable karyotype. In general, their overall and leukemia-free survival was the shortest with median time of 15 and 13 months, respectively; with incidence of acute leukemia almost twice as high as in the remaining patients (6.9 vs 3.6 cases per 100 person-years). Nevertheless, this observation remains mostly significant for patients with PMF, as those with PEV/PVT-MF have already significantly inferior prognosis with platelets <100 × 109 /L.


Significant Improvement in Electrical Conductivity and Figure of Merit of Nanoarchitectured Porous SrTiO3 by La Doping Optimization.
SrTiO3 is a well-studied n-type metal oxide based thermoelectric (TE) material. In this work, the first-principles calculation of La-doped SrTiO3 has been performed using the density functional theory. In addition, high TE properties of bulk SrTiO3 material have been achieved by introducing nanoscale porosity and optimizing carrier concentration by La doping. The X-ray diffraction, atomic resolution scanning transmission electron microscopy imaging, and energy-dispersive X-ray spectrometry results show that La has been doped successfully into the lattice. The scanning electron microscopy images confirm that all the samples have nearly similar nanoscale porosities. The significant enhancement of electrical conductivity over the broad temperature range has been observed through optimization of La doping. Additionally, the samples possess very low thermal conductivity, which is speculated because of the nanoscale porosity of the samples. Because of this dual mechanism of doping optimization and nanoscale porosity, there is a remarkable improvement in power factor, 1 mW/m2K from 650 to 800 K, and figure of merit, zT of 0.26 at 850 K, of the sample, 22 at. % La-doped SrTiO3.


Percutaneous MR imaging-guided radiofrequency interstitial thermal ablation of tongue base in porcine models: implications for obstructive sleep apnea syndrome.
To test the feasibility and safety of a percutaneous magnetic resonance (MR) imaging-guided technique for radiofrequency (RF) interstitial thermal ablation of the tongue base and to correlate MR appearance of induced thermal lesions with histopathologic findings in pigs in acute and chronic porcine models. A 1-cm-tip RF electrode was inserted percutaneously into the tongue in 10 pigs with 0.2-T real-time MR guidance. The RF electrode was advanced up the midline between lingual arteries and stopped short of tongue mucosa. RF interstitial thermal ablation was performed at 90 degrees C +/- 2 and lasted 10 minutes. Postablation images were obtained with a 1.5-T MR imager. Five pigs were sacrificed immediately (acute model), while five were followed up for 1 month (chronic model) before they were sacrificed. MR-compatible fiducial coils were inserted into tongues with MR imaging guidance prior to RF ablation in the chronic group. Tongues were harvested for histopathologic analysis. Mean thermal lesion volume was compared with the Student t test on images obtained immediately, 2 weeks, and 1 month after RF ablation. Interclass correlation coefficients of lesion diameters at gross pathologic analysis and corresponding diameters with each pulse sequence were calculated. Successful MR imaging-guided electrode positioning was achieved in all procedures without intra- or postprocedure complications because there was high vascular conspicuity and tissue contrast. Thermal lesions appeared hypointense with hyperintense surrounding rims with all sequences in both groups. At pathologic analysis, acute lesions appeared as pale necrotic areas surrounded by hyperemic rims, while chronic lesions demonstrated progressive circumferential fibrosis and significant volume shrinkage (P <.01). Thermal lesion diameters measured at gross pathologic analysis best agreed with corresponding diameters measured on short inversion time inversion-recovery images (interclass correlation coefficient = 0.85). The results of this investigation demonstrate MR imaging-guided RF interstitial thermal ablation of the tongue base is feasible and safe and illustrate imaging and pathologic phenomena associated with creation and evolution of the induced thermal lesions.


