Comparison between cylindrical axis-reference and articular surface-reference femoral bone cut for total knee arthroplasty.
Reproducing a functional flexion-extension axis (FEA) of the femur is key to achieving successful collateral ligament balance and joint line in total knee arthroplasty (TKA). This study compared the feasibility of cylindrical axis (CA)-reference bone cut and articular surface-reference bone cuts in reproducing the FEA for Japanese osteoarthritis patients. The study enrolled 122 knees from 86 patients who underwent primary TKA due to grade III or IV osteoarthritis. Data from pre-operative CT were reconstructed into three-dimensional (3D) models using 3D-planning software. Cylindrical radii of the condyles were measured, and femoral bone cut angles relative to anatomical landmarks were determined in the coronal and axial reference planes based on CA-reference and articular surface-reference methods. Mean cylindrical radii for medial and lateral femoral condyles were 17.4 ± 1.6 and 17.3 ± 1.4 mm, respectively. Of the 122 knees, 46 exhibited >1 mm of difference between condyles. Fifty-three and 22 knees exhibited >2° of angular difference between CA-reference and articular surface-reference bone cuts in the coronal and axial planes. Mean angle of the CA and surgical epicondylar axis in 3D space was 4.6 ± 2.1°. As practical parameters for TKA, the angle between CA and IM rod was significantly larger than that between the distal articular surface line and IM rod in the coronal plane (p < 0.0001), indicating that CA-reference involves a smaller valgus bone cut of the distal femur than articular surface reference. CA-reference bone cut of the femur is preferable to articular surface-reference bone cut for reproducing FEA in Japanese OA patients, in whom more than one-third of knees exhibited asymmetry of radii between medial and lateral condyles. In clinical practice, the CA-reference bone cut represents a good technical option for kinematically aligned TKA in the Japanese population.


Library outreach near and far: programs to staff and patients of the Piedmont Healthcare System.
The librarians at the Sauls Memorial Library at Piedmont Hospital describe two services they offer to Piedmont Healthcare personnel and patients. Included are the system-wide library outreach program and the Sauls Memorial Library Business Center at the main hospital. These services create good will between patients, employees, and the healthcare system, and are also vital elements in promoting and marketing the library. This article illustrates the steps that were taken to create these services within Piedmont Healthcare's growing system.


Expression of a bile acid transporter in biliary epithelial cells from normal and cholestatic rat livers.
A sodium dependent bile acid carrier has recently been cloned and characterized in rat ileum. The present study demonstrates the presence of a mRNA species specific for the rat ileal bile acid carrier (r-IBAT) in rat biliary epithelial cells. Moreover, immunohistochemistry with a peptide specific antibody demonstrates protein expression in biliary epithelial cells from normal and bile duct ligated rat livers. Besides a cytoplasmic staining a predominant staining of the apical membrane could be observed. These observations indicate that biliary epithelial cells are involved in bile acid transport across the biliary tree. In addition the carrier could also play a role in the signal transduction of bile acid induced ductular secretion.


Excited-state quantum phase transitions in the anharmonic Lipkin-Meshkov-Glick model: Dynamical aspects.
The standard Lipkin-Meshkov-Glick (LMG) model undergoes a second-order ground-state quantum phase transition (QPT) and an excited-state quantum phase transition (ESQPT). The inclusion of an anharmonic term in the LMG Hamiltonian gives rise to a second ESQPT that alters the static properties of the model [Gamito et al., Phys. Rev. E 106, 044125 (2022)2470-004510.1103/PhysRevE.106.044125]. In the present work, the dynamical implications associated to this new ESQPT are analyzed. For that purpose, a quantum quench protocol is defined on the system Hamiltonian that takes an initial state, usually the ground state, into a complex excited state that evolves on time. The impact of the new ESQPT on the time evolution of the survival probability and the local density of states after the quantum quench, as well as on the Loschmidt echoes and the microcanonical out-of-time-order correlator (OTOC) are discussed. The anharmonity-induced ESQPT, despite having a different physical origin, has dynamical consequences similar to those observed in the ESQPT already present in the standard LMG model.


Lung uptake of liposome-entrapped glutathione after intratracheal administration.
The intratracheal delivery of glutathione (GSH), in liposome-encapsulated form, prolongs retention of the drug in the rat lung. This study has been designed to determine the extent and time-course of pulmonary tissue uptake of administered 14C-labelled liposomes containing [3H]GSH. Liposomes, composed of dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine each with or without 30 mol% cholesterol showed a clearance greater than 80% from the bronchoalveolar lavage, 24 h after intratracheal instillation. Lung tissue content of 14C-lipid increased with time: by 72 h, 42-56% of the administered dose was recovered from the tissue. [3H]GSH was present in pulmonary tissue in relatively constant amounts throughout the 72 h, ranging from 14-35% of the administered dose. Vesicles composed of DMPC had a low entrapment for GSH. There were only minor differences in GSH entrapment efficiency and lung tissue uptake between vesicles of the other lipid compositions.


Population Pharmacokinetics of Nusinersen in the Cerebral Spinal Fluid and Plasma of Pediatric Patients With Spinal Muscular Atrophy Following Intrathecal Administrations.
Nusinersen is an antisense oligonucleotide intended for the treatment of spinal muscular atrophy. The pharmacokinetics of nusinersen, following intrathecal administrations, in the cerebrospinal fluid (CSF) and plasma of 72 pediatric patients (3 months to 17 years) with spinal muscular atrophy across 5 clinical trials was analyzed via population-based modeling. With sparse data in the CSF and profile data in the plasma, a linear 4-compartment model simultaneously described the time-concentration profiles in both matrices. The typical population parameters were: Qp = 0.572 L/h, QCSF = 0.069 L/h, CLp = 2.50 L/h, CLCSF = 0.133 L/hr, VCSF = 0.441 L, Vp = 32.0 L, Vsystemic_tissue = 429 L, and VCNS_tissue = 258 L. A full covariate modeling approach identified baseline body weight to be a statistically and clinically relevant covariate on VCSF , Vp , and CLp . The model predicted that the CSF volume of distribution increased steadily with age from 0 to 2 years but became relatively steady for children >2 years. Simulations from the final model showed that age-based dosing in children under 2 years ensured a more comparable exposure (peak concentration and area under the concentration-time curve) across subjects in the population relative to a fixed dosing scheme. However, because no dose-limiting toxicity has been reported in any of the trials, a fixed-dose scheme (12 mg across all age groups) was recommended. The median terminal half-life of nusinersen in the CSF was determined from the model to be 163 days, which supported infrequent dosing, once every 4 to 6 months in pediatric patients with spinal muscular atrophy.


Authentication of tejocote (Crataegus mexicana) dietary supplements based on DNA barcoding and chemical profiling.
Tejocote (Crataegus mexicana, Mexican hawthorn), known as a weight-loss supplement, has been marketed online and is easily available for overseas direct purchase. Alipotec (brand name) is known as one of the most popular products containing tejocote in Mexico and other countries. However, adverse effects have been reported by users of these supplements. Therefore it is necessary to find the reason for the side effect. Dietary supplement samples labelled as containing tejocote were analysed using mass spectrometry and DNA barcoding analysis. Our results demonstrate that Alipotec samples contained ingredients from different species, yellow oleander instead of tejocote. The rpoB barcode region was able to differentiate between tejocote and yellow oleander species. Moreover, it was also observed that three compounds, including thevetin B, neriifolin, and digitoxigenin, clearly distinguish between tejocote and yellow oleander samples. This is the first and preliminary investigation to use an integrated approach of both chemical and genomic profiling for the authentication of dietary supplement containing tejocote.


High density lipoprotein: a therapeutic target in type 2 diabetes.
High density lipoproteins (HDLs) have a number of properties that have the potential to inhibit the development of atherosclerosis and thus reduce the risk of having a cardiovascular event. These protective effects of HDLs may be reduced in patients with type 2 diabetes, a condition in which the concentration of HDL cholesterol is frequently low. In addition to their potential cardioprotective properties, HDLs also increase the uptake of glucose by skeletal muscle and stimulate the synthesis and secretion of insulin from pancreatic β cells and may thus have a beneficial effect on glycemic control. This raises the possibility that a low HDL concentration in type 2 diabetes may contribute to a worsening of diabetic control. Thus, there is a double case for targeting HDLs in patients with type 2 diabetes: to reduce cardiovascular risk and also to improve glycemic control. Approaches to raising HDL levels include lifestyle factors such as weight reduction, increased physical activity and stopping smoking. There is an ongoing search for HDL-raising drugs as agents to use in patients with type 2 diabetes in whom the HDL level remains low despite lifestyle interventions.


Assessment of the safety of long-term bazedoxifene treatment on the reproductive tract in postmenopausal women with osteoporosis: results of a 7-year, randomized, placebo-controlled, phase 3 study.
To evaluate the clinical safety of bazedoxifene (BZA) on the reproductive tract in postmenopausal women with osteoporosis over 7 years. This was a second, blinded, 2-year extension of a 3-year, randomized, double-blind, placebo (PBO)- and active-controlled phase 3 trial. In the core study, subjects were randomized to receive BZA 20 or 40mg, raloxifene 60mg, or PBO. During years 4-5, the raloxifene arm was discontinued and subjects receiving BZA 40mg were transitioned to BZA 20mg. Subjects continued to receive BZA 20mg or PBO during years 6-7. The primary endpoint was the incidence of new vertebral fractures at 7 years (reported separately). Reproductive tract safety findings at 7 years are reported here. Endometrial thickness was assessed by transvaginal ultrasonography for subjects in the endometrial safety substudy. Adverse events (AEs) were recorded throughout the study. At 7 years, the adjusted mean (±standard error) change in endometrial thickness was similar with BZA and PBO (-0.11 ± 0.21 and 0.07 ± 0.32 mm, respectively). The incidence of endometrial hyperplasia was low (0.1% for both groups). BZA showed significantly lower rates than PBO of endometrial carcinoma (0.1% vs. 0.4%; P=0.020) and vaginitis (6.1% vs. 7.6%; P=0.035). There were more cases of ovarian carcinoma with BZA (n=4 [0.1%]) than PBO (n=0); the difference was not statistically significant. Rates of breast-related and other gynecologic AEs were similar among groups. BZA was associated with a favorable reproductive safety profile in postmenopausal women with osteoporosis over 7 years.


