Directed adaptation of synchronization levels in oscillator communities.
We present an adaptive control scheme that realizes desired dynamics of an oscillator network with a given number of communities by adjusting the coupling weights between oscillators accordingly. The scheme allows, for example, to simultaneously establish different pregiven synchronization levels in the particular communities as well as phase relationships between them. We apply the method in numerical simulations with all-to-all and randomly coupled networks. Moreover, we provide an experimental proof of concept validating our numerical findings in a network of optically coupled photosensitive chemical micro-oscillators.


Recombinant human granulocyte colony-stimulating factor (G-CSF) combined conditioning regimen for allogeneic bone marrow transplantation (BMT) in standard-risk myeloid leukemia.
We previously suggested that using a combined conditioning regimen including rhG-CSF with allogeneic BMT in refractory AML and CML in blast crisis might reduce the rate of relapse and improve disease-free survival, without any major side effects. In this study, we used the same protocol for 10 AML patients in complete remission (CR) and 6 CML patients in the chronic phase (CP). We compared disease-free survival as well as toxic side effects of the regimen with 6 AML patients in CR and 6 CML patients in CP treated with chemoradiotherapy without G-CSF. The conditioning regimen consisted of TBI and high-dose AraC. RhG-CSF was infused continuously at a dose of 5 microg/kg/day, starting 24 hr before the initial dose of total body irradiation (TBI) until the end of AraC therapy. In all 28 cases, there were no early stage deaths due to regimen-related toxicity (RRT). None of the 10 AML cases treated with the G-CSF combined regime relapsed. In 6 AML cases treated conventionally without G-CSF, one patient died of infection and another relapsed. There were no relapses in either CML group. In the combined G-CSF group, one patient died of interstitial pneumonitis 48 days after BMT, while the rest of the CML cases are still alive. There were no relapses with rhG-CSF and no serious adverse effects in terms of RRT, acute graft vs. host disease (GVHD), or leukocyte recovery.


High Relative Parasitic Fitness of G22 Derivatives is Associated with the Epidemic Potential of Wheat Stripe Rust in China.
In total, 13 commercial wheat cultivars around China and four races of Puccinia striiformis f. sp. tritici (namely, CYR32, CYR33, G22-9, and G22-14) were employed for a test of relative parasitic fitness (RPF) using the drop method. The RPF values were measured, including the urediniospore germination rate, the latent period, the uredinial length, the uredinial density, the infection area, the sporulation intensity, the lesion expansion speed, and the sporulation period. The results indicated that the parameters of relative parasitic fitness of the four P. striiformis f. sp. tritici races on the 13 wheat cultivars were significantly different (P = 0.00) in sporulation intensity, lesion expansion speed, uredinial length, sporulation period, uredinial density, and latent period. The urediniospore germination rates of the four P. striiformis f. sp. tritici races for the test were significantly different (P = 0.00), whereas no correlation with the different cultivars was observed (P = 1.00). The infection areas of the tested races on the different cultivars were significantly different (P = 0.00) but there were no obvious manifestations among the various races (P = 0.20). Principal component analysis (PCA) showed that the sporulation intensity represented sporulation capacity and scalability, the latent period indicated infection ability, and the urediniospore germination rate represented urediniospore vigor, all of which fully contributed to the RPF in the interaction of the four races and 13 wheat cultivars, which was calculated by the following formula: RPF = (sporulation intensity × urediniospore germination rate)/latent period. The sporulation and infection of G22-9 on the 13 large-scale cultivated cultivars were the highest, and the RPF of G22-9 was higher than that of the predominant races, CYR32 and CYR33. This result suggested that G22-9 could become a new predominant race and potentially cause epidemics of wheat stripe rust in China. To prevent potential epidemics, susceptible wheat cultivars should be withdrawn from production and breeding programs should reduce the use of Yr10 and Yr26 and use other more effective resistance genes in combination with nonrace-specific resistance for developing wheat cultivars with durable resistance to stripe rust.


The effect of somatostatin on the production of human interferons by mononuclear cells.
Somatostatin (SMS) is a tetradecapeptide which can inhibit the secretion of a number of peptides produced by the endocrine or nervous systems. SMS 201-995 (octreotide) is a somatostatin analogue with very potent somatostatin activities. We have been investigating the effects of both SMS and octreotide on the production of human interferon (IFN). We obtained human peripheral blood mononuclear cells from normal donors and induced them to produce IFN in the presence or absence of a number of peptides possessing somatostatin activities. SMS and octreotide were shown to inhibit the secretion of INF-gamma but not IFN-alpha. Concentrations of 10(-6) M were shown to decrease yields when Concanavalin A or phytohemagglutin were used as the inducer. Higher concentrations had a progressively greater effect. No effects were observed on IFN-gamma production if interleukin 2, ionomycin, or various natural antigens were used to induce the cells. The 28-amino acid form of somatostatin had some effects on gamma IFN yields but the first 14-amino acid fragment of this peptide moiety did not. No effect of any of these compounds was observed on IFN bioactivity. These studies indicate SMS may have some regulatory action on the secretion of immunomodulators in vitro but the concentrations required are well above those encountered under physiologic circumstances, suggesting SMS may not play an important regulatory role governing such secretion in vivo.


Uptake of adjuvant breast cancer treatments recommended by multi-disciplinary meetings.
Adjuvant therapy for breast cancer is routinely discussed and recommended in multi-disciplinary meetings (MDMs). Current literature explores how treatments received by patients differ from national guidelines; however, it does not explore whether treatment is concordant with MDMs. This study provides an Australian perspective on the uptake of MDM recommendations and reasons for non-concordance. A retrospective cohort study of patients with breast cancer presented at The Royal Melbourne Hospital MDM in 2010 and 2014 to investigate the concordance between MDM recommendations and treatment received. The study group comprised 441 patients (161 from 2010 and 280 from 2014). A total of 375 patients were included in the analyses. Overall, 82% of patients had perfect concordance between recommended and received treatment for all modes of adjuvant therapy. Concordance to endocrine therapy was higher for invasive cancers than ductal carcinoma in situ (97% versus 81%, P < 0.0001). Concordance to radiotherapy was high and did not differ according to type of cancer or surgery (ranging from 88 to 91%). Concordance to chemotherapy recommendations was high overall (92%) and did not vary with nodal status. Women aged over 65 years were least likely to be recommended for adjuvant therapy but most likely to concordant with the recommendation. Uptake of MDM-recommended treatments is high. There is a minority of patients in whom MDM recommendations are not followed, highlighting that there are extra steps between recommendations at an MDM and decisions with patients. More attention to this issue is appropriate, and the reasons for non-concordance warrant further study.


Hemangioblastoma and renal clear cell carcinoma distinguished by means of the AgNOR method.
In view of the difficulty encountered in distinguishing between 2 degrees renal cell carcinoma (RCC) and hemangioblastoma (HBl) in the central nervous system, the AgNOR technique has been applied empirically to a series of 16 specimens of HBl, 5 primary RCC, and 6 specimens of secondary RCC in the CNS. To avoid tautology, the nature of these was confirmed by immunostaining for epithelial membrane antigen (EMA) and factor VIII-related antigen (FVII RAg). It was found that mean nuclear AgNOR counts in the stromal and endothelial cells of HBl exceeded significantly the counts in the tumor and endothelial cells of RCC, with no overlap in values. It is suggested that the AgNOR method is a useful adjunct in achieving the differential diagnosis of HBl and RCC in the nervous system.


Cholinesterase activity and behavior in chlorpyrifos-exposed Rana sphenocephala tadpoles.
Recent studies have found a correlation between organophosphate (OP) pesticide exposure and declines in amphibian populations. We evaluated the hypothesis that this relationship is driven by behavioral changes in developing larvae. Specifically, we examined how exposure to a common OP pesticide, chlorpyrifos, influenced cholinesterase (ChE) activity, mass, and swim speed in Rana sphenocephala tadpoles. We also determined how the presence of natural pond sediments in exposure chambers influenced response to the pesticide and how mass and survival were affected when tadpoles were exposed to an invertebrate (odonate) predator in addition to the pesticide. Mass and swim speed were measured after 4- and 12-d laboratory exposures to 1, 10, 100, and 200 microg/L of chlorpyrifos in test chambers that either did or did not contain pond sediments. These same parameters also were examined in mesocosms dosed with 200 microg/L of chlorpyrifos to evaluate responses under more environmentally realistic conditions. The effect of the invertebrate predators on survival and/or growth of tadpoles was evaluated in the mesocosm study and in separate laboratory experiments. In laboratory tests, no pesticide-induced mortality was observed; however, tadpole ChE activity in the two highest concentrations was significantly lowered, with a longer exposure duration further decreasing activity (maximum inhibition, 43%). Mass also was lower at higher concentrations, but this effect was not enhanced with longer duration of exposure. Reductions in ChE activity of tadpoles exposed in mesocosms were similar to those observed in laboratory experiments for the first 4 d. Tadpole swim speed and survival in the presence of a predator were not affected, with the latter largely resulting from pesticide-induced predator mortality.


A Synergistic Approach Therapy for Colorectal Cancer Based on Exosomes and Exploitation of Metabolic Pathways.
In order to reduce the side effects of traditional chemotherapy in the treatment of colorectal cancer (CRC), a new drug delivery system has been developed in this work, based on exosomes that can host two drugs that act synergistically: farnesol (that stops the cell cycle) and paclitaxel (prevents microtubule system depolymerization). Firstly, exosomes were isolated from different cell cultures (from colorectal cancer and from fibroblast as example of normal cell line) by different methods and characterized by western blot, TEM and DLS, and results showed that they express classical protein markers such as CD9 and HSP-70 and they showed spherical morphology with sizes from 93 nm to 129 nm depending on the source. These exosomes were loaded with both drugs and its effect was studied in vitro. The efficacy was studied by comparing the viability of cell cultures with a colorectal cancer cell line (HCT-116) and a normal cell line (fibroblast HS-5). Results showed that exosomes present a specific effect with more reduction in cell viability in tumour cultures than healthy ones. In summary, exosomes are presented in this work as a promising strategy for colorectal cancer treatment.


Comparative study of the methods of extracting mesenchymal stem cells from cryopreserved Wharton's Jelly.
The Wharton's Jelly (WJ) is an established source of mesenchymal stem cells (MSC). We compared 3 methods of extracting WJ-MSC from cryopreserved tissue and determined that enzymatic digestion of the WJ yielded the most viable MSC, compared to the explant and mechanical digestion methods. The enzymatically-released WJ-MSC conformed to the International Society for Cellular Therapy (ISCT) criteria: displayed plastic-adherence, co-expressed CD73, CD90, CD105 and were negative for hematopoietic lineage cell markers.