Cadaver-Based Trauma Procedural Skills Training: Skills Retention 30 Months after Training among Practicing Surgeons in Comparison to Experts or More Recently Trained Residents.
Long-term retention of trauma procedural core-competency skills and need for re-training after a 1-day cadaver-based course remains unknown. We measured and compared technical skills for trauma core competencies at mean 14 months (38 residents), 30 months (35 practicing surgeons), and 46 months (10 experts) after training to determine if skill degradation occurs with time. Technical performance during extremity vascular exposures and lower-extremity fasciotomy in fresh cadavers measured by validated individual procedure score (IPS) was the primary outcome. We performed a prospective study between May 2013 and September 2016. Practicing surgeons had lower IPS and IPS component scores (p = 0.02 to 0.001) than residents (p < 0.05) and experts (p < 0.002) for vascular procedures. Frequencies of errors were no different among residents and experts. Practicing surgeons made more critical errors (p < 0.05) than experts or residents. Experts had shortest time to proximal vascular control. Fasciotomy procedural errors occurred in all participants. Cluster analysis of anatomy vs procedural steps identified tertiles of performance and wide variance (32.5% practicing surgeons, 26.5% residents vs 13% experts) for vascular procedures. Vascular control duration > 20 minutes (n = 21) and failure to decompress fasciotomy compartments were correlated with incorrect landmarks and skin incisions. Modeling found interval trauma skills experience, not time since training, was associated with lower IPS. Practicing surgeons with low trauma skills experience since training had lower IPS and component scores (p = 0.02 to 0.001) and more errors compared with experts and residents (p < 0.05). Surgeons, including experts with low interval experience performing trauma procedures, may benefit from refreshing of correct landmarks and skin incision placement identification.


Rationally Engineering Phototherapy Modules of Eosin-Conjugated Responsive Polymeric Nanocarriers via Intracellular Endocytic pH Gradients.
Spatiotemporal switching of respective phototherapy modes at the cellular level with minimum side effects and high therapeutic efficacy is a major challenge for cancer phototherapy. Herein we demonstrate how to address this issue by employing photosensitizer-conjugated pH-responsive block copolymers in combination with intracellular endocytic pH gradients. At neutral pH corresponding to extracellular and cytosol milieu, the copolymers self-assemble into micelles with prominently quenched fluorescence emission and low (1)O2 generation capability, favoring a highly efficient photothermal module. Under mildly acidic pH associated with endolysosomes, protonation-triggered micelle-to-unimer transition results in recovered emission and enhanced photodynamic (1)O2 efficiency, which synergistically actuates release of encapsulated drugs, endosomal escape, and photochemical internalization processes.


Genetic structure and genealogy in the Sphagnum subsecundum complex (Sphagnaceae: Bryophyta).
Allopolyploidy is probably the most extensively studied mode of plant speciation and allopolyploid species appear to be common in the mosses (Bryophyta). The Sphagnum subsecundum complex includes species known to be gametophytically haploid or diploid, and it has been proposed that the diploids (i.e., with tetraploid sporophytes) are allopolyploids. Nucleotide sequence and microsatellite variation among haploids and diploids from Newfoundland and Scandinavia indicate that (1) the diploids exhibit fixed or nearly fixed heterozygosity at the majority of loci sampled, and are clearly allopolyploids, (2) diploids originated independently in North America and Europe, (3) the European diploids appear to have the haploid species, S. subsecundum, as the maternal parent based on shared chloroplast DNA haplotypes, (4) the North American diploids do not have the chloroplast DNA of any sampled haploid, (5) both North American and European diploids share nucleotide and microsatellite similarities with S. subsecundum, (6) the diploids harbor more nucleotide and microsatellite diversity than the haploids, and (7) diploids exhibit higher levels of linkage disequilibrium among microsatellite loci. An experiment demonstrates significant artifactual recombination between interspecific DNAs coamplified by PCR, which may be a complicating factor in the interpretation of sequence-based analyses of allopolyploids.


Bayesian selective response-adaptive design using the historical control.
High quality historical control data, if incorporated, may reduce sample size, trial cost, and duration. A too optimistic use of the data, however, may result in bias under prior-data conflict. Motivated by well-publicized two-arm comparative trials in stroke, we propose a Bayesian design that both adaptively incorporates historical control data and selectively adapt the treatment allocation ratios within an ongoing trial responsively to the relative treatment effects. The proposed design differs from existing designs that borrow from historical controls. As opposed to reducing the number of subjects assigned to the control arm blindly, this design does so adaptively to the relative treatment effects only if evaluation of cumulated current trial data combined with the historical control suggests the superiority of the intervention arm. We used the effective historical sample size approach to quantify borrowed information on the control arm and modified the treatment allocation rules of the doubly adaptive biased coin design to incorporate the quantity. The modified allocation rules were then implemented under the Bayesian framework with commensurate priors addressing prior-data conflict. Trials were also more frequently concluded earlier in line with the underlying truth, reducing trial cost, and duration and yielded parameter estimates with smaller standard errors.