Low-cost, office-based, screening colonoscopy.
Performing full colonoscopy at regular intervals and removing lesions at an early stage might significantly lower the incidence and mortality of colorectal cancer. Such a program must be inexpensive, safe, and time-efficient. Screening colonoscopy was performed on 639 patients. For a normal examination, the physician's time is limited to giving the medication for conscious sedation, performing the colonoscopy, and completing a written report form. The total charge for a normal screening colonoscopy is $150. Adenomatous and/or hyperplastic polyps were detected in 218 patients (34.1%). One hundred sixty adenomatous and 134 hyperplastic polyps were removed. Forty-eight percent (48.1%) of the adenomatous and 21.6% of the hyperplastic polyps were above the sigmoid colon. Six adenocarcinomas were detected in five patients. One patient had a delayed bleeding episode requiring no transfusion or therapeutic intervention, and one patient had a "post-polypectomy syndrome" requiring no therapeutic intervention. The average physician time in the endoscopy room for normal examinations was 18 min. Screening colonoscopy can be safely performed in an office facility. Physician time with the patient should be limited to allow a low cost that compares favorably with screening costs for other malignancies. Long-term studies to assess the capability of screening colonoscopy to lower mortality from colorectal cancer should continue.


Pairwise summation approximation of Casimir energy from first principles.
We obtain the pairwise summation approximation (PSA) of the Casimir energy from first principles in the soft dielectric and soft diamagnetic limit, this analysis let us find that the PSA is an asymptotic approximation of the Casimir energy valid for large distances between the objects. We also obtain the PSA for the electromagnetic coupling part of the Casimir energy, so we are able to complete the PSA limit for the first time for the complete electromagnetic field.


Efficacy response of inhaled HFA-albuterol delivered via the breath-actuated Autohaler inhalation device is comparable to dose in patients with asthma.
Handling difficulties, such as poor coordination of actuation and inhalation, are common in patients using press and breathe (P&Bs) metered-dose inhalers to administer asthma medication. Although spacers can help overcome some difficulties, the cumbersome nature of these devices often detracts from their use for the administration of rescue medications, where portability is important. This randomized, placebo-controlled, multicenter, crossover study investigated the efficacy, dose-response and safety of HFA-albuterol delivered via a breath-actuated Autohaler inhalation device in comparison with the same medication delivered using a conventional P&B device. In total, 39 patients received six study treatments in a random sequence at clinic visits separated by 2-7 days: 2 puffs from a HFA-placebo Autohaler; 1, 2, or 4 puffs from a HFA-albuterol Autohaler; I or 2 puffs from a HFA-albuterol P&B. Both active inhalers delivered 90 microg albuterol base equivalent/actuation from the actuator. The change from baseline in forced expiratory volume in 1 s (FEV1) and the area under the FEV1 curve (FEV1 AUC) were significantly greater than placebo for all active treatment groups (p < or = 0.01) and were suggestive of a dose response for each inhaler. Examination of the pooled slope of the dose responses for the Autohaler and P&B using Finney's Parallel Line Bioassay Methodology found a highly statistically significant relationship indicating the equivalence of the two inhalers on both parameters (p < or = 0.002). The relative potency of the two inhalers was 0.8 (95% CI: 0.47, 1.46) for the mean change from baseline in FEV1 and 0.9 (95% CI, 0.56, 1.48) for the change from baseline in FEV1 AUC. There was also a trend toward an increase in the mean percentage change from baseline in FEV1 as the number of puffs increased for both inhalers. Furthermore, there were no significant differences between the treatment groups with regard to time to onset of bronchodilator effect and the duration of effect was significantly greater than placebo (p < or = 0.01) in each of the active groups. Adverse events were generally mild to moderate in nature and were of similar incidence (< or = 18% of patients) in each group. This study demonstrates a dose-response for HFA-albuterol on bronchodilation using both the Autohaler and P&B devices and illustrates that, in patients with good coordination of inhalation with actuation, the efficacy and safety of the two inhalers is similar at equivalent doses.


Synchronization of endogenous and exogenous FSH stimuli in controlled ovarian hyperstimulation (COH).
We have previously observed that exogenous oestradiol can delay the intercycle increase in plasma follicle stimulating hormone (FSH). The increase in plasma FSH that follows discontinuation of exogenous oestradiol peaks after 3 days. We have now studied the possibility of using exogenous oestradiol to synchronize the increase in endogenous FSH with the onset of human menopausal gonadotrophin (HMG) treatment in controlled ovarian hyperstimulation (COH). A total of 30 women aged 35.1+/-6.3 years (mean+/-SD) undergoing ovarian stimulation received 2 mg of oestradiol valerate twice daily starting on day 25 of the previous menstrual cycle until the first Tuesday following menses. Ovarian stimulation was initiated 3 days later. On the last day of oestradiol treatment, plasma oestradiol, FSH and luteinizing hormone (LH) (mean+/-SEM) were 566+/-53 (pmol/l), 3.8+/-0.4 (IU/l) and 5.5+/-0.8 (IU/l) respectively. After 3 days, the FSH and LH (mean+/-SEM) had increased to 6.7+/-0.7 and 6.9+/-0.7 (IU/l) respectively while oestradiol decreased to 251+/-29 (pmol/l). The mean number (+/-SEM) of HMG ampoules used was 25.1+/-2.7 and treatment lasted 11.3+/-0.9 days. Five women became pregnant for a pregnancy rate (ongoing) of 19 (15)%. If all women aged >40 years (six women who did not become pregnant) were excluded from analysis the pregnancy rate (ongoing) was 24 (19%). These results indicate that exogenous oestradiol can safely be used for the synchronization of endogenous and exogenous FSH stimuli in COH. This approach provides the practical advantage of permitting an advanced timing of the onset of COH treatments when gonadotrophin-releasing hormone (GnRH) agonists are not used, which improves treatment convenience for patients and team members alike. Further development of this model may enable control of the onset of natural cycles which may find practical applications for timing assisted reproductive techniques (intrauterine insemination or in-vitro fertilization) in the natural cycle.


The toxicological effects of nano titanium dioxide on target organs and mechanisms of toxicity.
Nano-titanium dioxide (TiO2 NPs) is widely used for its extremely high stability, corrosion resistance, and photocatalytic properties and has penetrated into various fields of production and life. Assessing its toxicity to different organs should be a key part of preclinical toxicity assessment of TiO2 NPs, which is relatively incomprehensive yet. Therefore, this review focuses on the toxic effects of TiO2 NPs on various organs in mammals and biological mechanisms from different organs. The commonality of toxic effects on various target organs reflected in tissue structure damage and dysfunction, such as liver damage and dysfunction; pulmonary fibrosis; and renal impairment (including hematuria and nephritis); damage of brain tissue and neurons; alteration of intestinal villi; and weight loss. And effects on the reproductive system are affected by different sexes, including ovarian dysfunction, testicular development damage, and sperm viability reduction. We believe that the toxic mechanisms of TiO2 NPs in target organs have commonalities, such as oxidative stress, inflammatory responses, and organelle damage. However, different target organ toxicities also have their specificities. TiO2 NPs disturb the intestinal flora and cause undesirable changes in feces products. And in spleen are infiltration of neutrophils and lymphadenopathy and eventually immune deficiency. Although the toxic pathways are different, but there may be a close link between the different toxic pathways. In this article, the main manifestations of the toxic effects of titanium dioxide nanoparticles on major mammalian organs are reviewed, in order to provide basic data for their better application from a medical perspective.


[The diversity of human hematopoietic stem/progenitor cells: IX. Cell-cycles kinetics related macromolecules DNA, RNA and protein contents in CD34+ hematopoietic cells of human bone marrow].
DNA, RNA and PRO comprise the bulk of macromolecules in cells, which have been proven to play an important role in regulating cell cycle transverse capacity, cell division, growth, and size. Simultaneous analysis of these moieties could provide more comprehensive and accurate information on cell cycle kinetics. In this study, DNA, RNA and PRO contents related to cell cycle kinetics in CD34+ hematopoietic cells of human bone marrow were measured to understanding the cell cycle kinetic features in CD34+ hematopoietic cells. For this reason, CIMS-100 immunomagnetic isolator, a novel isolation system, was used to enrich efficiently CD34+ hematopoietic cells from human bone marrow. The purity of enriched CD34+ hematopoietic cells determined by both FACS and APAAP staining is ranging from 90%-95%. Cellular DNA, RNA and PRO were stained with fluorochromes propidium iodide, pyronin Y and fluorescein isothiocyante respectively The fluorescence intensities reflecting the DNA, RNA and PRO content of individual cell were analyzed in FACS can by different excitation wavelengthes. DNA, RNA and PRO contents in CD34+ hematopoietic cells were far lower than these of bone marrow mononuclear cells, only being 34 +/- 3% (DNA), 48 +/- 21% (RNA) and 62 +/- 14% (PRO) of BMMNCs respectively. Collectively, these data combined with previous results from both ours and others indicated that CD34+ hematopoietic cells are indeed an unique cell population, not only in reconstitute of hematopoietic and immunological functions, but also in cell cycle kinetics. This is, to our knowledge, the first detailed report on the analysis of DNA, RNA and PRO contents related to cell cycle kinetics in CD34+ hematopoietic cells. And the results provide more direct evidence that the majority of CD34+ hematopoietic cells are in resting state.