Valganciclovir: an advance in cytomegalovirus therapeutics.
To review the pharmacology, pharmacokinetics, and preliminary clinical data for valganciclovir, a new oral agent for the therapy of cytomegalovirus (CMV) retinitis. Relevant literature was extracted via MEDLINE/PUBMED and searchable abstracts from infectious diseases conferences covering the period from January 1990 to April 2002. Tertiary references provided background information. Current standard treatment for CMV retinitis consists of intravenous therapy, intraocular implant, and intraocular injection. The low bioavailability of oral ganciclovir restricts its use to prophylaxis and maintenance treatment. Oral valganciclovir, recently approved for both induction and maintenance therapy of CMV retinitis, may fill a niche for this disease. Although only 1 clinical study has been published for valganciclovir, its favorable pharmacokinetic profile, encouraging preliminary efficacy data, ease of administration, and lack of potential catheter-related complications make it a favorable option for the treatment of CMV retinitis in HIV-positive patients.


Terminology modeling for an enterprise laboratory orders catalog.
Laboratory test orders are used in a variety of clinical information systems at Partners HealthCare. At present, each site at Partners manages its own set of laboratory orders with locally defined codes. Our current plan is to implement an enterprise catalog, where laboratory test orders are mapped to reference terminologies and codes from different sites are mapped to each other. This paper describes the terminology modeling effort that preceded the implementation of the enterprise laboratory orders catalog. In particular, we present our experience in adapting HL7's "Common Terminology Services 2 - Upper Level Class Model" as a terminology metamodel for guiding the development of fully specified laboratory orders and related services.


Targeting methylguanine-DNA methyltransferase in the treatment of neuroblastoma.
The combination of temozolomide and irinotecan has preclinical schedule-dependent synergy against neuroblastoma but is not curative for relapsed high-risk patients. We hypothesized that the DNA repair protein methylguanine-DNA methyltransferase (MGMT) is an important resistance factor, and that inactivation of MGMT would sensitize neuroblastoma cells to these agents. MGMT protein expression was assessed in 74 primary neuroblastoma tumors. Growth inhibition assays were done to determine the IC(50) and the extent of synergy observed with various concentrations of temozolomide, irinotecan, and the MGMT-inactivating agent O(6)-benzylguanine, using cultured syngeneic neuroblastoma cells with either low or high levels of MGMT expression. We then assessed efficacy in a mouse xenograft model of metastatic neuroblastoma. MGMT was expressed by all 74 tumors evaluated. Pretreatment of neuroblastoma cells with O(6)-benzylguanine reduced the IC(50) of temozolomide by 10-fold regardless of level of MGMT expression, and pretreatment with BG followed by temozolomide + irinotecan further reduced the IC(50) in cells with high MGMT expression another 10-fold, to well below clinically achievable concentrations. The combination index was 0.27 to 0.30 for all three drugs in both cell lines, indicating strong synergy. Survival at 100 days for mice with metastatic neuroblastoma was 56% with three-drug treatment, compared with untreated controls (0%, P < 0.001) or temozolomide + irinotecan (10%, P = 0.081). MGMT is widely expressed in primary neuroblastoma tumors, and is a relevant therapeutic target. Both in vitro and in vivo studies suggest inactivation of MGMT with O(6)-benzylguanine may increase the activity of temozolomide and irinotecan against neuroblastoma.


[Surgical strategy for treatment of cholesteatoma otitis media].
To study the otologic surgical procedures for cholesteatoma otitis media and improve the surgery results and living quality of patients following the operation of tympanomastoidectomy. Two hundreds and sixty-six cases (269 ears) of tympanomastoidectomy for cholesteatoma otitis media followed up for more than 3 years between 1994 to 2003 were analyzed retrospectively. The long-term results of recurrence and hearing level was discussed on the procedure of canal wall up (CWU), canal wall down (CWD) and modified intact-bridge tympanomastoidectomy (IBM). On the contrast of improved hearing level, there were not significant difference between CWU group and CWD group (F = 3.686, P>0.05), but the results of IBM group was significantly better than others (F = 125.167 and 59.438, P <0.05). On the contrast of duration of getting dry ear, IBM and CWU groups [(5.0 +/- 1.9) weeks and (6.0 +/- 1.6) weeks respectively] were significantly shorter than CWD group [(9.0 +/- 2.8) weeks; F = 56.32 and 30.639, P <0.05]. As the recurrence rate, IBM group and CWD group were significantly lower than CWU group (CWU: 24.6%; CWD: 6.0%; IBM: 7.0%) chi2 = 6.162 and 6.007, P < 0.05). With the modified IBM technique, cholesteatoma could be removed completely and safely from the middle ear and a reasonable reconstruction of middle ear with approved hearing level could be achieved. The surgical procedure usually began with CWU and should be change according to the pathological founding of middle ear during operation. Modified IBM was a valuable choice for the surgical treatment of cholesteatoma otitis media.


A process evaluation of the Mind Your Back trial examining psychologically informed physical treatments for chronic low back pain.
In chronic conditions, such as back pain, the use of interventions that address physical, social and psychological aspects within a biopsychosocial framework are encouraged, however, applying this holistic multimodal approach in physical therapy practice (i.e., chiropractic and physiotherapy) is challenging. To explore the problem of delivering a biopsychosocially informed package of care in physical therapy practice a recent randomised control trial (RCT) called 'Mind Your Back' was conducted to evaluate the effectiveness of a combined physical and internet-delivered psychological intervention (psychologically informed physical treatments) compared to standard treatment for improving disability and self-efficacy in people with chronic LBP. The results of the trial indicated no difference between the two intervention groups. Although high-quality RCTs are considered gold standard for effectiveness of interventions, qualitative research methods embedded within a process evaluation framework are also used to reveal other issues and important information that help to explain clinical trial results, and to further the field of digital health interventions research. Therefore, within a process evaluation framework, the aim is to explore participants experiences of the interventions received throughout the Mind Your Back trial which led to a null result. In-line with recommendations for a process evaluation this study used in-depth interviews and qualitative thematic analysis with participants of both arms of the trial 5-6 months after study completion. Semi-structured telephone interviews were conducted with twenty-five participants to explore their experiences of taking part in the Mind Your Back trial. Interviews were conducted in November 2017, transcribed verbatim and data analysed thematically. Two main themes were identified: (1) Personalised support and therapeutic alliance are important, and (2) MoodGYM lacked relevant, personalised and tailored support. It is important to deliver tailored digital health supports that is personalised and fosters a therapeutic alliance.


[Prevalence and risk factors of retinopathy of prematurity].
To investigate the prevalence and the risk factors of retinopathy of prematurity (ROP). Totally 172 premature infants who were less than 37 weeks postconceptional age, or more than 37 weeks but weighing < 2 500 g at birth, and born at PUMC hospital from May 1, 2003 to November 30, 2004, were enrolled in this study. Their fundus were routinely checked. Diagnosis and staging of ROP were performed according to the international guidelines. Another 20 mature infants were selected as the control group. Twelve infants quitted the treatment or died. The remaining 160 infants completed the follow up. The prevalence of ROP in the premature group was 19.4%, while no ROP was found in the control group. The prevalence of ROP in subgroup with body weight < or = 2 000 g (28.4%) was significantly higher than in subgroup with body weight > 2 000 g (8.3%, chi2 = 10.217, P = 0.001) at birth. The prevalence of ROP in subgroup with postconceptional age < or = 32 weeks (42.5%) was significantly higher than in subgroup with postconceptional age > 32 weeks (11.7%, chi2 = 18.258, P = 0.000). The postconceptional age (OR = 0.959, P = 0.036) and body weight (OR = 0.999, P = 0.026) were the most important risk factors of ROP. Furthermore, blood transfusion ( OR = 0.076, P = 0.029) and Apgar score ( OR = 23.62, P = 0.012) were inversely correlated with ROP. Correlation was not found between ROP prevalence and oxygen inhalation mode, surface active substance, administration of dopamine and dexamethasone, and mother conditions. The prevalence of ROP is higher in premature infants than in mature infants. Shorter postconceptional age and lower body weight may result in higher ROP incidence. Routine screening of fundus in premature infants may be helpful for the early detection of ROP.


[Radiation-induced mucositis and neutrophil granulocytes in oral mucosa].
Chemotherapy-induced mucositis can be related to a decrease in oral neutrophils. We tested the relationship between radiation-induced mucositis and oral neutrophil counts. Oral neutrophil counts were obtained for ten patients with head and neck cancer who received radiotherapy of the pharynx and oral cavity. Four patients received additional chemotherapy (5-FU, Mitomycin). Counts were obtained before and during treatment; four healthy volunteers were included in the study as well. For evaluation, a quantitative mouth rinse assay, including neutrophil-staining with acridin-orange, was applied. We observed large inter-individual variations with respect to neutrophil counts for patients and control persons (Table 1). During treatment (irradiation or chemoirradiation), large intra-individual variations were seen additionally (Figure 1). We found a correlation between neutrophil counts and clinical reaction grade. Neutrophil counts increased with increasing mucositis (Figure 2). This increase was more pronounced for patients treated with chemoirradiation compared to radiation alone. Treatment breaks at weekends had no clear influence on neutrophil counts. We observed a weak correlation between neutrophil counts and clinical reaction grade. However, the variations in neutrophil counts are too large to utilize this parameter as a surrogate for clinical mucositis grading. The assumption that a decrease in oral neutrophils is associated with radiation-induced mucositis was clearly negated.


[Efficacy of Sildenafil oral spray for the treatment of erectile dysfunction in patients with type 2 diabetes mellitus and prediabetes].
To evaluate the results of using Sildenafil in the form of an oral spray (Gent) for the treatment of erectile dysfunction (ED) in men with type 2 diabetes mellitus (DM) and prediabetes. A total of 60 patients were divided into two groups of 30 people. The group 1 included patients with prediabetes, while group 2 consisted of patients with type 2 DM. All men had proven ED. The severity of ED was assessed using the International Index of Erectile Function (IIEF-5). To assess the state of penile blood flow, all patients underwent Doppler ultrasound before and after treatment. Patients with prediabetes used Sildenafil in the form of oral spray (Gent) 25 mg (2 doses) 1 time per day for 1 month, patients with type 2 diabetes received 50 mg (4 injections) every other day for 1 month. In addition, most of the subjects took metformin and followed diet therapy. In patients of both groups, the administration of Sildenafil oral spray led to a decrease in body weight, waist circumference, a decrease in insulin and Hemoglobin A1C level without changing of hypoglycemic therapy in those with type 2 DM. In men with prediabetes, a decrease in fasting insulin levels was found. During treatment, half of the persons with impaired glucose metabolism had an increase in the testosterone level. According to IIEF-5, a decrease in the severity of ED in both groups of patients was seen. In men with prediabetes, the average IIEF-5 score increased from 15.98 to 21.57 points (p<0.05), while in patients with type 2 DM it improved from 12.18 to 18.44 points (p<0.05). Doppler ultrasound indicated a significant increase in the maximum systolic blood flow velocity and arterial resistivity index after treatment with Sildenafil oral spray in patients with both prediabetes and type 2 diabetes. Sildenafil oral spray can be effectively used for the treatment of ED in men with type 2 DM and prediabetes.