Generation of convergent light beams by using surface plasmon locked Smith-Purcell radiation.
An electron bunch passing through a periodic metal grating can emit Smith-Purcell radiation (SPR). Recently, it has been found that SPR can be locked and enhanced at some emission wavelength and angle by excitation of surface plasmon (SP) on the metal substrate. In this work, the generation of a convergent light beam via using the SP-locked SPR is proposed and investigated by computer simulations. The proposed structure is composed of an insulator-metal-insulator (IMI) substrate with chirped gratings on the substrate. The chirped gratings are designed such that a convergent beam containing a single wavelength is formed directly above the gratings when an electron bunch passes beneath the substrate. The wavelength of the convergent beam changes with the refractive index of dielectric layer of the IMI structure, which is determined by the frequency of SP on the IMI substrate excited by the electron bunch. Moreover, reversing the direction of electron bunch will make the emitted light from the proposed structure to switch from a convergent beam to a divergent beam. Finally, the formation of a convergent beam containing red, green and blue lights just above the chirped gratings is also demonstrated. This work offers potential applications in the fields of optical imaging, optical beam steering, holography, microdisplay, cryptography and light source.


Identifying neck and back pain in administrative data: defining the right cohort.
We reviewed existing methods for identifying patients with neck and back pain in administrative data. We compared these methods using data from the Department of Veterans Affairs. To answer the following questions: (1) what diagnosis codes should be used to identify patients with neck pain and back pain in administrative data; (2) because the majority of complaints are characterized as nonspecific or mechanical, what diagnosis codes should be used to identify patients with nonspecific or mechanical problems in administrative data; and (3) what procedure and surgical codes should be used to identify patients who have undergone a surgical procedure on the neck or back. Musculoskeletal neck and back pain are pervasive problems, associated with chronic pain, disability, and high rates of health care utilization. Administrative data have been widely used in formative research, which has largely relied on the original work of Volinn, Cherkin, Deyo, and Einstadter and the Back Pain Patient Outcomes Assessment Team first published in 1992. Significant variation in reports of incidence, prevalence, and morbidity associated with these problems may be due to nonstandard or conflicting methods to define study cohorts. A literature review produced 7 methods for identifying neck and back pain in administrative data. These code lists were used to search Veterans Health Administration data for patients with back and neck problems, and to further categorize each case by spinal segment involved, as nonspecific/mechanical and as surgical or not. There is considerable overlap in most algorithms. However, gaps persist. Gaps are evident in existing methods and a new framework to identify patients with neck pain and back pain in administrative data is proposed.


Different curcumin forms selectively bind fibrillar amyloid beta in post mortem Alzheimer's disease brains: Implications for in-vivo diagnostics.
The combined fluorescent and Aβ-binding properties of the dietary spice curcumin could yield diagnostic purpose in the search for a non-invasive Aβ-biomarker for Alzheimer's disease (AD). However, evidence on the binding properties of curcumin, its conjugates and clinically used bio-available formulations to AD neuropathological hallmarks is scarce. We therefore assessed the binding properties of different curcumin forms to different neuropathological deposits in post-mortem brain tissue of cases with AD, other neurodegenerative diseases, and controls. Post mortem brain tissue was histochemically assessed for the binding of curcumin, its isoforms, conjugates and bio-available forms and compared to routinely used staining methods. For this study we included brains of early onset AD, late onset AD, primary age-related tauopathy (PART), cerebral amyloid angiopathy (CAA), frontotemporal lobar degeneration (FTLD) with tau or TAR DNA-binding protein 43 (TDP-43) inclusions, dementia with Lewy bodies (DLB), Parkinson's disease (PD) and control cases without brain pathology. We found that curcumin binds to fibrillar amyloid beta (Aβ) in plaques and CAA. It does not specifically bind to inclusions of protein aggregates in FTLD-tau cases, TDP-43, or Lewy bodies. Curcumin isoforms, conjugates and bio-available forms show affinity for the same Aβ structures. Curcumin staining overlaps with immunohistochemical detection of Aβ in fibrillar plaques and CAA, and to a lesser extent cored plaques. A weak staining of neurofibrillary tangles was observed, while other structures immunopositive for phosphorylated tau remained negative. In conclusion, curcumin, its isoforms, conjugates and bio-available forms selectively bind fibrillar Aβ in plaques and CAA in post mortem AD brain tissue. Curcumin, being a food additive with fluorescent properties, is therefore an interesting candidate for in-vivo diagnostics in AD, for example in retinal fluorescent imaging.