Structural waters in the minor and major grooves of DNA--a major factor governing structural adjustments of the A-T mini-helix.
The role of microhydration in structural adjustments of the AT-tract in B-DNA was studied at the B97-D/def2-SV(P) level. The (dA:dT)5 complexes with 10 water molecules in minor and 15 water molecules in major grooves were studied. The obtained network of hydrogen bonds revealed the dependence between the groove width and the types of water patterns. In the minor groove, the following patterns were observed: interstrand one-water bridges similar to that of the Dickerson "water spine" and interstrand two-water bridges. The network of structural waters in the major groove is more diverse than that in the minor groove, which agrees with crystallographic data. As the major groove is wider, it is enriched by water molecules forming two- and three-water bridges. Results suggest the nucleobase-water interactions in both grooves prevent AT-tract twisting and its "collapse" along the minor groove. Whereby, a helix structure with narrow minor and wide major grooves is formed. The structural waters affect the polynucleotide conformation so that it becomes similar to poly(dA)·poly(dT) in fibers and acquires features of the A-tracts in DNA in solution. We suggest that formation of specific water patterns in both grooves is the factor responsible for stabilization of A-tracts with a narrowed minor groove, leading in turn to their strong intrinsic bending in DNA.


Atypical anatomy of maxillary second premolar with three roots and four canals.
Knowledge and understanding the anatomical configuration of individual tooth play a significant role in success of endodontic treatment, in addition to through debridement and obturation of the canals. The canal anatomy of maxillary second premolar has been studied extensively, and the presence of a significant variety of multirooted canals is relatively rare in it. A 27-year-old female reported with a chief complaint of pain in her upper right posterior region for 10 days. On intraoral hard tissue examination, ill-defined access preparation was seen in maxillary right second premolar with exposed pulp. An intraoral periapical radiograph reveals radiolucency involving the pulp space and varied morphology in the same tooth. The occurrence of three roots with four canals in the maxillary second premolar is rare and not documented in the literature so far. This case report describes the nonsurgical endodontic management of such varied anatomical configuration using cone beam computed tomography as an evaluating diagnostic tool.


Application of mass spectrometry in proteomics.
Mass spectrometry has arguably become the core technology in proteomics. The application of mass spectrometry based techniques for the qualitative and quantitative analysis of global proteome samples derived from complex mixtures has had a big impact in the understanding of cellular function. Here, we give a brief introduction to principles of mass spectrometry and instrumentation currently used in proteomics experiments. In addition, recent developments in the application of mass spectrometry in proteomics are summarised. Strategies allowing high-throughput identification of proteins from highly complex mixtures include accurate mass measurement of peptides derived from total proteome digests and multidimensional peptide separations coupled with mass spectrometry. Mass spectrometric analysis of intact proteins permits the characterisation of protein isoforms. Recent developments in stable isotope labelling techniques and chemical tagging allow the mass spectrometry based differential display and quantitation of proteins, and newly established affinity procedures enable the targeted characterisation of post-translationally modified proteins. Finally, advances in mass spectrometric imaging allow the gathering of specific information on the local molecular composition, relative abundance and spatial distribution of peptides and proteins in thin tissue sections.


Induction of protective CTL immunity against peptide transporter TAP-deficient tumors through dendritic cell vaccination.
A large proportion of human cancers show deficiencies in the MHC class I antigen-processing machinery. Such defects render tumors resistant to immune eradication by tumoricidal CTLs. We recently identified a unique population of CTL that selectively targets tumor immune-escape variants through recognition of MHC-presented peptides, termed TEIPP (T cell epitopes associated with impaired peptide processing), expressed on cells lacking functional TAP-peptide transporters. Previously, we showed that vaccination with TEIPP peptides mediates protection against TAP-deficient tumors. Here, we further explored the concept of TEIPP-targeted therapy using a dendritic cell (DC)-based cellular vaccine. Impairment of TAP function in DC induced the presentation of endogenous TEIPP antigens by MHC class I molecules, and immunization with these DCs protected mice against the outgrowth of TAP-deficient lymphomas and fibrosarcomas. Immune analysis of vaccinated mice revealed strong TEIPP-specific CTL responses, and a crucial role for CD8(+) cells in tumor resistance. Finally, we show that TEIPP antigens could be successfully induced in wild-type DC by introducing the viral TAP inhibitor UL49.5. Our results imply that immune intervention strategies with TAP-inhibited DC could be developed for the treatment of antigen processing-deficient cancers in humans.


Interaction between histamine and vagal stimulation on tracheal smooth muscle in dogs.
We examined the interaction between histamine and vagal efferent activity on airway smooth muscle reactivity in 11 anesthetized vagotomized dogs using an isolated closed segment of the intrathoracic trachea filled with Tyrode solution under an isovolumetric condition. Intratracheal pressure change was measured as an index of tracheal smooth muscle tone. The administration into the tracheal segment of histamine (0.1 or 1.0 mg/ml) in six dogs and methacholine chloride (0.001 or 0.01 mg/ml) in the other five dogs elevated intratracheal pressure by about 5 cmH2O. The electrical stimulation of the peripheral ends of both of the cut cervical vagus nerves in the presence of histamine produced significantly greater responses than the additive responses of these two stimuli applied individually (two-way analysis of variance, P less than 0.025). However, the combined effects of vagal stimulation and methacholine were not significantly different from the additive responses of these two stimuli applied individually. The average values of intratracheal pressure elevated by the combined effects of vagal stimulation and histamine were significantly higher than those obtained by the combination of vagal stimulation and methacholine (two-way analysis of variance, P less than 0.01). This suggests that histamine potentiates tracheal smooth muscle reactivity to electrical vagal stimulation, which may contribute to the hyperreactivity observed in patients with asthma.


A 2-Cys peroxiredoxin in response to oxidative stress in the pine wood nematode, Bursaphelenchus xylophilus.
The pine wood nematode, Bursaphelenchus xylophilus, is the causal agent of pine wilt disease that has devastated pine forests in Asia. Parasitic nematodes are known to have evolved antioxidant stress responses that defend against host plant defenses. In this study, the infestation of whitebark pine, Pinus bungean, with B. xylophilus led to a significant increase in plant hydrogen peroxide (H2O2) and salicylic acid levels. Correspondingly, the expression of an antioxidative enzyme, 2-Cysteine peroxiredoxin (BxPrx), was elevated in B. xylophilus following the H2O2 treatments. Recombinant BxPrx, a thermal stabile and pH tolerant enzyme, exhibited high level of antioxidant activity against H2O2, suggesting that it is capable of protecting cells from free radical attacks. Immunohistochemical localization study showed that BxPrx was broadly expressed across different tissues and could be secreted outside the nematode. Finally, the number of BxPrx homologs in both dauer-like and fungi-feeding B. xylophilus were comparable based on bioinformatics analysis of existing EST libraries, indicating a potential role of BxPrx in both propagative and dispersal nematodes. These combined results suggest that BxPrx is a key genetic factor facilitating the infestation and distribution of B. xylophilus within pine hosts, and consequently the spread of pine wilt disease.


Short- and long-term outcomes of moyamoya patients post-revascularization.
The post-bypass stroke risk factors and long-term outcomes of moyamoya patients are not well documented. Therefore, the authors studied 30-day stroke risks and patients' long-term physical, functional, and social well-being. This was a single-institution combined moyamoya disease (MMD) database interrogation and questionnaire study. From 1991 to 2014, 1250 revascularization procedures (1118 direct bypasses, 132 indirect bypasses) were performed in 769 patients. Completed questionnaires were received from and available for analysis on 391 patients, and 6-month follow-up data were available for 96.4% (741/769) of the patients. The patients consisted of 548 females and 221 males, with a mean age of 32 years (range 1-69 years). Three hundred fifty-eight bypasses were performed in 205 pediatric patients (73% direct bypasses), and 892 revascularizations were performed in 564 adults (96% direct bypasses). Fifty-two patients (6.8%) developed major strokes with a worsening modified Rankin Scale (mRS) score within 30 days postoperatively. The 30-day major stroke risk was 5.3% (41/769) and 2.6% (12/467) after the first and second bypasses, respectively. Logistic regression analysis revealed that older age, modified MRI (mMRI) score, and hemodynamic reserve (HDR) score are clearly associated with higher postoperative stroke risks. Over a mean follow-up of 7.3 years (range 0.5-26 years), the long-term stroke risk among 741 patients was 0.6% per patient-year; 75% of these patients had excellent outcomes (mRS score 0-1). The long-term outcome questionnaire study showed that 84% (234/277) of patients reported resolution or improvement in their preoperative headache, 83% (325/391) remained employed or in school, and 87% (303/348) were self-caring. In this large, single-center surgical series, most of the adult and pediatric patients had direct revascularization, with a 4.2% per-bypass-procedure (6.8% per patient) 30-day major stroke risk and a 0.6% per-patient-year long-term stroke risk. The authors identified various risk factors that are highly correlated with postoperative morbidity (age, mMRI score, and HDR score) and are involved in ongoing work to develop the predictive modeling for future patient selection and treatment.


Projected economic burden of pancreatic cancer in Sweden in 2030.
Pancreatic cancer is predicted to become the second most common cause of cancer-related death by 2030. The objective of this study was to estimate the economic burden of pancreatic cancer for the years 2018 and 2030 based on changing demographics and incidence rates in Sweden. The incidence of pancreatic cancer in Sweden and additional relevant data were obtained from official statistics. A linear regression model and the mean incidence rates 2008-2018 were applied to calculate the incidence in 2030. An economic model based on the human capital method was created to calculate the indirect cost of pancreatic cancer in 2018 and 2030. Costs associated with surgery, radiology, oncology, and palliative care constituted the direct costs. A sensitivity analysis was performed. The incidence of pancreatic cancer in Sweden in the year 2018 was 1352 patients and projected to between 1554 (+15%) and 1736 (+28%) in 2030. The total cost was calculated to €125 million in 2018 and between €210 million (+68%) and €225 million (+80%) in 2030. The indirect cost in the ≤65-year-old group was €328,344 in 2018 and between €380,738 and €382,109 per individual in 2030. The economic burden of pancreatic cancer is expected to increase in Sweden by 2030 due to the increasing incidence of the disease and changing demographics. Pancreatic cancer is a growing health care problem in urgent need of advancements in prevention, early detection, treatment, and control of the disease.