Exploring the Genome of a Butyric Acid Producer, Clostridium butyricum INCQS635.
The draft genome sequence of Clostridium butyricum INCQS635 was obtained by means of ion sequencing. The genome provides further insight into the genetic repertoire involved with metabolic pathways related to the fermentation of different compounds and organic solvents synthesis (i.e., butyric acid) with biofuel applications.


A study of reservoir implantation--especially with saphenous vein graft catheterization.
Intra-arterial infusion chemotherapy is commonly used to treat hepatocellular carcinomas (HCC) and metastatic liver cancer after hepatectomy or in unresectable patients, and it has been adopted at Kurume University Hospital as a treatment for HCC. As complications of reservoir implantation have been encountered, the implantation procedure needs improvement. Procedures were compared in a study with 109 patients who were available for follow-up observation among 116 patients who underwent reservoir implantation. Fifty-six of the patients received intraoperative implantation through the gastroduodenal artery (GDA catheterization), 31 received external catheterization (EXT catheterization) and 22 received catheterization using a saphenous vein graft (SVG catheterization). The complication rates were 75.0%, 9.7% and 13.9% and the one-year patencies were 44.1%, 70.6% and 79.4%, respectively. GDA catheterization was no better than the other two procedures and it had a higher incidence of complications and a lower patency. SVG catheterization achieved good patency, although it had a little higher incidence of complications than external catheterization. It was presumed to be a procedure that would ensure reservoir implantation even in patients with a winding or variation of hepatic artery.


Saline enhanced thermal sealing of tissue: Potential for bloodless surgery.
A new technology has been introduced that combines radiofrequency (RF) energy with simultaneous saline irrigation. We present a description of the technology, its fundamental effect on tissue, selected preclinical results, and early clinical outcomes in a variety of surgical disciplines. The initial product that incorporates this technology is the TissueLink Floating Ball™, a monopolar surface coagulator, available in both laparoscopic and open shaft lengths. The low flow rate of saline couples RF to tissue and provides Cooling to limit the tissue temperature to no greater than 100°C. This prevents desiccation, eschar, smoke, and sticking associated with conventional dry electrosurgical devices with dry electrodes. The primary tissue effect OCcurs at tissue temperatures in the range of 60-80°C and involves the shrinkage of the Type I collagen that OCcurs in the walls of blood vessels, airways, bile ducts and other biological vessels. The shrinkage of the collagen closes the lumen and seals the vessel. Data is presented on the depth of the tissue effect and the chronic healing response in porcine liver. Early clinical results in the form of case reports are presented for both general and thoracic surgical applications, particularly for highly vascularized parenchymatous organs such as liver and lung. The use of the TissueLink device for liver resections has shown the potential to dramatically reduce blood loss. Its use in thoracic surgery has demonstrated it is capable of achieving both hemostasis and aerostasis.


Effect of Elagolix Exposure on Clinical Efficacy End Points in Phase III Trials in Women With Endometriosis-Associated Pain: An Application of Markov Model.
Elagolix is an oral gonadotropin-releasing hormone antagonist approved by the US Food and Drug Administration (FDA) for the management of moderate-to-severe pain associated with endometriosis and in combination with estradiol/norethindrone acetate approved for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. The objective of this work was to characterize the relationships between elagolix exposures and clinical efficacy response rates for dysmenorrhea (DYS) and nonmenstrual pelvic pain (NMPP) in premenopausal women enrolled in the pivotal phase III studies with moderate-to-severe pain associated with endometriosis. Relationships between elagolix average concentrations (Cavg ) and efficacy responses (DYS and NMPP) were characterized using a nonlinear mixed-effects discrete-time first order Markov modeling approach. Only age was statistically significant for NMPP but not considered clinically relevant. This work indicates that the selection of elagolix dose is not determined based on tested patient demographics, baseline, or endometriosis disease severity measures in covariate analysis. In other words, the work suggests no preference of one regimen over the other to treat endometriosis-associated pain (DYS or NMPP) for any patient subpopulation based on tested covariate groups.


five years' experience with proximal gastric (highly selective) vagotomy.
In the five-year period 1972 to 1976 the author's preferred treatment for patients with chronic duodenal or prepyloric peptic ulcer requiring surgery was proximal gastric vagotomy. In spite of this preference, only two-thirds of such patients were so treated. Most patients with bleeding and stenosis were treated by bilateral truncal vagotomy and drainage, and a few by Pólya gastrectomy. Proximal gastric vagotomy proved to be a safe elective operation without mortality and with a proven ulcer recurrence rate so far of 6%. Compared with those who had bilateral truncal vagotomy and drainage, the proximal gastric vagotomy patients complained less often of diarrhoea but more often of weight loss and reflux. Two patients have had persistent postprandial non-peptic pain, thought possibly due to upper gastric ischaemia.


Visible cameras as a non-invasive diagnostic to study negative ion beam properties.
Beam tomography is a non-invasive diagnostic that allows us to reconstruct the beam emission profile by measuring the light emitted by the beam particles interacting with the background gas, along an elevated number of lines of sight, which is related to the beam density by assuming a uniform background gas. In the framework of the heating and current drive of future nuclear fusion reactors, negative ion beams of hydrogen and deuterium are required for neutral beam injectors (NBIs) due to their elevated neutralization efficiency at high energy (in the MeV range). Beside the beam energy, beam divergence and homogeneity are two critical aspects in the design of future NBIs. In this paper, the characterization of the negative ion beam of the negative ion source NIO1 (a small-sized radio-frequency driven negative ion source, with 130 mA of total extracted H- current and 60 kV of maximum acceleration) using the tomographic system composed of two visible cameras is presented. The Simultaneous Algebraic Reconstruction Technique (SART) is used as an inversion technique to reconstruct the 3 × 3 matrix of the extracted beamlets, and the beam divergence and homogeneity are studied. The results are compared with the measurements of the other diagnostics and correlated with the source physics. The suitability of visible cameras as a diagnostics system for the characterization of the NIO1 negative ion beam is a small-scale experimental demonstration of the possibility to reconstruct more complicated multi-beamlet profiles, resulting in a powerful diagnostic for large NBIs.


Peripheral metabolism of branched-chain keto acids in patients with chronic renal failure.
Peripheral tissue metabolism of branched-chain amino acids (BCAA) and branched-chain keto acids (BCKA) in the postabsorptive state was evaluated in 8 patients with chronic renal failure (CRF) and 7 controls by measuring the arterial-deep forearm venous differences for BCAA and BCKA. Arterial whole blood levels of BCAA and BCKA were also measured in an additional 7 patients and 11 controls. In CRF, total BCKA levels are reduced owing to a decrease in ketoisocaproic acid (KICA) and ketoisovaleric acid (KIVA) levels, parallel to changes in BCAA levels, whereas levels of ketomethylvaleric acid (KMVA) are not different from controls. Both in normal conditions and in patients, arterial levels of individual BCAA are directly correlated with arterial levels of the corresponding BCKA. However, in CRF, the ratios of leucine to KICA and of isoleucine to KMVA are increased. A direct correlation between KICA and HCO3- levels is observed. In CRF, the release of leucine and valine as well as of KICA and KMVA from peripheral tissues is reduced, whereas KIVA is neither released nor taken up by the forearm. The lack of KICA release from peripheral tissues likely accounts for its low circulating levels. The depressed peripheral release of leucine associated with the lack of KICA release suggests an increased degradation of leucine which proceeds beyond the transamination step.


Porcine IgG: structure, genetics, and evolution.
Eleven genomic porcine Cgamma gene sequences are described that represent six putative subclasses that appear to have originated by gene duplication and exon shuffle. The genes previously described as encoding porcine IgG1 and IgG3 were shown to be the IgG1(a) and IgG1(b) allelic variants of the IGHG1 gene, IgG2a and IgG2b are allelic variants of the IGHG2 gene, while "new" IgG3 is monomorphic, has an extended hinge, is structurally unique, and appears to encode the most evolutionarily conserved porcine IgG. IgG5(b) differs most from its putative allele, and its C(H)1 domain shares sequence homology with the C(H)1 of IgG3. Four animals were identified that lacked either IgG4 or IgG6. Alternative splice variants were also recovered, some lacking the C(H)1 domain and potentially encoding heavy chain only antibodies. Potentially, swine can transcribe >20 different Cgamma chains. A comparison of mammalian Cgamma gene sequences revealed that IgG diversified into subclasses after speciation. Thus, the effector functions for the IgG subclasses of each species should not be extrapolated from "same name subclasses" in other species. Sequence analysis identified motifs likely to interact with Fcgamma receptors, FcRn, protein A, protein G, and C1q. These revealed IgG3 to be most likely to activate complement and bind FcgammaRs. All except IgG5(a) and IgG6(a) should bind to FcgammaRs, while all except IgG6(a) and the putative IgG5 subclass proteins should bind well to porcine FcRn, protein A, and protein G.


Successful treatment of doxorubicin-induced cardiomyopathy with low-dose sacubitril/valsartan: a case report.
Cancer therapy-related cardiac dysfunction (CTRCD) is a challenging and life-threatening complication of many chemotherapeutic regimens. CTRCD prevention, diagnosis, and therapy require both careful interdisciplinary assessment and management. For patients with CTRCD, current guidelines of the European Society of Cardiology (ESC) recommend an angiotensin-converting-enzyme inhibitor in combination with a beta-blocker. Recent studies indicate a beneficial effect of sacubitril/valsartan in this patient population. A 68-year-old female patient with a pleural epithelioid angiosarcoma developed heart failure with reduced ejection fraction and elevated serum biomarkers following doxorubicin treatment. After implementation of a recommended cardioprotective medical therapy including torasemide, ramipril, carvedilol, and spironolactone, the patient suffered two cardiac decompensations within 4 weeks after initiation of a paclitaxel regimen and pleural radiation therapy due to pain exacerbation. Despite a continuous application of the cardioprotective medical treatment regimen, no improvement of left-ventricular ejection fraction (LVEF) was detected in a 4-month follow up. Interestingly, after omitting ramipril and implementing low-dose sacubitril/valsartan (26/24 mg), we observed a decrease in serum biomarkers within 3 months as well as a significant improvement of LVEF within 6 months. After nearly 10 months of disease stabilization under paclitaxel, the patient suffered progressive cancer disease and deceased 1 week later after the initiation of a therapeutic attempt with pazopanib. This case report highlights the importance of interdisciplinary care in cancer patients as well as the promising role of (low-dose) sacubitril/valsartan in patients with CTRCD even in the setting of delayed initiation.