Polymorphisms that affect GABA neurotransmission predict processing of aversive prediction errors in humans.
Learning is one of our most adaptive abilities, allowing us to adjust our expectations about future events. Aberrant learning processes may underlie disorders such as anxiety, motivating the search for the neural mechanisms that underpin learning. Animal studies have shown that the neurotransmitter GABA is required for the computation of prediction errors, the mismatches between anticipated and experienced outcomes, which drive new learning. Given that evidence from human studies is lacking, we sought to determine whether these findings extend to humans. Here, in two samples of Caucasian individuals, we investigated whether genetically determined individual differences in GABA neurotransmission predict the P3 event-related potential, an EEG component known to reflect prediction error processing. Consistent with the results of animal studies, we show that a weighted genetic risk score computed from the number of GABRB2 rs1816072 A alleles (associated with increased expression of the GABAA receptor β2 subunit gene) and the number of ErbB4 rs7598440 T alleles (associated with increased GABA concentration) predicts optimal prediction error processing during aversive classical conditioning with both visual (Experiment 1, N = 90; p = .010) and auditory (Experiment 2; N = 92; p = .031) unconditioned stimuli. Our finding that optimal processing of aversive prediction errors is reduced in individuals genetically predisposed towards decreased GABA neurotransmission suggests a potential mechanism linking GABA and anxiety. Specifically, reduced GABA signalling via GABAA receptors could result in aberrant learning from aversive experiences and vulnerability to anxiety disorders.


Seminal fluid androgen levels in infertile patients.
Seminal fluid concentrations of testosterone (T), dihydrotestosterone (DHT), androstenedione (A), and 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol) were measured in 34 male patients of infertile couples. Patients were subdivided into oligospermic (less than 20 X 10(6)/mL) and asthenospermic (typical motility less than 20%; total motility less than 40%) groups. Steroids were measured by specific radioimmunoassay after ether extraction and celite column chromatography. 3 alpha-Diol was present in seminal fluid, and its concentration was significantly correlated with DHT (r = .49, P less than .05). In oligospermic patients, seminal levels of T (78 +/- 29 pg/mL, mean +/- SD) and DHT (323 +/- 132 pg/mL) were significantly reduced in comparison with normospermic men (T, 119 +/- 56, P less than .05; DHT, 557 +/- 255, P less than .01), while A and 3 alpha-diol concentrations were similar in the two groups. Seminal T and DHT levels were also reduced in asthenospermic specimens, which showed increased 3 alpha-diol concentrations (75 +/- 44 pg/mL) with respect to normokinetic samples (45 +/- 20, P less than .05). Finally, a positive linear relationship was observed between DHT and both sperm density (P less than .01) and total motility (P less than .01). These data demonstrate the existence of a significant amount of 3 alpha-diol in seminal plasma and suggest DHT as the androgen most closely related to sperm quality.


Locally advanced head and neck squamous cell carcinoma treatment efficacy and safety: a systematic review and network meta-analysis.
Head and neck squamous cell carcinoma (HNSCC) accounts for approximately 3% of new cancer cases and 3% of all deaths worldwide. Most HNSCC patients are locally advanced (LA) at diagnosis. The combination of radiotherapy (RT), chemotherapy, targeted therapy, and immunotherapy are the primary LA-HNSCC treatment options. Nevertheless, the choice of optimal LA-HNSCC treatment remains controversial. We systematically searched public databases for LA-HNSCC-related studies and assess treatment effectiveness and safety by assessing the objective response rate (ORR), ≥3 adverse events (AEs), overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), local-region control (LRC), and disease-specific survival (DSS). 126 randomized controlled clinical trials (RCTs) were included in this study. We show that concurrent RT with nimotuzumab or conventional concurrent chemo-radiotherapy (CCRT) had significantly better efficacy and long-term survival without increasing AEs than RT alone. Accelerated fractionated radiotherapy (AFRT) showed better efficiency than conventional fractionated RT, although it had higher AEs. In addition, concurrent cetuximab combined with RT failed to show a significant advantage over RT alone. Trial registration: PROSPERO CRD42022352127.