Copper and zinc status in rheumatoid arthritis: studies of plasma, erythrocytes, and urine, and their relationship to disease activity markers and pharmacological treatment.
We studied the status of copper and zinc in rheumatoid arthritis (RA). The aims of the work were to ascertain whether or not RA is associated with copper and/or zinc deficiency, to establish the relationship between these trace metals and the main biohumoral and clinical indices of the disease, and to examine the effect on copper and zinc of the drugs normally used by RA patients. Metal levels were measured by atomic absorption spectroscopy in the plasma, whole blood cells and 24 hr urine of 120 RA patients; 70 patients suffering from primary osteoarthritis were used as the control group. In the plasma of RA patients copper and ceruloplasmin levels were found to be significantly increased whereas zinc levels were significantly decreased. No major variations were observed in the blood cell and 24 hr urine copper and zinc levels. Plasma copper was significantly correlated with some of the biohumoral markers of RA, but did not correlate with any of the clinical indices of the disease. Plasma zinc was significantly correlated with numerous of the biohumoral as well as clinical markers of RA. With the exception of an increased urinary excretion of copper in D-penicillamine treated RA patients, drug therapy did not influence the copper status in RA. Conversely, plasma zinc was found to be lower in RA patients taking NSAIDs and/or steroids. These results suggest the following conclusions: i) RA patients do not seem to be deficient in either copper or zinc; ii) plasma copper appears to be a poor index of RA severity; iii) plasma zinc could have some practical value in defining the overall severity of the disease.


Detection and genotyping of Entamoeba histolytica, Entamoeba dispar, Giardia lamblia, and Cryptosporidium parvum by oligonucleotide microarray.
Entamoeba histolytica, Giardia lamblia, and Cryptosporidium parvum are the most frequently identified protozoan parasites causing waterborne disease outbreaks. The morbidity and mortality associated with these intestinal parasitic infections warrant the development of rapid and accurate detection and genotyping methods to aid public health efforts aimed at preventing and controlling outbreaks. In this study, we describe the development of an oligonucleotide microarray capable of detecting and discriminating between E. histolytica, Entamoeba dispar, G. lamblia assemblages A and B, and C. parvum types 1 and 2 in a single assay. Unique hybridization patterns for each selected protozoan were generated by amplifying six to eight diagnostic sequences/organism by multiplex PCR; fluorescent labeling of the amplicons via primer extension; and subsequent hybridization to a set of genus-, species-, and subtype-specific covalently immobilized oligonucleotide probes. The profile-based specificity of this methodology not only permitted for the unequivocal identification of the six targeted species and subtypes, but also demonstrated its potential in identifying related species such as Cryptosporidium meleagridis and Cryptosporidium muris. In addition, sensitivity assays demonstrated lower detection limits of five trophozoites of G. lamblia. Taken together, the specificity and sensitivity of the microarray-based approach suggest that this methodology may provide a promising tool to detect and genotype protozoa from clinical and environmental samples.


Predictors of possible exposure to rabies in travellers: A case-control study.
Timely administration of post-exposure prophylaxis (PEP) can prevent rabies. For non-vaccinated persons, PEP consists of multiple vaccinations and rabies immunoglobulin (RIG) on indication. Since RIG is scarce, the need for PEP could be restricted through preventing animal contact and pre-exposure vaccination. We aimed to identify determinants for possible rabies exposure among travellers to provide more targeted pre-travel advice. A case-control study was performed. Cases were defined as persons with a possible rabies exposure (category II or III injury according to WHO classification guidelines) in a rabies endemic country. Controls did not report exposure during travel. Multivariable logistic regression was performed. 229 cases and 1427 controls were included. Predictors (p < 0.05) of possible rabies exposure were young age, male sex, travelling to Western or Southeastern Asia, visiting a monkey park, pet ownership, previously visited the same country and considering oneself an experienced traveller. Negative predictors were travelling for business, visiting friends and relatives, and fear of animals. Pre-travel advice should take the identified predictors into account to provide better targeted information and pre-exposure prophylaxis.


Nuss procedure: pediatric surgical solution for adults with pectus excavatum.
The aim of the study was to compare results of the Nuss procedure in adults and children. The data were collected prospectively. Antibiotic prophylaxis was used in all patients. Differences were tested statistically. A total of 35 adults (28 men; male/female ratio 4:1) with a median age of 23 years (range 18 years to 47 years 1 month) were included in the study. A previous Welch operation had been performed in one (3%). The median operating time was 65 minutes (range 45-105 minutes). Two bars were inserted in one patient, and stabilizers were used in all. Pneumothorax occurred in 9 (26%), wound abscess in 3 (9%), and bar slips in 5 (14%). The median hospital stay was 7 days (range 4-10 days). Bars were removed in 14 (40%) patients without complications. Follow-up occurred 6 and 12 months after bar removed, at which times no recurrence of the pectus and no sternal protrusions were seen. In the other part of the study, 141 children and adolescents (105 boys; male/female ratio 3:1) with a median age of 13 years (range 4 years 11 months to 17 years 8 months) were included. A previous Welch operation had been performed in five (4%). Two bars were inserted in four, and stabilizers were used in 100 (71%). The median operating time was 65 minutes (40-185 minutes). Pneumothorax occurred in 33 (24%), wound abscess in 1 (0.7%), and bar slips in 18 (13%). The median hospital stay was 7 days (range 5-18 days). Bars were removed in 77 (55%) without complications. Follow-up occurred 6 and 12 months after bar removed, and the last follow-up was eventually planned at the end of growth (age 18). The pectus recurred in one patient with Marfan syndrome, and sternal protrusion occurred in one. Differences between groups were as follows: a significantly higher proportion of adult patients were treated with stabilizers (P < 0.001), and there were significantly more wound abscesses in adults (P < 0.001). The Nuss procedure is as effective for correcting pectus excavatum in adults as it is in children. However, in adults the bars tended to be less stable, and wound abscesses occurred more frequently.


Superoxide generation and granule enzyme release induced by ionophore A23187. Studies on the early events of neutrophil activation.
The responses of isolated human peripheral neutrophils to activation by the divalent cation ionophore A23187 (4 x 10(-8) M to 2 x 10(-5) M) were studied over the course of 15 min at 37 degrees C. Dose-dependent increases were noted in the following A23187-induced functions: (1) membrane depolarization, as assessed by a fluorescent cyanine dye, (2) altered membrane permeability to 22Na+ and 45Ca2+, (3) increased intracellular levels of cAMP, (4) O2-generation, and (5) granule enzyme release. Membrane depolarization and the cAMP response preceded the onset of O2- generation and exocytosis, which began after a latency period of approximately 30 sec. All five functions induced by 2 x 10(-5) M A23187 required approximately 1 mM Ca0 for optimal expression and declined substantially as Ca0 was reduced towards a nominal O mM. In contrast, the Na+ ionophore gramicidin D (0.1 to 10 microgram/ml) caused cell depolarization and increased 22Na+ ionophore gramicidin D (0.1 to 10 microgram/ml) caused cell depolarization and increased 22Na+ uptake but did not stimulate 45Ca2+ uptake, the cAMP response, O2- generation, or exocytosis of granule constituents. The observations dissociate membrane depolarization and altered Na+ permeability, on the one hand, from a Ca2+ influx, cAMP response, O2- release, and exocytosis on the other. These studies, then, are consistent with a hypothesis that a Ca2+ influx is required for the biologic expressions of cell activation.


Diagnostic value of chromogranin A in pancreatic neuroendocrine tumors depends on tumor size: A prospective observational study from a single institute.
Chromogranin A has recently been recommended as the most practical tumor marker in patients with pancreatic neuroendocrine tumors. However, the diagnostic effectiveness of circulating chromogranin A levels remains controversial. Here, we aimed to assess the clinical diagnostic value of plasma chromogranin A levels for pancreatic neuroendocrine tumors. Between June 2012 and June 2015, 110 consecutive patients with a suspected pancreatic neuroendocrine tumor were prospectively enrolled. We evaluated the diagnostic value of the chromogranin A assay for differentiating pancreatic neuroendocrine tumors from other tumors. The plasma chromogranin A levels in the pancreatic neuroendocrine tumor patients were examined according to various clinicopathologic factors. A total of 65 patients were diagnosed as having pancreatic neuroendocrine tumors, whereas 45 had other tumors. The median chromogranin A level in pancreatic neuroendocrine tumor cases was higher than that in cases of other tumors (pancreatic neuroendocrine tumors: 126.62 ng/mL, other tumors: 69.82 ng/mL). The sensitivity, specificity, and accuracy of the chromogranin A assay for pancreatic neuroendocrine tumor diagnosis were 49.2%, 77.8%, and 60.9%, respectively. The chromogranin A levels after operative resection were reduced or were confirmed as being within the normal range (78.9%) in most cases. Moreover, the chromogranin A level in pancreatic neuroendocrine tumors cases was correlated with tumor size based on comparisons with other tumors in the pancreas (P = .038). The sensitivity, specificity, and accuracy of the chromogranin A assay for large tumors were greater, at 64.3%, 100.0%, and 81.5%, respectively. In clinical settings, the identification of pancreatic neuroendocrine tumors is vital for the development of therapeutic strategies. In large pancreatic tumors, the measurement of chromogranin A levels is very useful for distinguishing pancreatic neuroendocrine tumors from other tumors in the pancreas.


Interaction between keratinocytes and fibroblasts cultured in vitro: morphology, morphometry and growth.
In order to elucidate the interactions between fibroblasts and keratinocytes co-cultured in vitro, the morphology and growth of rat keratinocytes cultured with and without a feeder layer were compared. Morphological analysis was coupled with a simple morphometric method of image analysis performed with a computer aided system to demonstrate statistically significant differences between keratinocyte cultures obtained with and without a feeder layer. Epidermal cells cultured without fibroblasts but with a conditioning medium showed a slower growth rate and significant a greater cellular dimensions in comparison with cells grown in the presence of a feeder layer. These results suggest that the conditioning medium induces a morphological change of keratinocytes. The electrophoretic patterns of proteins extracted from cells cultured with and without a feeder layer were identical, whereas densitometric analysis revealed that the quantitative expression of proteins was clearly different. These data confirm that of keratinocyte growth is dependent on fibroblasts or fibroblast products.