Sanctacaris uncata: the oldest chelicerate (Arthropoda).
The morphology of the arthropod Sanctacaris uncata, from the Middle Cambrian Burgess Shale of Canada, is reinterpreted based on a restudy of previously described material. Although originally considered a chelicerate-like arthropod, these affinities were dismissed based primarily on interpretations of the anterior appendages and hypotheses which considered the megacheirans ('great-appendage' arthropods) as putative ancestors of chelicerates. The similarities between megacheirans and chelicerates appear to be overstated however, and this study instead reaffirms the identity of putative chelicerate feature in S. uncata and similar arthropods such as Sidneyia and Emeraldella, both also from the Middle Cambrian Burgess Shale. Newly interpreted features, including the presence of pediform exites, multi-partite trunk exopods, and a trunk differentiated into an anterior limb-bearing area and a differentiated posterior limbless abdomen, were coded into an extensive phylogenetic data set of fossil and recent arthropods. In all analyses, Sanctacaris resolved as the basal-most member of total-group Euchelicerata (the least inclusive group including horseshoe crabs and arachnids but not pycnogonids), thus making it the oldest chelicerate in the fossil record. The vicissicaudates (including Sidneyia, Emeraldella, aglaspidids, and cheloniellids--all of which have previously been allied to chelicerates) resolved as sister-taxon to crown-group Chelicerata. This topology indicates that many purported chelicerate features, such as lamellar gills, and a differentiated posterior abdomen evolved sequentially in the chelicerate stem-lineage.


Including the online feedback site, Patient Opinion, in the nursing curriculum: Exploratory study.
Globally, universities aim to involve people who use health services to enrich the nursing curriculum for students, but there can be barriers to this involvement. Many also want students to contribute to local communities. Online communication can help connect students to service users to achieve these aims. The online British patient feedback site, Patient Opinion, gathers comments from service users about services and encourages service responses to the comments. To explore the feasibility and acceptability of five ways of including Patient Opinion in the undergraduate nursing curriculum. Five case studies using mixed data collection methods. British University with nursing students across two campuses, accustomed to using webinars, video presentations and social media. Students from different years participated in the five approaches of making use of Patient Opinion in the curriculum; 18 students took part in an online forum to discuss Patient Opinion in the curriculum. We trialled timetabled webinars, video-linked lectures, optional enhanced access for self-study, optional audit of service user comments for two local hospitals, and optional Twitter and Tweetchat. Students discussed the aims and approaches in an online forum. Of the five approaches trialled, webinars seemed effective in ensuring that all nursing students engaged with the topic. Video-linked lectures provided an alternative when timetabling did not allow webinars, but were less interactive. The three optional approaches (Tweetchats, audit exercise, self-directed study) provided opportunities for some students to enhance their learning but students needed guidance. Sending a summary of student reviews of patients' feedback to local hospitals illustrated how students might be agents of change in local health services. Experience from these case studies suggests that webinars followed by use of Patient Opinion preparing for placements may be a sustainable way of embedding feedback sites in the nursing curriculum.


Initial Power of Rigid Gas Permeable Contact Lenses in Patients with Keratoconus.
To simplify the fitting process, this study was designed to predict the initial power of contact lenses using the regression model based on manual Javal keratometry data and refractive errors. In this retrospective study, 121 eyes of 69 patients with keratoconus (KCN) were fitted with a specific trial set of rigid gas permeable contact lenses based on the standard criterion of "three-point touch" over a 7-year period. Power of the cornea was measured using Javal keratometer. Refractive errors and over refraction of patients were diagnosed using Topcon autorefractometer (RM-A2000) and confirmed by Heine beta 2000 retinoscope. The results of multiple linear regression showed the following equation: power of contact lens = -14.368 (constant of the final multiple regression model), +0.475 (spherical refraction), and +0.275 (flatter corneal power). The results of this study revealed that lens power has a significant relationship with the power of the flat corneal meridian and spherical refractive error in KCN patients. The obtained regression model can be used to shorten patients' chair time and optometric examination for predicting the power of contact lens.


Is now the time for a Rubiscuit or Ruburger? Increased interest in Rubisco as a food protein.
Much of the research on Rubisco aims at increasing crop yields, with the ultimate aim of increasing plant production to feed an increasing global population. However, since the identification of Rubisco as the most abundant protein in leaf material, it has also been touted as a direct source of dietary protein. The nutritional and functional properties of Rubisco are on a par with those of many animal proteins, and are superior to those of many other plant proteins. Purified Rubisco isolates are easily digestible, nutritionally complete, and have excellent foaming, gelling, and emulsifying properties. Despite this potential, challenges in efficiently extracting and separating Rubisco have limited its use as a global foodstuff. Leaves are lower in protein than seeds, requiring large amounts of biomass to be processed. This material normally needs to be processed quickly to avoid degradation of the final product. Extraction of Rubisco from the plant material requires breaking down the cell walls and rupturing the chloroplast. In order to obtain high-quality protein, Rubisco needs to be separated from chlorophyll, and then concentrated for final use. However, with increased consumer demand for plant protein, there is increased interest in the potential of leaf protein, and many commercial plants are now being established aimed at producing Rubisco as a food protein, with over US$60 million of funding invested in the past 5 years. Is now the time for increased use of Rubisco in food production as a nitrogen source, rather than just providing a carbon source?


Enhancing Circulation and Tumor Accumulation of Carboplatin via an Erythrocyte-Anchored Prodrug Strategy.
The short circulatory half-lives and low tumor accumulation of carboplatin greatly limit the drug's efficacy in vivo. Herein, we address these challenges by using a prodrug strategy and present the rational design of a novel platinum(IV) anticancer prodrug that can hitchhike on erythrocytes. This prodrug, designated as ERY1-PtIV , can bind to erythrocytes efficiently and stably, possessing a circulatory half-life 18.5 times longer than that of carboplatin in mice. This elongated circulatory half-life enables platinum to accumulate at levels 7.7 times higher than with carboplatin, with steady levels in the tumors. As a consequence, the ERY1-PtIV prodrug is proved to exhibit significantly enhanced antitumor activity and reduced side effects compared with carboplatin. Collectively, our novel approach highlights an efficient strategy to utilize intrinsic erythrocytes as auto-binding carriers to enhance the tumor accumulation and subsequent antitumor efficacy of platinum drugs.


Does the effectiveness of the ketogenic diet in different epilepsies yield insights into its mechanisms?
The ketogenic diet (KD) has been used successfully in a variety of epilepsy syndromes. This includes syndromes with multiple etiologies, including Lennox-Gastaut syndrome and infantile spasms; developmental syndromes of unknown etiology, such as Landau-Kleffner syndrome; and idiopathic epilepsies, such as myoclonic-astatic (Doose) epilepsy. It also includes syndromes where genetics play a major role, such as Dravet syndrome, tuberous sclerosis, and Rett syndrome. Study of the KD in humans and animals harboring various genetic mutations may yield insights into the diet's mechanisms. Comparison of the diet's effectiveness with other treatments in specific syndromes may be another useful tool for mechanistic studies. The diet's utility in epilepsy syndromes of various etiologies and in some neurodegenerative disorders suggests it may have multiple mechanisms of action.


The impact of LncRNA dysregulation on clinicopathology and survival of pancreatic cancer: a systematic review and meta-analysis (PRISMA compliant).
An increasing number of studies have reported a significant association between long non-coding RNAs (lncRNAs) dysregulation and pancreatic cancers. In the present study, we aimed to gather articles to evaluate the prognostic value of long non coding RNA in pancreatic cancer. We systematically searched all eligible articles from databases of PubMed, Web of Science, and Scopus to meta-analysis of published articles and screen association of multiple lncRNAs expression with clinicopathology and/or survival of pancreatic cancer. The pooled hazard ratios (HRs) and their 95% confidence intervals (95% CIs) were used to analysis of overall survival, disease-free survival and progression-free survival were measured with a fixed or random effects model. A total of 39 articles were included in the present meta-analysis. Our results showed that dysregulation of lncRNAs were linked to overall survival (39 studies, 4736 patients HR = 0.41, 95% CI 0.25 ± 0.58, random-effects in pancreatic cancer. Moreover, altered lncRNAs were also contributed to progression-free survival (8 studies, 1180 patients HR: 1.88, 95% CI (1.35-2.62) and disease-free survival (2 studies, 285 patients, HR: 6.07, 95% CI 1.28-28.78). In addition, our findings revealed the association between dysregulated RNAs and clinicopathological features in this type of cancer. In conclusion, dysregulated lncRNAs could be served as promising biomarkers for diagnosis and prognosis of pancreatic cancer.


Regenerable cobalt oxide loaded magnetosphere catalyst from fly ash for mercury removal in coal combustion flue gas.
To remove Hg(0) in coal combustion flue gas and eliminate secondary mercury pollution of the spent catalyst, a new regenerable magnetic catalyst based on cobalt oxide loaded magnetospheres from fly ash (Co-MF) was developed. The catalyst, with an optimal loading of 5.8% cobalt species, attained approximately 95% Hg(0) removal efficiency at 150 °C under simulated flue gas atmosphere. O2 could enhance the Hg(0) removal activity of magnetospheres catalyst via the Mars-Maessen mechanism. SO2 displayed an inhibitive effect on Hg(0) removal capacity. NO with lower concentration could promote the Hg(0) removal efficiency. However, when increasing the NO concentration to 300 ppm, a slightly inhibitive effect of NO was observed. In the presence of 10 ppm of HCl, greater than 95.5% Hg(0) removal efficiency was attained, which was attributed to the formation of active chlorine species on the surface. H2O presented a seriously inhibitive effect on Hg(0) removal efficiency. Repeated oxidation-regeneration cycles demonstrated that the spent Co-MF catalyst could be regenerated effectively via thermally treated at 400 °C for 2 h.