Trigeminal neuralgia: what are the important factors for good operative outcomes with microvascular decompression.
Microvascular decompression has been widely used as the first choice in treating trigeminal neuralgia, but in a few patients, facial pain cannot be effectively controlled by microvascular decompression. We sought to clarify the important factors for good operative outcomes. We reviewed 62 patients with trigeminal neuralgia treated by microvascular decompression during the period 2000 through 2002, including clinical presentation, operative findings, techniques, and outcomes. Neurovascular conflicts were divided into single contact, contact and indentation, single adhesion, adhesion and indentation, and trigeminal nerve atrophy. Operative outcomes were graded into immediate postoperative complete pain relief (excellent), delayed postoperative complete pain relief (better), significant pain relief (good), and no response to microvascular decompression (poor). All patients' presentations were typical at the time of pain onset, but the symptom in 17 patients changed to atypical before surgery. During operation, single contact and single adhesion was found in 14 patients and 15 patients, respectively; contact or adhesion in combination with indentation was found in 7 patients and 18 patients, respectively; atrophy occurred in 8 patients. Postoperatively, immediate and delayed complete pain relief was achieved in 32 (51.6%) patients and 17 (27.4%) patients, respectively; 11(17.7%) patients got significant pain relief; and 2 patients showed no response. The overall rate of complete pain relief in patients with shorter duration, typical presentation, artery compression and complete decompression was higher than that in patients with longer duration, atypical presentation, venous compression, and incomplete decompression. Shorter duration, typical presentation, single artery compression, and complete decompression are the positive factors for better operative outcomes with microvascular decompression. Worse outcomes are usually related to venous compression, longer duration, and atypical presentation.


The function of the superficial root mat in the biogeochemical cycles of nutrients in congolese eucalyptus plantations.
The importance of superficial root mats inside the forest floor for the nutrition of Amazonian rain forests has been extensively investigated. The present study was aimed at assessing the function of a root mat adherent to decomposing organic material observed in Eucalyptus plantations. The development of the root mat was studied through micromorphological observations of thin litter sections, and the influence of soil microtopography and soil water repellency on root mat biomass was assessed in situ on an area of 5 m2. In addition, input-output budgets of nutrients within the forest floor were established from measurements of litterfall, dissolved nutrients in gravitational solutions, and forest floor nutrient contents. The amounts of nutrients released during litter decay in this ecosystem during the period of study were, on average, 46, 3, 4, 19 and 17 kg ha-1 year-1 for N, P, K, Ca and Mg, respectively. The simultaneous measurements of the chemical composition of throughfall solutions and leachates beneath the forest floor showed a very quick uptake of nutrients by the root mat during the decomposition processes. Indeed, the solutions did not become noticeably enriched in nutrients during their passage through the holorganic layer, despite large amounts of elements being released during litter decay. The root mat biomass decreased significantly during the dry season, and a preferential development in microdepressions at the soil surface was observed. A strong water repellency observed in these depressions might enhance the ability of the roots to take up water and nutrients during the dry periods. The root mat was active throughout the year to catch the flux of nutrients from the biodegradation of the forest floor, preventing the transfer of dissolved nutrients toward deeper soil horizons. This mechanism is involved in the successful adaptation of this Eucalyptus hybrid in areas covered by 'climacic' savannas in Congo.


Pulmonary mechanics of normal very-low-birth-weight infants at 40 weeks postconception: a comparison with normal term infants.
We evaluated pulmonary function status in healthy, nonventilated very-low-birth-weight (VLBW) infants at 40 weeks postconception because little is known about the pulmonary function status of these infants at the time of discharge. Seven normal VLBW infants were evaluated at 40 weeks postconception, and five normal term infants were examined as a control. The neonates were placed supine with their heads in the neutral position. Data were obtained while the infant was resting quietly and breathing spontaneously prior to feeding. Pulmonary mechanics and energetics were measured with a CP-100 pulmonary monitor (Bicore Co. Ltd.). Pulmonary mechanics and energetics were determined by the least mean square technique. Dynamic compliance (Cdyn), resistance (Rtot, Re), and work of breathing (WOB) were calculated for the total breath, and tidal volume, minute ventilation, ratio of inspiratory time to respiratory period (Ti/Ttot), and respiratory rate were measured. There were no significant differences between normal VLBW infants and term infants in regard to ventilation, mechanics, or energetics. Although the respiratory system of normal VLBW infants is immature at birth, its development caught up to term infants by the time of discharge.