Intracellular Information Processing through Encoding and Decoding of Dynamic Signaling Features.
Cell signaling dynamics and transcriptional regulatory activities are variable within specific cell types responding to an identical stimulus. In addition to studying the network interactions, there is much interest in utilizing single cell scale data to elucidate the non-random aspects of the variability involved in cellular decision making. Previous studies have considered the information transfer between the signaling and transcriptional domains based on an instantaneous relationship between the molecular activities. These studies predict a limited binary on/off encoding mechanism which underestimates the complexity of biological information processing, and hence the utility of single cell resolution data. Here we pursue a novel strategy that reformulates the information transfer problem as involving dynamic features of signaling rather than molecular abundances. We pursue a computational approach to test if and how the transcriptional regulatory activity patterns can be informative of the temporal history of signaling. Our analysis reveals (1) the dynamic features of signaling that significantly alter transcriptional regulatory patterns (encoding), and (2) the temporal history of signaling that can be inferred from single cell scale snapshots of transcriptional activity (decoding). Immediate early gene expression patterns were informative of signaling peak retention kinetics, whereas transcription factor activity patterns were informative of activation and deactivation kinetics of signaling. Moreover, the information processing aspects varied across the network, with each component encoding a selective subset of the dynamic signaling features. We developed novel sensitivity and information transfer maps to unravel the dynamic multiplexing of signaling features at each of these network components. Unsupervised clustering of the maps revealed two groups that aligned with network motifs distinguished by transcriptional feedforward vs feedback interactions. Our new computational methodology impacts the single cell scale experiments by identifying downstream snapshot measures required for inferring specific dynamical features of upstream signals involved in the regulation of cellular responses.


Multi-domain features for reducing false positives in automated detection of clustered microcalcifications in digital breast tomosynthesis.
In digital breast tomosynthesis (DBT) imaging, a microcalcification (MC) cluster may span across different slices and blurring exists in the out-of-focus slices. We developed a radiomics approach to extract features from focus slice and combine multiple spatial domains to reduce false positives (FPs) in an automated pipeline of detecting MC clusters. We performed a retrospective study on a cohort of 290 Chinese women patients with a total of 580 DBT volumes. We developed an automated MC detection pipeline that consists of two stages: an initial detection to identify a set of MC candidates that may include many FPs, followed by a radiomics-based classification model to identify and reduce the FPs. We extract both two-dimensional (2D) and three-dimensional (3D) radiomics features from multiple spatial domains, including a focus slice, projection image, and tomographic volume. A linear discriminant classifier was used coupled with a sequential forward feature selection procedure. The free-response operating characteristics (FROC) curve and partial area under the FROC curve (pAUC) in the FP rate range of 0 to 2 per DBT volume were used to evaluate the model's performance. At a sensitivity of 90%, the FP rate was reduced from 1.3 to 0.2 per DBT volume after applying the multi-domain-based classification on the initial detections. The multi-domain yielded a significantly higher pAUC compared to the initial detection (increase of pAUC = 0.2278, P < 0.0001), focus slice (increase of pAUC = 0.0345, P = 0.0152), project image (increase of pAUC = 0.1043, P < 0.0001), and tomographic volume (increase of pAUC = 0.0791, P = 0.0032). The radiomic features extracted from the three domains may provide complementary information and their integration can significantly reduce FPs in automated detection of MCs in DBT volumes on a large Chinese women population.


Intra-operative protective mechanical ventilation in lung transplantation: a randomised, controlled trial.
Primary graft dysfunction occurs in up to 25% of patients after lung transplantation. Contributing factors include ventilator-induced lung injury, cardiopulmonary bypass, ischaemia-reperfusion injury and excessive fluid administration. We evaluated the feasibility, safety and efficacy of an open-lung protective ventilation strategy aimed at reducing ventilator-induced lung injury. We enrolled adult patients scheduled to undergo bilateral sequential lung transplantation, and randomly assigned them to either a control group (volume-controlled ventilation with 5 cmH2 O, positive end-expiratory pressure, low tidal volumes (two-lung ventilation 6 ml.kg-1 , one-lung ventilation 4 ml.kg-1 )) or an alveolar recruitment group (regular step-wise positive end-expiratory pressure-based alveolar recruitment manoeuvres, pressure-controlled ventilation set at 16 cmH2 O with 10 cmH2 O positive end-expiratory pressure). Ventilation strategies were commenced from reperfusion of the first lung allograft and continued for the duration of surgery. Regular PaO2 /FI O2 ratios were calculated and venous blood samples collected for inflammatory marker evaluation during the procedure and for the first 24 h of intensive care stay. The primary end-point was the PaO2 /FI O2 ratio at 24 h after first lung reperfusion. Thirty adult patients were studied. The primary outcome was not different between groups (mean (SD) PaO2 /FI O2 ratio control group 340 (111) vs. alveolar recruitment group 404 (153); adjusted p = 0.26). Patients in the control group had poorer mean (SD) PaO2 /FI O2 ratios at the end of the surgical procedure and a longer median (IQR [range]) time to tracheal extubation compared with the alveolar recruitment group (308 (144) vs. 402 (154) (p = 0.03) and 18 (10-27 [5-468]) h vs. 15 (11-36 [5-115]) h (p = 0.01), respectively). An open-lung protective ventilation strategy during surgery for lung transplantation is feasible, safe and achieves favourable ventilation parameters.


Recurrence of acute lymphoblastic leukemia manifesting as serous retinal detachments and optic disc swelling.
The aim of this case report is to describe a patient with acute lymphoblastic leukemia (ALL) who developed bilateral serous retinal detachments and unilateral optic disc swelling. A 23-year-old woman with ALL presented to the ophthalmology clinic with bilateral subacute visual loss. Ophthalmologic examination revealed bilateral serous retinal detachments and unilateral optic disc swelling. Magnetic resonance imaging for differential diagnosis was inconclusive; however, cerebrospinal fluid sampling demonstrated leukemic involvement of the central nervous system. The patient's vision improved and fundus findings resolved with the institution of systemic and intrathecal chemotherapy. Serous retinal detachment and optic disc swelling are unusual ocular manifestations of ALL. They may occur due to leukemic infiltration of ocular structures and may indicate extramedullary recurrence of the disease. Early recognition and treatment is crucial to improve prognosis.


Multiparametric Quantitative MRI for the Detection of IgA Nephropathy Using Tomoelastography, DWI, and BOLD Imaging.
The aim of this study was to noninvasively evaluate changes in renal stiffness, diffusion, and oxygenation in patients with chronic, advanced stage immunoglobulin A nephropathy (IgAN) by multiparametric magnetic resonance imaging using tomoelastography, diffusion-weighted imaging (DWI), and blood oxygen level-dependent (BOLD) imaging. In this prospective study, 32 subjects (16 patients with biopsy-proven IgAN and 16 age- and sex-matched healthy controls) underwent multifrequency magnetic resonance elastography with tomoelastography postprocessing at 4 frequencies from 40 to 70 Hz to generate shear wave speed (meter per second) maps reflecting tissue stiffness. In addition, DWI and BOLD imaging were performed to determine the apparent diffusion coefficient in square millimeter per second and T2* relaxation time in milliseconds, respectively. Regions including the entire renal parenchyma of both kidneys were analyzed. Areas under the receiver operating characteristic (AUCs) curve were calculated to test diagnostic performance. Clinical parameters such as estimated glomerular filtration rate and protein-to-creatinine ratio were determined and correlated with imaging findings. Success rates of tomoelastography, DWI, and BOLD imaging regarding both kidneys were 100%, 91%, and 87%, respectively. Shear wave speed was decreased in IgAN (-21%, P < 0.0001), accompanied by lower apparent diffusion coefficient values (-12%, P = 0.004). BOLD imaging was not sensitive to IgAN (P = 0.12). Tomoelastography detected IgAN with higher diagnostic accuracy than DWI (area under the curve = 0.9 vs 0.8) and positively correlated with estimated glomerular filtration rate (r = 0.66, P = 0.006). Chronic, advanced stage IgAN is associated with renal softening and restricted water diffusion. Tomoelastography is superior to DWI and BOLD imaging in detecting IgAN.


Ferulic acid inhibits 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis.
The aim of this study was to assess the chemopreventive efficacy of ferulic acid in 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis. We induced oral squamous cell carcinoma in the buccal pouch of male Syrian golden hamsters by painting with 0.5% DMBA in liquid paraffin three times a week for 14 weeks. The tumor incidence, tumor volume, and tumor burden that were formed in the hamster buccal pouch were determined. The activities of carcinogen detoxification agents and status of lipid peroxidation and antioxidants were also estimated by specific colorimetric methods. We observed 100% tumor formation in DMBA-painted animals. The status of carcinogen-detoxifying agents, lipid peroxidation, and antioxidants was significantly disrupted in DMBA-painted animals. Oral administration of ferulic acid at a dose of 40 mg/kg of body weight to DMBA-painted animals on days alternate to DMBA painting for 14 weeks significantly prevented the tumor incidence, tumor volume, and tumor burden. Ferulic acid exhibited potent anti-lipid peroxidative effects as well as the ability to modulate the status of carcinogen-detoxifying agents and antioxidants in DMBA-painted animals. Our results demonstrate that ferulic acid has potent chemopreventive and antioxidant functions in DMBA-induced hamster buccal pouch carcinogenesis.


CD8+ regulatory T cells generated by neonatal recognition of peripheral self-antigen.
In comparison with CD4+ regulatory T cells, the generation and function of immunomodulatory CD8+T cells is less well defined. Here we describe the existence of regulatory anti-Kb-specific CD8+ T cells that are rendered tolerant during neonatal life via antigen contact exclusively on keratinocytes. These regulatory T cells maintain tolerance during adulthood as they prevent Kb-specific graft rejection by naïve CD8+ T cells. Third-party immune responses remain unaffected. Up-regulation of TGF-beta1 and granzyme B in the regulatory CD8+ T cell population suggests the involvement of these molecules in common suppressive pathways shared with CD4+ regulatory T cells. In summary, CD8+ regulatory T cells can be induced extrathymically through antigen contact on neonatally accessible parenchymal cells and maintain tolerance throughout adult life.