[Correlative study between portal vein pressure and portal hemodynamics in patients with portal hypertension].
To explore the characteristics of the portal vein hemodynamics and the correlation with the portal vein pressure. There were 41 cases of hepatic cirrhosis complicating portal hypertension. The liver function was graded Child-Pugh A+B in 31 cases and Child-Pugh C in 10 cases. The inner-diameter and blood stream speed of the portal vein (PV), the spleen vein (SV) and the superior mesentery vein (SMV) were measured by the color Doppler ultrasonography. The vascular acreage and blood flow volume were calculated. The portal vein pressure was directly measured during the operation. Thirty-two healthy people and 26 patients with chronic hepatitis B (CHB) served as controls in this study. The inner-diameter of the three veins was obviously wider and the blood flow speed was slower in two portal hypertension groups than in CHB and normal groups (P<0.01). In Child C group, the speed was the slowest. The speed of SV and SMV in two hypertension groups did not show any significant difference (P>0.05). In Child A+B group, the blood flow volume of the three veins was larger than that in normal and CHB groups (P<0.01 or P<0.05). The volume of PV was less in Child C group than Child A+B group (P<0.01), but the volume of SV and SMV was not obviously different (P>0.05). In Child A+B group, the portal vein pressure (Ppv) had a close correlation with the portal vein width, blood flow quantitation (Qpv), and blood stream volume (Qsv) of the spleen vein. The Qpv in Child A+B grade can be measured by the color Doppler ultrasonography technique, and the portal vein pressure can be monitored easily by the equation of Ppv=1.8951+0.0011Qpv.


Synergistic effects of GhSOD1 and GhCAT1 overexpression in cotton chloroplasts on enhancing tolerance to methyl viologen and salt stresses.
In plants, CuZn superoxide dismutase (CuZnSOD, EC l.15.1.1), ascorbate peroxidase (APX, EC 188.8.131.52), and catalase (CAT, EC l.11.1.6) are important scavengers of reactive oxygen species (ROS) to protect the cell from damage. In the present study, we isolated three homologous genes (GhSOD1, GhAPX1, and GhCAT1) from Gossypium hirsutum. Overexpressing cassettes containing chimeric GhSOD1, GhAPX1, or GhCAT1 were introduced into cotton plants by Agrobacterium transformation, and overexpressed products of these genes were transported into the chloroplasts by transit peptide, as expected. The five types of transgenic cotton plants that overexpressed GhSOD1, GhAPX1, GhCAT1, GhSOD1 and GhAPX1 stack (SAT), and GhSOD1 and GhCAT1 stack (SCT) were developed. Analyses in the greenhouse showed that the transgenic plants had higher tolerance to methyl viologen (MV) and salinity than WT plants. Interestingly, SCT plants suffered no damage under stress conditions. Based on analyses of enzyme activities, electrolyte leakage, chlorophyll content, photochemical yield (Fv/Fm), and biomass accumulation under stresses, the SCT plants that simultaneously overexpressed GhSOD1 and GhCAT1 appeared to benefit from synergistic effects of two genes and exhibited the highest tolerance to MV and salt stress among the transgenic lines, while the SAT plants simultaneously overexpressing GhSOD1 and GhAPX1 did not. In addition, transgenic plants overexpressing antioxidant enzymes in their chloroplasts had higher tolerance to salt stress than those expressing the genes in their cytoplasms, although overall enzyme activities were almost the same. Therefore, the synergistic effects of GhSOD1 and GhCAT1 in chloroplasts provide a new strategy for enhancing stress tolerance to avoid yield loss.


On the road to well-being: the development of a communication framework for sexual health.
Recognizing the need to work with all partners who have an interest in addressing sexual health issues, we explored values held by diverse stakeholders in the United States. Based on these findings, we developed a framework for use in communicating about sexual health issues and potential solutions. Our methods included an environmental scan, small-group metaphor elicitation and message framing assessments, interviews, and online surveys with diverse members of the public and health professionals. Of four overarching value-based themes, two were best accepted across audiences: the first theme emphasized the importance of protecting health along the road of life through enabling good choices, and the second called for adding health promotion approaches to traditional disease prevention control. Nearly all supporting statements evaluated were effective and can be used to support either of the two best accepted overarching themes. Although there is a great diversity of opinion regarding how to address sexual health issues in the U.S., among diverse stakeholders we found some common values in our exploratory work. These common values were translated into message frameworks. In particular, the idea of broadening sexual health programs to include wellness-related approaches to help expand disease control and prevention efforts resonated with stakeholders across the political spectrum. These findings show promise for improved sexual health communication and a foundation on which to build support across various audiences, key opinion leaders, and stakeholders.


Clinical and pathological prognostic factors in patients with stage III-IVA-B oral squamous cell carcinoma.
The aim of the work was to study clinical and pathological factors affecting the prognosis of the disease in patients with stage III-IVA-B oral squamous cell carcinoma (OSCC). A retrospective review of medical records of 234 patients with stage III-IVA-B OSCC was performed in order to study the impact of clinical and pathological factors on disease-free survival (DFS) and overall survival (OS). Multivariable analysis of clinical factors revealed a statistically significant effect of stage IVA-B and the presence of surgical complications on DFS (hazard ratio (HR) = 4.9 (95% confidence interval (CI) 2.9-8.3), p < 0.001; HR = 1.6 (95% CI 1.0-2.6), p = 0.047), respectively. Stage IVA-B, the presence of surgical complications and the retromolar trigone subsite were found to have a statistically significant impact on OS (HR = 4.0 (95% CI 2.5-6.5), p < 0.001; HR = 1.8 (95% CI 1.1-2.8), p = 0.01; HR = 1.9 (95% CI 1.1-3.2), p = 0.02), respectively. Multivariable analysis of pathological factors showed a statistically significant effect of positive resection margins, the multiple lymph node involvement and high-grade tumor on DFS (HR = 3.7 (95% CI 2.0-6.6), p < 0.001; HR = 4.3 (95% CI 2.8-6.7), p < 0.001; HR = 1.6 (95% CI 1.1-2.2), p = 0.01), respectively. Besides, positive resection margins and multiple lymph node involvement were found to cause a statistically significant impact on the OS (HR = 3.6 (95% CI 2.0-6.5), p < 0.001; HR = 3.7 (95% CI 2 5-5.6), p < 0.001), respectively. A tumor grade tended to worsen OS (HR = 1.4 (95% CI 1.0-1.9), p = 0.053). Stage IVA, B, the presence of surgical complications, the retromolar trigone subsite, positive resection margins, multiple lymph node involvements and high-grade tumor were found to be significant clinical and pathological prognostic factors in patients with stage III-IVA-B OSCC.


Payment change: 3 ways to set your course for success.
Healthcare organizations can take three approaches to preparing for significantly slower spending growth: Reflect on lessons learned from past spending cuts. Chart their course for the payment reform journey. Learn from early adopters: accountable care organizations.


Fabrication of Efficient Electrocatalysts for Electrochemical Water Oxidation Using Bimetallic Oxides System.
The study focused on the fabrication of nickel, cobalt, and their bimetallic oxide via a facile electrodeposition approach over the surface of conducting glass has been reported here. Fabricated electrodes have been employed as binder-free and effective anode materials toward oxygen evolution reactions (OER) in electrochemical water splitting at high pH. Nickel and cobalt oxides showed overpotential values of 520 mV and 536 mV at the current density of 10 mAcm-2 with charge transfer resistances of 170 and 195 Ω. For bimetallic oxides (NiCoO@FTO), the overpotential depressed up to 460 mV and lower charge transfer value of 80 Ω. Additionally, double-layer capacitance also boosted for the bimetallic oxide with a value of 199 μF as compared to monometallic nickel oxide (106 μF) and cobalt oxide (120 μF). Multimetal oxides of Ni-Co showed the best performance, which was further supported with larger electrochemical surface area. This facile approach toward the electrode fabrication could be a charming alternate to replace the Ru- and Ir-based expensive materials for OER in electrochemical water splitting.


Comprehensive bioinformatics analyses of Crohn's disease.
Crohn's disease (CD) is a chronic, relapsing inflammatory disease with increasing incidence and prevalence worldwide. In previous years, the accumulation of microarray data has provided us an approach to obtain further insight into CD. In the present study, the microarray data of CD was comprehensively analyzed using multiple bioinformatics methods, and the pathobiological process of the disease was examined. Gene expression data from colon tissues of patients with CD were obtained from the Gene Expression Omnibus database; following which differentially expressed genes were identified between CD and control sample groups. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to investigate which functions and pathways in which the differentially expressed genes enriched. TargetScan and miRDB databases were then used to predict which microRNAs (miRNAs) regulated the differentially expressed genes. As a result, a total of 432 differentially expressed genes, including 229 upregulated and 203 downregulated genes, including matrix metallopeptidase 3 and glutathione S‑transferase α1, were identified in CD samples. These differentially expressed genes were significantly involved in regulation of the inflammatory response, innate immune response, cell migration, extracellular matrix organization, Janus kinase/signal transducers and activators of transcription signaling pathway, and cytokine‑cytokine receptor interaction. The miRNA-gene network showed that miR‑149‑3p and miR‑4447 regulated the most differentially expressed genes. These findings extend current understanding of the mechanisms underlying CD, and the differentially expressed genes and regulator miRNAs identified may be used as potential biomarkers and therapeutic targets for CD.


[Prognostic value of (18)F-FDG PET/CT in newly diagnosed multiple myeloma patients].
Objective: To assess the prognostic value of (18)F-FDG PET/CT and its relationship with clinical features in newly diagnosed MM patients. Methods: A total of 123 patients with newly diagnosed MM in Tianjin Medical University Cancer Institute and Hospital from September 2008 to December 2017 were retrospectively reviewed. The overall survival (OS) and progression free survival (PFS) were estimated by Kaplan-Meier analysis and the distribution of OS and PFS were compared using log-rank test. Cox regression was used to identify the independent prognostic factors. Results: Of all 123 patients, there were 43 patients (35.0%) who had extramedullary diseases (EMD). Compared to the patients without EMD, the PFS (24.5 months vs 37.8 months, P<0.05) and OS (30.1 months vs 51.4 months, P<0.05) of the patients with EMD at diagnosed was significantly inferior. In multivariate analysis, β2-MG≥5.5 mg/L, age≥65, EMD on (18)F-FDG PET/CT and without CR at the ending of treatments were the four factors leading to poor prognosis. According to the above four factors, the patients were regrouped into low risk, medium risk and high risk groups, the significant difference existed (P<0.01) in these groups. Conclusion: (18)F-FDG PET/CT is helpful in predicting the prognosis of newly diagnosed MM patients.


Immunogenicity and tolerability of a trivalent influenza subunit vaccine (Influvac) in high-risk children aged 6 months to 4 years.
Fifty-two children, aged less than 5 years, with chronic lung disease or congenital heart disease were entered into a two-centre open study to determine the immunogenicity and tolerability of Influvac, a trivalent influenza sub-unit vaccine. Seroresponses were determined following two intramuscular vaccinations with 0.25 ml of Influvac, four weeks apart. Any local or systemic reaction was sought. Seroresponses were age and antigen specific, with children older than 9 months showing better seroresponses to all three antigens. Both A/Taiwan and B/Panama strains met all efficacy criteria. A/Shangdong met two of the three criteria: seroconversion and mean geometric titre increase. Local (23%) and systemic (48%) reactions following either of the two vaccinations were minor in nature and resolved within a few days. The vaccine induced a strong antibody response against all three haemagglutinin antigens and was well tolerated. The incidence of local and systemic reactions was comparable with those reported in healthy adults.


Incomplete radiofrequency ablation accelerates proliferation and angiogenesis of residual lung carcinomas via HSP70/HIF-1α.
Radiofrequency ablation (RFA) therapy has been proved effective and feasible for lung cancer. However, the molecular mechanisms of local lung cancer recurrence following RFA are poorly understood. The present study aimed to evaluate the ability of HSP70/HIF-1α to affect the proliferation and angiogenesis of non-small cell lung cancers (NSCLCs) following insufficient RFA to uncover the molecular mechanisms of local recurrence. In vitro heat treatment was used to establish sublines of NCI-H1650 cells. The NCI-H1650 subline that was established by heat treatment at 54˚C had a relatively higher viability and significantly elevated heat tolerance (compared to the parental strain). After treatment with the HSP70 inhibitor VER-155008, the HIF-1α inhibitor YC-1 and PI3K/Akt inhibitor wortmannin, the viability and proliferation rate of the cells was measured. At the same time, HSP70, HIF-1α and Akt were detected by real-time PCR and western blotting. In vivo xenograft tumors were created by subcutaneously inoculating nude mice with NCI-H1650 cells. HSP70, HIF-1α and Akt were detected by western blotting, and CD34 expression was detected by immunohistochemistry before and after RFA or treatment with the VER-155008, YC-1 or wortmannin inhibitors. The heat-adapted NCI-H1650 subline established in vitro had a higher viability and proliferative activity compared to parental cells. Inhibiting HSP70/HIF-1α abolished this difference. Blocking the PI3K/Akt signaling pathway decreased HSP70/HIF-1α expression levels. In vivo, we found that incomplete RFA treatment promoted HSP70/HIF-1α and CD34 expression. Additionally, the combination of RFA and treatment targeting HSP70/HIF-1α resulted in a synergistic reduction in tumor growth compared to incomplete RFA alone. The PI3K/Akt signaling pathway is also involved in regulating HSP70/HIF-1α expression during this process. We conclude that the accelerated proliferation and angiogenesis potential of residual lung carcinomas following RFA treatment was induced by HSP70/HIF-1α, expression of which is regulated by the PI3K/Akt signaling pathway.


Barriers and Facilitators for the Implementation of Geriatric Oncology Principles in Mexico: A Mixed-Methods Study.
There is limited information regarding the use of the geriatric assessment (GA) for older adults with cancer in developing countries. We aimed to describe geriatric oncology practice among Mexican oncology professionals and to identify barriers and facilitators for the implementation of GA into the routine care of older adults with cancer in Mexico. We conducted an explanatory sequential mixed-methods study. We administered an online survey to cancer specialists in Mexico about the routine use of GA and barriers for its use. We then conducted online semistructured interviews with survey respondents selected by their use of GA, expanding on barriers and facilitators for performing GA. Descriptive statistical analyses were performed for quantitative data; qualitative data were analyzed inductively through thematic analysis. We developed joint displays to integrate quantitative/qualitative results. We obtained 196 survey responses: 37 physicians (18.9%) reported routinely performing a GA. Medical oncologists (P = .002) and physicians seeing ≤ 10 patients/day (P = .010) were more likely to use GA. The most frequent barriers for GA use were lack of qualified personnel (49%), limited knowledge (43.9%), and insufficient time (37.2%). In the interviews (n = 22), the limited availability of geriatricians was commonly mentioned. Respondents highlighted the lack of geriatric oncology knowledge among cancer specialists and geriatricians. Saturation of oncology services and a lack of effective referral pathways for GA were also common issues. Facilitators included availability of geriatricians, system/administrative facilitators, presence of a multidisciplinary team, and availability of geriatric oncology education. The routine use of geriatric oncology principles in Mexico is limited by the availability of qualified personnel and by insufficient knowledge. An educational intervention could improve the implementation of GA in cancer care.


Burden, depression, and anxiety in caregivers of people with amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease caused by the degeneration of motor neurons. The burden for ALS caregivers is quite high. There are still few studies that have investigated the emotional impact of ALS care. We conducted a cross-sectional study among 40 ALS caregivers, assessing general worries, burden of care, depression, anxiety, perception of social support, and patients' severity of disease. Caregiver burden, depression, and anxiety were positively related with each other, and all these variables had a negative relation with social support. Patient's loss of physical functions was positively related with caregiver burden, anxiety, and somatic expression of depression. Caregivers expressed worries for their own health conditions. Given these results, we consider the hypothesis of an emotional-somatic impact of ALS care. The implications and limitations are discussed.


Combination delivery of two oxime-loaded lipid nanoparticles: Time-dependent additive action for prolonged rat brain protection.
A novel approach for brain protection against poisoning by organophosphorus agents is developed based on the combination treatment of dual delivery of two oximes. Pralidoxime chloride (2-PAM) and a novel reactivator, 6-(5-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)pentyl)-3-hydroxy picolinaldehyde oxime (3-HPA), have been loaded in solid-lipid nanoparticles (SLNs) to offer distinct release profile and systemic half-life for both oximes. To increase the therapeutic time window of both oximes, SLNs with two different compartments were designed to load each respective drug. Oxime-loaded SLNs of hydrodynamic diameter between 100 and 160 nm and negative zeta potential (-30 to -25 mV) were stable for a period of 10 months at 4 °C. SLNs displayed longer circulation time in the bloodstream compared to free 3-HPA and free 2-PAM. Oxime-loaded SLNs were suitable for intravenous (iv) administration. Paraoxon-poisoned rats (0.8 × LD50) were treated with 3-HPA-loaded SLNs and 2-PAM+3-HPA-loaded SLNs at the dose of 3-HPA and 2-PAM of 5 mg/kg. Brain AChE reactivation up to 30% was slowly achieved in 5 h after administration of 3-HPA-SLNs. For combination therapy with two oximes, a time-dependent additivity and increased reactivation up to 35% were observed.


Status and strategies for the management of head and neck cancer during COVID-19 pandemic: Indian scenario.
In India, oral cancer is the most common head and neck cancer (HNC) in men, mainly caused by the consumption of smoked and smokeless tobacco. During the current pandemic, delaying surgery for even 1 or 2 months may lead to more extensive surgery or inoperability, where only supportive care can be provided. Being semi-emergent in nature, treatment for these patients is currently on hold or delayed in most centers across the country. This study was conducted to assess the impact of COVID-19 pandemic and inability of the health system to treat HNC in a timely fashion and how surgeons are coping to this emergent situation. This article highlights the situation in India, a country burdened with one of the highest incidence rates of HNC.


Spatial priorities for invasive alien species control in protected areas.
Given the limited funds available for the management of invasive alien species (IASs), there is a need to design cost-effective strategies to prioritize their control. In this paper, we propose a cost-benefit optimization framework that incorporates the spatially explicit costs and benefits of invasion control, as well as the spatial invasion dynamics. Our framework offers a simple yet operational priority-setting criterion for the spatially explicit management of IASs under budget constraints. We applied this criterion to the control of the invasion of primrose willow (genus Ludwigia) in a protected area in France. Using a unique geographic information system panel dataset on control costs and invasion levels through space for a 20-year period, we estimated the costs of invasion control and a spatial econometric model of primrose willow invasion dynamics. Next, we used a field choice experiment to estimate the spatially explicit benefits of invasion control. Applying our priority criterion, we show that, unlike the current management strategy that controls the invasion in a spatially homogeneous manner, the criterion recommends targeted control on heavily invaded areas that are highly valued by users. We also show that the returns on investment are high, justifying the need to increase the allocated budgets and to treat the invasion more drastically. We conclude with policy recommendations and possible extensions, including the development of operational cost-benefit decision-support tools to assist local decision-makers in setting management priorities.


Identification of OATP1B3 as a high-affinity hepatocellular transporter of paclitaxel.
Interindividual variability in paclitaxel and docetaxel pharmacokinetics, toxicity and response is extensive, and largely unexplained. We hypothesized that this is due to affinity of taxanes for an uptake transporter that indirectly regulates elimination pathways. Here, we studied accumulation of [3H]docetaxel and [3H]paclitaxel in Xenopus laevis oocytes injected with cRNA of the liver-specific organic anion transporting polypeptide (OATP) family members OATP1B1 (OATP2) or OATP1B3 (OATP8). Taxane transport by OATP1B1 expressing oocytes was not significantly different from that by water-injected controls, whereas uptake by OATP1B3 was 2.2-fold higher for docetaxel (p = 0.0007) and 3.3-fold higher for paclitaxel (p < 0.0001). OATP1B3-mediated paclitaxel transport was saturable (Michaelis-Menten constant, 6.79 microM), time-dependent, and highly sensitive to chemical inhibition. Paclitaxel uptake was not inhibited by ketoconazole or tariquidar. However, uptake was inhibited by the formulation excipient Cremophor (74.4% inhibition, p < 0.0001), cyclosporin A (25.2%, p = 0.005), glycyrrhizic acid (24.6%, p = 0.012), and hyperforin (28.4%, p = 0.003). Consistent with this finding, Cremophor was found to significantly affect the hepatic uptake of paclitaxel in mice. These data suggest that OATP1B3 is a key regulator of hepatic uptake, and may therefore play a role in the variable response to treatment with taxanes.


Paclitaxel induces primary and postmitotic G1 arrest in human arterial smooth muscle cells.
Paclitaxel (PTX), a microtubule-active drug, causes mitotic arrest leading to apoptosis in certain tumor cell lines. Here we investigated the effects of PTX on human arterial smooth muscle cell (SMC) cells. In SMC, PTX caused both (a) primary arrest in G(1) and (b) post-mitotic arrest in G(1). Post-mitotic cells were multinucleated (MN) with either 2C (near-diploid) or 4C (tetraploid) DNA content. At PTX concentrations above 12 ng/ml, MN cells had 4C DNA content consistent with the lack of cytokinesis during abortive mitosis. Treatment with 6-12 ng/ml PTX yielded MN cells with 2C DNA content. Finally, 1-6 ng/ml of PTX, the lowest concentrations that affected cell proliferation, caused G(1) arrest without multinucleation. It is important that PTX did not cause apoptosis in SMC. The absence of apoptosis could be explained by mitotic exit and G(1) arrest as well as by low constitutive levels of caspase expression and by p53 and p21 induction. Thus, following transient mitotic arrest, SMC exit mitosis to form MN cells. These post-mitotic cells were subsequently arrested in G(1) but maintained normal elongated morphology and were viable for at least 21 days. We conclude that in SMC PTX causes post-mitotic cell cycle arrest rather than cell death.