Three-dimensional reconstruction of a vascular network by dynamic tracking of magnetite nanoparticles.
Visualization of small blood vessels feeding tumor sites provides important information on the tumors and their microenvironment. This information plays an important role in targeted drug therapies using magnetic gradients. However, capabilities of current clinical imaging modalities may be insufficient to resolve complex microvascular networks. The purpose of this study is to map the vascular network, 3D, based on the magnetic susceptibility contrast. Magnetic particles induce an inhomogeneity in the MRI's magnetic field in an order much larger than their real size. This is an approach to compensate the spatial resolution insufficiency of a clinical MR scanner. Micron-sized agglomerations of magnetite nanoparticles were injected in a 3D phantom vascular network, and a fast multislice, multiacquisition MR sequence was applied to track the agglomerations along their trajectories. The experiment was performed twice for two different imaging planes: coronal and transversal. The susceptibility artifact in the images indicated the presence and the position of the agglomerations. The calculated positions through multiple images were assembled to build up the 3D distribution of the vascular network. The calculated points were compared with the centerline of the channels, extracted from the 3D reference image, to determine the absolute measurement error. The mean error was measured to be approximately half of the pixel's size. It was found that the positioning error on the axis perpendicular to the imaging slice was nearly twice as high as on the imaging plane axes due to the slice thickness. In order to compensate for the lack of resolution on the perpendicular axis, the reconstruction was performed using a combination of coronal and transversal data. The combination of the coordinates led to a significant decrease in the mean measurement error at each segment in the vascular network (p < 0.001). A method for 3D reconstruction of a microvascular network based on the susceptibility contrast in MRI and using a clinical scanner and a commercial receiver coil was proposed. The method presents a novel approach for reconstruction of vascular networks using the susceptibility effect. The proposed method may be applied to resolve vascular networks at a micrometric scale.


Anti-oncogenic activity of Chibby in the development of human nasopharyngeal carcinoma.
The Wnt/β-catenin pathway serves important roles in cancer development. The expression and function of Chibby (Cby), as a direct antagonist of β-catenin, in nasopharyngeal carcinoma (NPC) has not been fully investigated. The present study revealed that the mRNA and protein expression of Cby was significantly lower in NPC tissue than in the adjacent normal tissue. Low expression of Cby was significantly associated with the tumor and the clinical staging. Furthermore, Cby overexpression inhibited the proliferation of human NPC SUNE1 cells and induced cell cycle arrest. In addition, Cby overexpression also significantly enhanced the susceptibility of SUNE1 cells to apoptosis. These results indicated that Cby might serve as an anti-oncogenic gene in the development of NPC and could represent a potential therapeutic target for the human NPC therapy.


Antiviral activity of telaprevir (VX-950) and peginterferon alfa-2a in patients with hepatitis C.
Telaprevir (VX-950), an inhibitor of the hepatitis C virus (HCV) NS3/4A protease, substantially decreased plasma HCV RNA levels in a prior clinical study. The present study evaluated viral kinetics and safety during dosing with telaprevir alone and in combination with peginterferon alfa-2a for 14 days. Previously untreated patients with genotype 1 hepatitis C were randomized to receive placebo and peginterferon alfa-2a (n = 4); telaprevir (n = 8); or telaprevir and peginterferon alfa-2a (n = 8). Telaprevir was given as 750 mg oral doses every 8 hours; peginterferon alfa-2a was given as weekly 180 mug subcutaneous injections. The median change in HCV RNA from baseline to day 15 was -1.09 log(10) (range, -2.08 to -0.46) in the placebo and peginterferon alfa-2a group; -3.99 log(10) (range, -5.28 to -1.26) in the telaprevir group, and -5.49 log(10) (range, -6.54 to -4.30) in the telaprevir and peginterferon alfa-2a group. Day 15 HCV RNA levels were undetectable in 4 patients who received telaprevir and peginterferon alfa-2a and in 1 patient who received telaprevir alone. No viral breakthrough occurred in patients who received telaprevir and peginterferon alfa-2a. The majority of adverse events were mild. There were no serious adverse events or premature discontinuations. Twelve weeks after starting off-study standard therapy, HCV RNA was undetectable in all 8 patients in the telaprevir and peginterferon alfa-2a group, 5 patients in the telaprevir group, and 1 patient in the placebo and peginterferon alfa-2a group. This study confirmed the substantial antiviral effects of telaprevir and showed an increased antiviral effect of telaprevir combined with peginterferon alfa-2a.


Fluorinated CYTOP passivation effects on the electrical reliability of multilayer MoS₂ field-effect transistors.
We demonstrated highly stable multilayer molybdenum disulfide (MoS2) field-effect transistors (FETs) with negligible hysteresis gap (ΔV(HYS) ∼ 0.15 V) via a multiple annealing scheme, followed by systematic investigation for long-term air stability with time (∼50 days) of MoS2 FETs with (or without) CYTOP encapsulation. The extracted lifetime of the device with CYTOP passivation in air was dramatically improved from 7 to 377 days, and even for the short-term bias stability, the experimental threshold voltage shift, outstandingly well-matched with the stretched exponential function, indicates that the device without passivation has approximately 25% larger the barrier distribution (ΔE(B) = k(B)T(o)) than that of a device with passivation. This work suggests that CYTOP encapsulation can be an efficient method to isolate external gas (O2 and H2O) effects on the electrical performance of FETs, especially with low-dimensional active materials like MoS2.


Experimental and theoretical investigations of a tunable dissipative soliton fiber laser.
A tunable dissipative soliton fiber laser based on carbon nanotubes and the nonlinear polarization rotation (NPR) technique has been investigated experimentally and numerically for the first time to the author's best knowledge. The laser proposed delivers strongly chirped solitons with pulse duration of ∼220 ps and a spectral width of ∼5.6 nm. With the NPR-related filtering effect, the output pulses are wavelength tunable over the range from 1566 to 1593 nm by adjusting the polarization controller (PC). Numerical results are in good agreement with experimental observations and clearly reveal that the tunable mode-locking operation is attributed to the variation of phase delay caused by the PCs.


Outcomes of single- vs two-stage primary joint arthroplasty for septic arthritis: a systematic review and meta-analysis.
Septic arthritis (SA) is an intra-articular infection caused by purulent bacteria and the only effective method is surgical intervention. Two-stage arthroplasty is considered the gold standard treatment for SA, but recent studies have found that single-stage arthroplasty can achieve the same efficacy as two-stage arthroplasty. This study aimed to compare the efficacy of single- vs two-stage arthroplasty in the treatment of (acute or quiescent) SA. The review process was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched the PubMed, EMBASE, Medline, and Cochrane Library databases to identify all literature on the treatment of SA using single- and two-stage arthroplasty from the date of database inception to November 10, 2022. Data on reinfection rates were expressed as odds ratios and 95% CIs. Seven retrospective studies with a total of 413 patients were included. Pooled analysis showed no difference in the reinfection rate between single- and two-stage arthroplasty. Subgroup analysis found no difference between the single- and two-stage arthroplasty groups in the incidence of purulent infection of the hip and knee. Cumulative meta-analysis showed gradual stabilization of outcomes. Based on our meta-analysis of available retrospective studies, we found no significant difference in reinfection rates between single- and two-stage arthroplasty for SA. Further prospective cohort studies are needed to confirm our results, although our meta-analysis provides important insights into the current literature on this topic.


Redox signaling modulates Rho activity and tissue contractility in the Caenorhabditis elegans spermatheca.
Actomyosin-based contractility in smooth muscle and nonmuscle cells is regulated by signaling through the small GTPase Rho and by calcium-activated pathways. We use the myoepithelial cells of the Caenorhabditis elegans spermatheca to study the mechanisms of coordinated myosin activation in vivo. Here, we show that redox signaling modulates RHO-1/Rho activity in this contractile tissue. Exogenously added as well as endogenously generated hydrogen peroxide decreases spermathecal contractility by inhibition of RHO-1, which depends on a conserved cysteine in its nucleotide binding site (C20). Further, we identify an endogenous gradient of H2O2 across the spermathecal tissue, which depends on the activity of cytosolic superoxide dismutase, SOD-1. Collectively, we show that SOD-1-mediated H2O2 production regulates the redox environment and fine tunes Rho activity across the spermatheca through oxidation of RHO-1 C20.


[Similarities and differences of myocardial metabolic characteristics between HFpEF and HFrEF mice based on LC-MS/MS metabolomics].
Objective: To reveal the similarities and differences in myocardial metabolic characteristics between heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) mice using metabolomics. Methods: The experimental mice were divided into 4 groups, including control, HFpEF, sham and HFrEF groups (10 mice in each group). High fat diet and Nω-nitroarginine methyl ester hydrochloride (L-NAME) were applied to construct a"two-hit"HFpEF mouse model. Transverse aortic constriction (TAC) surgery was used to construct the HFrEF mouse model. The differential expression of metabolites in the myocardium of HFpEF and HFrEF mice was detected by untargeted metabolomics (UHPLC-QE-MS). Variable importance in projection>1 and P<0.05 were used as criteria to screen and classify the differentially expressed metabolites between the mice models. KEGG functional enrichment and pathway impact analysis demonstrated significantly altered metabolic pathways in both HFpEF and HFrEF mice. Results: One hundred and nine differentially expressed metabolites were detected in HFpEF mice, and 270 differentially expressed metabolites were detected in HFrEF mice. Compared with the control group, the most significantly changed metabolite in HFpEF mice was glycerophospholipids, while HFrEF mice presented with the largest proportion of carboxylic acids and their derivatives. KEGG enrichment and pathway impact analysis showed that the differentially expressed metabolites in HFpEF mice were mainly enriched in pathways such as biosynthesis of unsaturated fatty acids, ether lipid metabolism, amino sugar and nucleotide sugar metabolism, glycerophospholipid metabolism, arachidonic acid metabolism and arginine and proline metabolism. The differentially expressed metabolites in HFrEF mice were mainly enriched in arginine and proline metabolism, glycine, serine and threonine metabolism, pantothenate and CoA biosynthesis, glycerophospholipid metabolism, nicotinate and nicotinamide metabolism and arachidonic acid metabolism, etc. Conclusions: HFpEF mice have a significantly different myocardial metabolite expression profile compared with HFrEF mice. In addition, biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, glycerophospholipid metabolism and arginine and proline metabolism are significantly altered in both HFpEF and HFrEF mice, suggesting that these metabolic pathways may play an important role in disease progression in both types of heart failure.