Identification of Natural Products That Inhibit the Catalytic Function of Human Tyrosyl-DNA Phosphodiesterase (TDP1).
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme crucial for cleavage of the covalent topoisomerase 1-DNA complex, an intermediate in DNA repair. TDP1 plays a role in reversing inhibition of topoisomerase I by camptothecins, a series of potent and effective inhibitors used in the treatment of colorectal, ovarian, and small-cell lung cancers. It is hypothesized that inhibition of TDP1 activity may enhance camptothecin sensitivity in tumors. Here, we describe the design, development, and execution of a novel assay to identify inhibitors of TDP1 present in natural product extracts. The assay was designed to address issues with fluorescent "nuisance" molecules and to minimize the detection of false-positives caused by polyphenolic molecules known to nonspecifically inhibit enzyme activity. A total of 227,905 purified molecules, prefractionated extracts, and crude natural product extracts were screened. This yielded 534 initial positives (0.23%). Secondary prioritization reduced this number to 117 (0.05% final hit rate). Several novel inhibitors have been identified showing micromolar affinity for human TDP1, including halenaquinol sulfate, a pentacyclic hydroquinone from the sponge Xestospongia sp.


Mifepristone for management of Cushing's syndrome.
Cushing's syndrome is a debilitating endocrine disorder caused by elevated circulating glucocorticoid levels. Although uncommon, Cushing's syndrome is associated with significant morbidity necessitating rapid reversal of hypercortisolemia. Primary therapy for most patients with Cushing's syndrome is surgical, but many patients will require additional treatments with radiation or drugs. Although several options for drug therapy exist, few are readily available and all have dose-limiting adverse effects. Mifepristone (RU 486), a first-in-class glucocorticoid receptor antagonist, was approved by the United States Food and Drug Administration in 2012 for use in Cushing's syndrome to control hyperglycemia in patients who are not surgical candidates or have not achieved remission from surgery. The drug is approved for oral once-daily administration. In its pivotal trial, 60% of patients responded to mifepristone with significant improvements in glycemic control and 38% had a reduction in diastolic blood pressure. The most common adverse events were nausea, fatigue, headache, endometrial hyperplasia, and hypokalemia. Adrenal insufficiency occurred in fewer than 5% of patients. The recommended starting dosage of mifepristone is 300 mg/day. The dosage may be increased every 2-4 weeks up to a maximum of 1200 mg/day, although it should not exceed 20 mg/kg/day. Significant drug-drug interactions exist due to mifepristone's effects on a number of cytochrome P450 enzymes. Despite its limitations, mifepristone is a welcome addition and an appropriate alternative to the available drug therapy for Cushing's syndrome.


[Results of mobilization under anesthesia in adhesive capsulitis in relation to stage of the disease].
Mobilisation under anaesthesia is a well approved method for the treatment of idiopathic adhesive capsulitis, the best time to perform the mobilisation, however, is difficult to define. Thirty-nine patients who had been treated with mobilisation under anaesthesia for idiopathic adhesive capsulitis stage II or III were examined at an average follow-up time of 3.4 years. This therapy failed in 10.3% of the patients. There were no differences in the follow-up results between both groups of patients, limitations in the range of motion remained in 20% of all patients. At follow up the average CONSTANT Score of the stage II patients was 86.8, that of the stage III patients was 89.9 points. However, manipulation under anaesthesia showed a significantly better influence on the course of the disease in patients with stage III than in patients with stage II adhesive capsulitis. Mobilisation under anaesthesia is a successful therapy in adhesive capsulitis stage III, but should be performed in adhesive capsulitis stage II only in cases of decreasing pain in which the limitation in the range of motion is the main symptom.


[Expression of saponin biosynthesis related genes in different tissues of Panax quinquefolius].
The relationship between saponin content of Panax quinquefolius in different parts of the organization and expression of ginsenoside biosynthesis related gene was obtained by the correlation analysis between saponin content and gene expression. The 14 tissue parts of P. quinquefolius were studied, six saponins in P. quinquefolius. Samples (ginsenoside Rg₁, Re, Rb₁, Rc, Rb₂ and Rd), group saponins and total saponins were determined by high performance liquid chromatography and vanillin-sulfuric acid colorimetric method. Simultaneously, the expression levels of 7 ginsenoside biosynthesis related genes (SQS, OSC, DS, β-AS, SQE, P450 and FPS) in different tissues of P. quinquefolius were determined by Real-time fluorescence quantitative PCR. Although 7 kinds of ginsenoside biosynthesis related enzyme gene in the P. quinquefolius involved in ginsenoside synthesis, the expression of β-AS and P450 genes had no significant effect on the content of monosodium saponins, grouping saponins and total saponins, FPS, SQS, OSC, DS and SQE had significant or extremely significant on the contents of single saponins Re, Rg1, Rb1, Rd, group saponin PPD and PPT, total saponin TMS and total saponin TS (P<0.05 or P<0.01). The biosynthesis of partial saponins, grouping saponins and total saponins in P. quinquefolius was affected by the interaction of multiple enzyme genes in the saponin synthesis pathway, the content of saponins in different tissues of P. quinquefolius was determined by the differences in the expression of key enzymes in the biosynthetic pathway. Therefore, this study further clarified that FPS, SQS, OSC, DS and SQE was the key enzyme to control the synthesis of saponins in P. quinquefolius by correlation analysis, the biosynthesis of ginsenosides in P. quinquefolius was regulated by these five kind of enzymes in cluster co-expression of interaction mode.


In vivo bioactivity of porous polyetheretherketone with a foamed surface.
The in vivo bioactivity of porous polyetheretherketone (PEEK) with a foamed surface was evaluated using rabbit femoral bone. Cylindrical porous PEEK scaffolds, with pore diameter of 550 μm and porosity of 70%, were first prepared and immersed in 98% sulfuric acid, and then washed and immersed in 3 M potassium carbonate solution used as a foaming reagent. Numerous open pores of various sizes, as well as new functional groups, were visualized on the treated PEEK surface by scanning electron microscopy and X-ray photoelectron spectroscopy, respectively. Micro computed tomography (micro-CT) showed that the volumetric density of treated PEEK was higher than that of bare PEEK at 8 weeks after surgery (p<0.05). Additionally, von Kossa staining indicated ingrowth of mature new bone tissue at 4 weeks relative to the bare PEEK group. Our data indicate that surface-treated PEEK exhibited improved bioactivity in vivo.


ESCAPE PROCESSES IN EMBRYOS OF DICYEMIDS (PHYLUM DICYEMIDA).
Dicyemid mesozoans usually consist of 10 to 40 cells. They are characterized by 2 distinct embryos, vermiform and infusoriform, that develop within the axial cell of the adult. The means of escape of each embryo from the parent body was studied in Dicyema japonicum and Dicyema misakiense, parasites of Octopus sinensis. There were no differences in means of escape between species or embryo type, apparently due to morphological constraints whereby the parents (nematogen or rhombogen) share a similar body organization. Escapes were effected through the gap between adjacent peripheral cells of the adult, rupturing the axial cell membrane and the membrane that envelopes the embryo. After the embryo escaped, the path was closed by the enveloping membrane left behind by the embryo. Vermiform embryos can escape from any region of the body, although more embryos were observed to escape from anterior regions than from posterior regions. Infusoriform embryos escaped from both anterior and posterior regions in the axial cell, with more embryos observed to escape from the posterior regions. The different escape regions for the 2 types of embryo are presumably related to the adult body plan lacking a genital opening, so each different type of embryo has its appropriate site of escape.


CN-HMBC: a powerful NMR technique for the simultaneous detection of long-range 1H,13C and 1H,15N connectivities.
[structure: see text] A new one-shot NMR experiment (CN-HMBC) is proposed for the simultaneous acquisition of 2D 1H,13C and 1H,15N HMBC spectra. Important sensitivity enhancements (up to 41% simultaneously for both 13C and 15N) or time savings (about 50%) can be achieved when compared to the separate acquisition of individual HMBC spectra. The experiment is highly recommended for the complete structural analysis and simultaneous chemical shift assignments of protonated and nonprotonated 13C and 15N resonances in nitrogen-containing organic compounds.


Hepatic poly(ADP-ribose) polymerase activity in rat is controlled by thyroid hormones.
The in vivo effect of the thyroidal state on poly(ADP-ribose) polymerase activity was investigated in eu- and hypothyroid rats after treatment with L-triiodothyronine. Untreated hypothyroids showed an increased basal rate of the enzyme. The treatment of both eu- and hypothyroid rats with L-triiodothyronine induced a prompt drop of the endogenous activity not due to a reduction of the catalytic protein. This decrease well evident 1 h after treatment was transient, returning to controls values within 8 h. In isolated liver nuclei from euthyroids the in vitro exposure to increasing L-triiodothyronine concentrations from 10(-18) to 10(-6) M resulted in a progressive inhibition of the enzyme. This loss in activity was not derived from a reduction of the total level of the catalytic protein. The pretreatment with the antagonist amiodarone suppressed the hormone effect, suggesting that nuclear receptors could mediate poly(ADP-ribose) polymerase activity.


Genetic and phenotypic intra-species variation in Candida albicans.
Candida albicans is a commensal fungus of the human gastrointestinal tract and a prevalent opportunistic pathogen. To examine diversity within this species, extensive genomic and phenotypic analyses were performed on 21 clinical C. albicans isolates. Genomic variation was evident in the form of polymorphisms, copy number variations, chromosomal inversions, subtelomeric hypervariation, loss of heterozygosity (LOH), and whole or partial chromosome aneuploidies. All 21 strains were diploid, although karyotypic changes were present in eight of the 21 isolates, with multiple strains being trisomic for Chromosome 4 or Chromosome 7. Aneuploid strains exhibited a general fitness defect relative to euploid strains when grown under replete conditions. All strains were also heterozygous, yet multiple, distinct LOH tracts were present in each isolate. Higher overall levels of genome heterozygosity correlated with faster growth rates, consistent with increased overall fitness. Genes with the highest rates of amino acid substitutions included many cell wall proteins, implicating fast evolving changes in cell adhesion and host interactions. One clinical isolate, P94015, presented several striking properties including a novel cellular phenotype, an inability to filament, drug resistance, and decreased virulence. Several of these properties were shown to be due to a homozygous nonsense mutation in the EFG1 gene. Furthermore, loss of EFG1 function resulted in increased fitness of P94015 in a commensal model of infection. Our analysis therefore reveals intra-species genetic and phenotypic differences in C. albicans and delineates a natural mutation that alters the balance between commensalism and pathogenicity.