Ophthalmologic findings in fifteen patients with Wolfram syndrome.
To look for ophthalmologic abnormalities in 15 patients with Wolfram syndrome, also known as DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, optic atrophy and deafness). Fifteen patients from four inbred families diagnosed as having Wolfram syndrome at the National Center for Diabetes, Endocrinology and Genetics, in Amman, Jordan, were evaluated ophthalmologically. Their examination included best-corrected visual acuity, color vision testing, pupillary light reflexes, slit-lamp biomicroscopy and fundus examination. Fundus fluorescein angiography was done in all patients. The prevalence of optic atrophy was (93.3%), colordefect (92.9%), cataract (66.6%), pigmentary retinopathy (30%) and diabetic retinopathy (20%). Abnormal pupillary light reflexes and nystagmus were also reported. Although ourgroup of patients was genetically heterogeneous, the ophthalmic findings are consistent with those reported in other series, except for cataract which was highly prevalent but mild and did not contribute significantly to loss of vision.


Biogas Cook Stoves for Healthy and Sustainable Diets? A Case Study in Southern India.
Alternative cook stoves that replace solid fuels with cleaner energy sources, such as biogas, are gaining popularity in low-income settings across Asia, Africa, and South America. Published research on these technologies focuses on their potential to reduce indoor air pollution and improve respiratory health. Effects on other cooking-related aspects, such as diets and women's time management, are less understood. In this study, in southern India, we investigate if using biogas cook stoves alters household diets and women's time management. We compare treatment households who are supplied with a biogas cook stove with comparison households who do not have access to these stoves, while controlling for several socio-economic factors. We find that diets of treatment households are more diverse than diets of comparison households. In addition, women from treatment households spend on average 40 min less cooking and 70 min less collecting firewood per day than women in comparison households. This study illustrates that alongside known benefits for respiratory health, using alternative cook stoves may benefit household diets and free up women's time. To inform development investments and ensure these co-benefits, we argue that multiple dimensions of sustainability should be considered in evaluating the impact of alternative cook stoves.


Broad-spectrum physical fitness benefits of recreational football: a systematic review and meta-analysis.
A previous meta-analysis showed that maximal oxygen uptake increased by 3.51 mL/kg/min (95% CI 3.07 to 4.15) during a recreational football programme of 3-6 months in comparison with continuous moderate-intensity running, strength training or a passive control group. In addition, narrative reviews have demonstrated beneficial effects of recreational football on physical fitness and health status. The purpose of this systematic review and meta-analysis was to evaluate the magnitude of effects of recreational football on blood pressure, body composition, lipid profile and muscular fitness with reference to age, gender and health status. Systematic review and meta-analysis. MEDLINE, PubMed, SPORTDiscus, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Google Scholar were searched prior to 1 February 2017. In addition, Google Scholar alerts were set up in January 2012 to identify potential papers with the following key terms: recreational football, recreational soccer, street football and street soccer. Randomised and matched controlled trials with participants allocated to a recreational football group or any other type of exercises or passive control group were included. Training programmes had to last at least 2 weeks to meet the inclusion criteria. The primary outcome measures were blood pressure, resting heart rate, body composition, muscular fitness, and blood lipids and glucose tolerance. A total of 31 papers met the inclusion criteria and were included. The effect of recreational football on systolic blood pressure (SBP) versus no-exercise controls was most likely extremely largely beneficial (effect size (ES)=4.20 mm Hg; 95% CI 1.87 to 6.53). In addition, a most likely very large beneficial (ES=3.89 mm Hg; 95% CI 2.33 to 5.44) effect was observed for diastolic blood pressure (DBP), when compared with non-active groups. Furthermore, a most likely extremely large beneficial effect was shown for SBP and DBP in participants with mild hypertension (11 and 7 mm Hg decrease, respectively) and participants with prehypertension (10 and 7 mm Hg decrease, respectively). Meta-analysis of recreational football determined the impact on resting heart rate as most likely extremely largely beneficial (ES=6.03 beats/min; 95% CI 4.43 to 7.64) when compared with non-active groups. The observed recreational football effect on fat mass was most likely largely beneficial (ES=1.72 kg; 95% CI 0.86 to 2.58) and the effect on countermovement jump (CMJ) performance was most likely very largely beneficial (ES=2.27 cm; 95% CI 1.29 to 3.25) when compared with non-active groups. Possibly beneficial decreases were found in low-density lipoprotein levels (ES=0.21 mmol/L; 95% CI 0.06 to 0.36). Possibly largely beneficial effect was observed for DBP in comparison with continuous running training. Small harmful and unclear results were noted for SBP, fat and lean body mass, body mass index, as well as muscular fitness when compared with running and Zumba training. The present meta-analysis demonstrated multiple broad-spectrum benefits of recreational football on health-related physical fitness compared with no-exercise controls, including improvements in blood pressure, resting heart rate, fat mass, low-density lipoprotein cholesterol and CMJ performance. Additionally, recreational football is efficient and effective as Zumba and continuous running exercise regimens with highlighted social, motivational and competitive components.


Reconstructing the neuromuscular ground pattern of phylactolaemate bryozoans: new data from the Lophopodidae.
The solely freshwater inhabiting Phylactolaemata is a sister taxon to all other bryozoans. Among phylactolaemates, Lophopodidae represents an early branching clade that is therefore crucial for ground pattern reconstruction. While more recent morphological data of most phylactolaemate families are present, data of lophopodids are scarce. The genus Asajirella especially, which was previously assigned to the family Pectinatellidae, lacks any detailed analysis with more recent morphological methods. This study provides the first morphological analyses of three lophopodid species using serial-sectioning histology and 3D reconstruction, but also immunocytochemical stainings and confocal laserscanning microscopy. There are several lophopodid-specific traits in the nervous system such as the large ganglion with extensive lumen and two prominent protrusions referred to as epistomial horns. The epistome in all lophopodids is rather small and dome-shaped. Contrary to previous reports, we can confirm that duplicature bands insert at the tentacle sheath rather than the diaphragmatic sphincter in all phylactolaemates. The morphology of the digestive tract of lophopodids is identical to other phylactolaemates and possesses exclusively circular muscles. Altogether, this study fills significant gaps in our knowledge on phylactolaemate neuromuscular systems and general morphology. It shows that the insertion of the duplicature bands at the tentacle sheath and the circular musculature of the digestive tract to be the ground pattern in phylactolaemates. In addition, we found apomorphic characters for lophopodids such as the dome-shaped epistome with its musculature and the voluminous ganglion with its epistomial horns, which aid in defining and delineating the family.


Retracted: Multilevel Predictors of Math Classroom Climate: A Comparison Study of Student and Teacher Perceptions.
The above article, published online on June 23, 2014 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor-in-Chief, Nancy Guerra, and Wiley Periodicals, Inc. The retraction has been agreed upon following the discovery that this article contained inaccurate data. It came to the author's attention that the names of some of the items reported in the Measures section of the paper could not be correct because such items did not exist in the surveys. The authors tried to identify exactly which items had been used in the data analyses but they could not establish without some doubt exactly which items had actually been used. Reference Wang, M.-T. and Eccles, J. S. (2014), Multilevel Predictors of Math Classroom Climate: A Comparison Study of Student and Teacher Perceptions. Journal of Research on Adolescence. doi: 10.1111/jora.12153.


Expression of the sigmaF-directed csfB locus prevents premature appearance of sigmaG activity during sporulation of Bacillus subtilis.
During sporulation, sigma(G) becomes active in the prespore upon the completion of engulfment. We show that the inactivation of the sigma(F)-directed csfB locus resulted in premature activation of sigma(G). CsfB exerted control distinct from but overlapping with that exerted by LonA to prevent inappropriate sigma(G) activation. The artificial induction of csfB severely compromised spore formation.


Uptake and effectiveness of a community pharmacy intervention programme to improve asthma management.
Pharmacists frequently see patients with asthma in the community who have suboptimal management. This study aimed to compare the uptake and effectiveness of pharmacist-initiated mailed and face-to-face interventions for patients whose asthma may not be well managed. Seventy-one community pharmacies in South Australia, Tasmania and Victoria (Australia) installed a software application that data-mined dispensing records, generating a list of patients who had received six or more asthma reliever inhalers in the preceding 12 months. The pharmacists were randomized, by pharmacy, to perform either a mailed or face-to-face intervention, whereby these patients received educational material and a referral to their general practitioner (GP) for an asthma management review. Matching patients from each pharmacy were also randomly assigned to a control group for 'usual care'. A total of 1483 patients were identified and grouped as follows: 510 (34·4%) mailed intervention, 480 (32·4%) face-to-face intervention and 493 (33·2%) controls. Significantly fewer face-to-face interventions were offered than mailed interventions (66·6% vs. 89·4%, respectively; χ(2) = 64·2, P < 0·0001). There were significant improvements in the preventer-to-reliever ratio after the intervention period (P < 0·0001) in each group. In a per-protocol analysis, the magnitude of improvement in the face-to-face intervention group was greater than in the mailed intervention group. The reverse was true in an intention-to-treat analysis. The improvement in the P : R ratios was mainly due to significant decreases in reliever usage. Community pharmacy dispensing records can effectively identify patients with suboptimal asthma management, who can then be referred to their GP for review. Time constraints in busy pharmacies may limit the uptake and effectiveness of face-to-face interventions in the 'real world' setting, making mailed interventions an attractive option.