Care of the child with the desire to change gender--Part I.
This article is the first in a three-part series describing the nursing and medical care of a child wishing to change genders. Part I will depict the psychological and hormonal treatment for children who express a desire to change genders. Part II will describe surgical treatments and nursing care for gender reassignment from female to male. Part III will present the surgical needs of transition from male to female.


The Genetic Background of Metabolic Trait Clusters in Children and Adolescents.
It is well known that metabolic risk factors of cardiovascular diseases are correlated, but the background of this clustering in children is more poorly known than in adults. Thus, we studied the contribution of genetic and environmental factors to the clustering of metabolic traits in childhood and adolescence. Nine metabolic traits were measured in 214 complete twin pairs aged 3-18 years in the Autonomous Region of Madeira, Portugal, in 2007 and 2008. The variation of and covariations between the traits were decomposed into genetic and environmental components by using classical genetic twin modeling. A model, including additive genetic and environmental factors unique for each twin individual, explained the variation of metabolic factors well. Under this model, the heritability estimates varied from 0.47 (systolic blood pressure in children under 12 years of age) to 0.91 (high-density lipoprotein [HDL] cholesterol in adolescents 12 years of age or older). The most systematic correlations were found between adiposity (body mass index and waist circumference) and blood lipids (HDL cholesterol, low-density lipoprotein cholesterol, and triglycerides), as well as blood pressure. These correlations were mainly explained by common genetic factors. Our results suggest that obesity, in particular, is behind the clustering of metabolic factors in children and adolescents. Both general and abdominal obesity partly share the same genetic background as blood lipids and blood pressure. Obesity prevention early in childhood is important in reducing the risk of metabolic diseases in adulthood.


[Construction and validation of a dual-luciferase reporter gene system for screening and evaluating anti-liver fibrosis drugs that inhibit transcription of the gene encoding collagen I, chain a1].
To construct a dual-reporter gene system that will be applicable for use as a tool to screen and evaluate therapeutic drug compounds that inhibit transcription of the gene encoding collagen I, chain at1 (COL1A1). The full-length eDNA of transforming growth factor beta1 (TGFbeta1) was cloned by RT-PCR and inserted into two vectors, pcDNA3.1 and pJW4303, for construction of two eukaryotic expression vectors, pcDNA3.1-TGFbeta1 and pJW4303-TGFbeta1.Next, the promoter region of COL1A1, cloned by PCR using human genome DNA as template, was inserted into the vector pGL4.29 to construct the reporter gene vector, pGL4.29-COL1A1 promoter.All three recombinant vectors were verified by restriction enzyme digestion and DNA sequencing.Either the pcDNA3.1-TGFbeta1 or pJW4303-TGFbeta1 vector along with the pGL4.29-COL1A1 promoter vector or a pRL-null, control reporter, vector were co-transfected into the LX-2 human hepatic stellate cells to establish the transcription-activated dualreporter gene system.This system was used as a cell model for screening anti-liver fibrosis compounds that inhibit the transcription of COL1A1.Dexamethasone, a model drug that is known to inhibit the expression of COL1A1, was used as a control to validate the dual-reporter gene system. The two TGFbeta1-expressing vectors and the reporter gene vector containing the promoter region of COL1A1 were successfully constructed.The results of a dual-reporter gene assay showed that TGFbeta1 co-expression increased the activity of the COL1A1 promoter by above 200-fold (t =21.78, P =0.0001), whereas in the absence of TGF31 co-expression the activity was below 2-fold (t =3.396, P =0.0274).The transcriptionactivated dual-reporter gene system was successfully established.The model drug, dexamethasone, effectively inhibited the activity of the COL 1A1 promoter in dose-dependent manner; the activity decreased 29.6% with 10 mumol/L dexamethasone (t =4.140, P =0.0144) and 53.9% with 100 mumol/L (t =6.193, P =0.0035). The dual-luciferase reporter system of TGFbeta1 and COL1A1 co-expression developed here can be used as a cell model to screen and evaluate anti-liver fibrosis compounds that inhibit activity of the COL1A1.


Roux-Y intestinal bypass for administration of sorbents in uremia.
In order to minimize interaction of sorbents with food and digestive secretions, an intestinal bypass was created for sorbent administration in normal and uremic rats (N = 18) and goats (N = 5). Two separate limbs of small intestine were fashioned, one for food absorption and one for sorbent function, which joined at a Roux-Y anastomosis before the cecum. Particulate sorbent suspensions were injected into the intestine via a cutaneous stoma, and were excreted with food wastes in the feces. In animals with normal kidneys, sorbent function was calculated from changes in fecal and urinary excretion. Nitrogen clearance by the intestinal bypass was 20 to 40% of normal renal clearance in rats and goats. Potassium clearance was 40% of normal renal clearance in rats, and over 100% in goats. Sorbent treatment in anephric animals caused serum urea nitrogen concentrations to stabilize at 210 mg/dl in rats, and 110 mg/dl in goats. Serum potassium concentrations stabilized at 4.5 mEq/liter in rats, and fell to 2 mEq/liter in goats. Water balance was maintained by producing a mild osmotic diarrhea. At least three substances which accumulate in renal failure--urea, potassium, and water--were removed in therapeutically significant amounts.


Highly Efficient and Stable 2D/3D Heterojunction Perovskite Solar Cells by In Situ Interface Modification with [(p-Fluorophenyl)ethyl]ammonium Acetate.
2D/3D heterojunction perovskites, meaning a rationally prepared 2D capping layer on 3D perovskite films, have been demonstrated as an effective avenue for simultaneously enhancing the efficiency and stability in perovskite solar cells (PSCs). However, the mechanism of the 2D perovskite induced by organic agents is still not extensively studied. Here, we report 2D/3D heterojunction PSCs by in situ fabricating a 2D modified layer on 3D perovskite films with [(p-fluorophenyl)ethyl]ammonium acetate (FPEAAc). During the annealing process, FPEAAc melts and uniformly covers the 3D perovskite films. Then, the excess acetate salt is volatilized, eventually forming a compact 2D perovskite thin layer. On the one hand, the organic agents can effectively rivet onto the 3D perovskite surface, ensuring formation of the necessary 2D perovskites with hydrophobic FPEA+ ions. On the other hand, the reaction generates some PbI2, which passivates the defects on 3D perovskite films and improves the interface contact, significantly enhancing the open-circuit voltage (VOC) and fill factor (FF) in 2D/3D PSCs. The highest power conversion efficiency of 22.53% is achieved compared with 20.16% in 3D PSCs. The 2D/3D-heterojunction-structured PSCs modified by FPEAAc exhibit high stability, retaining about 90% of the initial device efficiency after 500 h at 85 °C and 40 ± 5% relative humidity. Our research provides a simple method to control the 2D perovskite layer formation and effectively enhance the performance and stability in 2D/3D heterojunction perovskite cells.


2-bit coding metasurface with a double layer random flip structure for wide band diffuse reflection and reciprocity protected transmission.
Coding metasurfaces based on random-flip structures have attracted great attention due to their ability to achieve distortion-free transmission and diffuse reflection simultaneously. However, previous implementation based on 1-bit coding metasurface has a narrow bandwidth and insufficient bandwidth coverage in the near infrared region. Here, we propose a novel vertical 2-bit coding metasurface composed of double-layer random-flip meta-atoms (DLRFM). while the main transmission lobe is unchanged, the zero-order diffraction intensity of DLRFM's reflection direction is less than 10% of the total reflection in the range of 0°∼ 30° incidence angle, which proves its excellent diffuse reflection and distortion-free transmission effect. Such design strategy can be extended to multiple wide band coverage in near-infrared regime by tailoring the geometric parameters, which indicates good application potential in advanced display and lens designs.


Potent stimulation of vascular endothelial cell growth by differentiated 3T3 adipocytes.
3T3 cells that have undergone adipose differentiation in vitro secrete into the culture medium a potent growth stimulatory activity for bovine aortic endothelial cells. When medium containing 2% fetal calf serum, which does not support significant endothelial cell growth, is conditioned by 3T3-F442A adipocytes, the endothelial cells grow rapidly (doubling time, 24 hr) at a rate equal to the growth rate in 20% fetal calf serum. The potency of the conditioned medium is further shown by the fact that it can be diluted 1:5 with little apparent loss of activity and shows a half-maximal stimulation at 10 microliter/ml. Serum is not required for either the secretion of this mitogen by the adipocytes or its action on the endothelial cells, as shown by the fact that the latter are stimulated to divide in serum-free medium conditioned by the adipocytes. The growth stimulatory activity appears to be specific for vascular endothelial cells in that no other cell type examined, including vascular smooth muscle cells and pericytes, are significantly stimulated by medium conditioned by 3T3-F442A cells. Similarly, medium conditioned by no other cell type examined has more than 10% of the activity of medium conditioned by the adipocytes. The specificity and potency of the adipocyte-derived factor suggest that it may play a role in the vascularization of this tissue during development. Preliminary biochemical analysis indicates that the adipocyte factor is nondialyzable and is not inactivated by heat or proteases. The protease insensitivity distinguishes the adipocyte growth stimulatory activity from the low levels of activity secreted by fibroblasts and preadipocytes, suggesting that the adipocyte mitogen is a product specifically related to the differentiation process.


New concepts on the therapeutic control of complement anaphylatoxin receptors.
The complement system is a pivotal driver of innate immunity, coordinating the host response to protect against pathogens. At the heart of the complement response lie the active fragments, C3a and C5a, acting through their specific receptors, C3aR, C5aR1, and C5aR2, to direct the cellular response to inflammation. Their potent function however, places them at risk of damaging the host, with aberrant C3a and C5a signaling activity linked to a wide range of disorders of inflammatory, autoimmune, and neurodegenerative etiologies. As such, the therapeutic control of these receptors represents an attractive drug target, though, the realization of this clinical potential remains limited. With the success of eculizumab, and the progression of a number of novel C5a-C5aR1 targeted drugs to phase II and III clinical trials, there is great promise for complement therapeutics in future clinical practice. In contrast, the toolbox of drugs available to modulate C3aR and C5aR2 signaling remains limited, however, the emergence of new selective ligands and molecular tools, and an increased understanding of the function of these receptors in disease, has highlighted their unique potential for clinical applications. This review provides an update on the growing arsenal of drugs now available to target C5, and C5a and C3a receptor signaling, and discusses their utility in both clinical and pre-clinical development.