Roles of 12-Lipoxygenase and Its Interaction with Angiotensin II on p21 and p27 Expression in Diabetic Nephropathy.
12-Lipoxygenase (12-LO) and angiotensin II (Ang II) are involved in the development of diabetic renal hypertrophy, in which cyclin-kinase inhibitors, p21 and p27 play pivotal roles. Here, we study the effects of 12-LO and its interaction with Ang II on glomerular p21 and p27 expression in diabetic conditions. Models used in the current study include glomerular mesangial cells (MCs); and glomeruli from (1) type 2 diabetic db/db mice; (2) type 2 diabetic rats induced by high-fat diet feeding followed by streptozotocin injection; (3) 12-LO knockout (12-LOKO) mice; and (4) normal rats infused with Ang II or 12(S)-hydroxyeicosatetraenoic acid (12[S]-HETE, arachidonic acid metabolite of 12-LO). The protein expression levels of p21 and p27 were increased in high glucose-stimulated MCs and in glomeruli isolated from db/db mice. In type 2 diabetic rats, cinnamyl-3,4-dihydroxy-α-cynanocinnamate (inhibitor of 12-LO) attenuated the increases in glomerular p21 and p27 protein expression, while in normal rats, 12(S)-HETE injection increased glomerular p21 and p27 expression. 12(S)-HETE and Ang II were mutually stimulated in glomeruli. Glomerular p21 and p27 expression were decreased in 12-LOKO mice compared to levels in control mice, and Ang II stimulation increased the protein expression of p27 in control but not 12-LOKO mice. Ang II stimulation had no effect on p21 protein expression in 12-LOKO mice. 12-LO is involved in diabetic renal hypertrophy via the induction of p21 and p27 protein expression and interacts with Ang II to induce p27 upregulation in diabetes. The current results suggest a potential amplifying loop in the pathogenesis of diabetic nephropathy.


Tobacco Industry Promotional Strategies Targeting American Indians/Alaska Natives and Exploiting Tribal Sovereignty.
American Indians/Alaska Natives have the highest commercial tobacco use in the United States, resulting in higher tobacco-caused deaths and diseases than the general population. Some American Indians/Alaska Natives use commercial tobacco for ceremonial as well as recreational uses. Because federally recognized Tribal lands are sovereign, they are not subject to state cigarette taxes and smoke-free laws. This study analyzes tobacco industry promotional efforts specifically targeting American Indians/Alaska Natives and exploiting Tribal lands to understand appropriate policy responses in light of American Indians'/Alaska Natives' unique sovereign status and culture. We analyzed previously secret tobacco industry documents available at the Truth Tobacco Documents Library (https://industrydocuments.library.ucsf.edu/tobacco/). Tobacco companies used promotional strategies targeting American Indians/Alaska Natives and exploiting Tribal lands that leveraged the federally recognized Tribes' unique sovereign status exempting them from state cigarette taxes and smoke-free laws, and exploited some Tribes' existing traditional uses of ceremonial tobacco and poverty. Tactics included price reductions, coupons, giveaways, gaming promotions, charitable contributions, and sponsorships. In addition, tobacco companies built alliances with Tribal leaders to help improve their corporate image, advance ineffective Youth Smoking Prevention programs, and defeat tobacco control policies. The industry's promotional tactics likely contribute to disparities in smoking prevalence and smoking-related diseases among American Indians//Alaska Natives. Proven policy interventions to address these disparities including tobacco price increases, cigarette taxes, comprehensive smoke-free laws, and industry denormalization campaigns to reduce smoking prevalence and smoking-related disease could be considered by Tribal communities. The sovereign status of federally recognized Tribes does not prevent them from adopting these measures. American Indians/Alaska Natives suffer disparities in smoking prevalence and smoking-related diseases as compared with other groups. The tobacco industry has used promotional tactics including price reductions, coupons and giveaways, casino and bingo promotions, charitable contributions and sponsorships, and so-called Youth Smoking Prevention (YSP) programs to specifically target American Indians/Alaska Natives and exploit Tribal sovereignty, which likely contribute to disparities in tobacco use and related diseases and deaths among this population. Tribal and public health policy makers should consider rejecting ineffective YSP programs and instead consider adopting proven policy interventions including tobacco price increases, cigarette and casino taxes, comprehensive smokefree laws, and anti-industry denormalization campaigns to reduce smoking and smoking-related disease.


A poison education program for primary school.
A program with which to teach children in grades 1 and 2 to identify poisons and hazard symbols, to learn where poisons should be stored and to recognize a poisoning and contact a poison control center in the event of a poisoning was developed. Each objective was taught in one 30-minute lesson by the children's school teachers. Evaluation of the approximately 400 children who received the program by pre- and post-tests demonstrated that they learned to identify poisons, to recognize hazard symbols and the telephone number of the local poison control center. The children were also asked to identify their source of knowledge about poisons and cited parents, television and school as their most important sources.


Endotoxin stimulates arginine transport in pulmonary artery endothelial cells.
The pulmonary endothelium plays an important role in the metabolism of the amino acid arginine, the exclusive precursor molecule for nitric oxide (NO). Despite decreased circulating arginine levels, endothelial NO production is elevated during endotoxemia. However, the regulation of pulmonary artery endothelial arginine transport has not been studied. We hypothesized that endotoxin stimulates carrier-mediated arginine transport by the pulmonary endothelium. The relative contributions of the various transport systems to total arginine transport by porcine pulmonary artery endothelial cells (PAECs) was determined by assaying the uptake of 3H-L-arginine in the presence or absence of Na+. PAECs were then incubated with various concentrations of Escherichia coli endotoxin, and y(+)-mediated arginine transport was measured at different time points thereafter. Kinetic studies were performed over a range of arginine concentrations to determine changes in transport affinity and maximum rate of metabolism. To address the role of RNA and protein synthesis in the increased transport, uptake was measured after exposure of cells to the transcriptional inhibitor actinomycin D and the protein synthesis inhibitor cycloheximide. Most (75%) of arginine transport by PAECs was mediated by the high-affinity Na(+)-independent transport system y+. Endotoxin stimulated y(+)-mediated arginine transport by PAECs twofold to fivefold, a response that was time and dose dependent. The accelerated transport was detectable within 2 hours and maximal at 12 hours. Kinetic studies revealed that the accelerated arginine transport was the result of a 68% increase in the maximal transport velocity (1519 +/- 65 pmol/mg protein/30 sec in endotoxin-treated cells vs 903 +/- 96 in control cells; p < 0.01) without a change in transport affinity. The endotoxin-mediated increase in arginine uptake was abrogated by actinomycin D and cycloheximide. Endotoxin stimulates Na(+)-independent arginine transport by PAECs through a process that requires de novo RNA and protein synthesis, possibly of the transporter itself. This response may be designed to support arginine-dependent biosynthetic pathways in the lung during septic states.


Effect of TLR4/MyD88 signaling pathway on sepsis-associated acute respiratory distress syndrome in rats, via regulation of macrophage activation and inflammatory response.
The present study aimed to investigate the effects of the Toll-like receptor (TLR)4/myeloid differentiation primary response (MyD)88 signaling pathway on sepsis-associated acute respiratory distress syndrome (ARDS) in rats, and the involvement of macrophage activation and the inflammatory response. A total of 36 specific pathogen-free male Sprague-Dawley rats were selected to establish the rat model of sepsis-associated ARDS using cecal ligation and puncture (CLP). Rats were assigned into the Ab (anti-TLR4 monoclonal antibody)-CLP, CLP and Sham groups. Arterial partial pressure of oxygen (PaO2) was detected using blood gas analysis. Bronchoalveolar lavage fluid (BALF) and alveolar macrophages were collected. The pathological structure of lung tissue was observed following hematoxylin-eosin staining. The ultrastructural alterations of alveolar epithelial cells were observed under transmission electron microscope. The ratios of wet/dry weight of lung tissue and total protein content in BALF were measured. The concentration of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in BALF and peripheral blood was determined by enzyme-linked immunosorbent assay. The TLR4, TLR9, MyD88 and nuclear factor (NF)-κΒ mRNA and protein expression levels in alveolar macrophages were measured by reverse transcription-quantitative polymerase chain reaction and western blotting. Compared with the Sham group, the rats in the CLP group demonstrated significantly increased respiratory frequency, lung permeability, lung edema, inflammatory infiltration, TNF-α and IL-1β expression levels in BALF and peripheral blood and TLR4, TLR9, MyD88 and NF-κΒ expression levels in macrophages, however decreased arterial PaO2. Following pretreatment with anti-TLR4 monoclonal antibody, rats exhibited decreased lung injury, inflammatory infiltration, lung edema, TNF-α and IL-1β expressions in BALF and peripheral blood, and TLR4, TLR9, MyD88 and NF-κΒ expression levels in macrophages, with increased arterial PaO2. These results suggested that the inhibition of TLR4/MyD88 signaling pathway may relieve sepsis-associated ARDS in rats through regulating macrophage activation and the inflammatory response.


Tempering Proactive Cognitive Control by Transcranial Direct Current Stimulation of the Right (but Not the Left) Lateral Prefrontal Cortex.
Behavioral and neuroimaging data support the distinction of two different modes of cognitive control: proactive, which involves the active and sustained maintenance of task-relevant information to bias behavior in accordance with internal goals; and reactive, which entails the detection and resolution of interference at the time it occurs. Both control modes may be flexibly deployed depending on a variety of conditions (i.e., age, brain alterations, motivational factors, prior experience). Critically, and in line with specific predictions derived from the dual mechanisms of control account (Braver, 2012), findings from neuroimaging studies indicate that the same lateral prefrontal regions (i.e., left dorsolateral cortex and right inferior frontal junction) may implement different control modes on the basis of temporal dynamics of activity, which would be modulated in response to external or internal conditions. In the present study, we aimed to explore whether transcraneal direct current stimulation over either the left dorsolateral prefrontal cortex or the right inferior frontal junction would differentially modulate performance on the AX-CPT, a well-validated task that provides sensitive and reliable behavioral indices of proactive/reactive control. The study comprised six conditions of real stimulation [3 (site: left dorsolateral, right dorsolateral and right inferior frontal junction) × 2 (polarity: anodal and cathodal)], and one sham condition. The reference electrode was always placed extracephalically. Performance on the AX-CPT was assessed through two blocks of trials. The first block took place while stimulation was being delivered, whereas the second block was administered after stimulation completion. The results indicate that both offline cathodal stimulation of the right dorsolateral prefrontal cortex and online anodal stimulation of the right inferior frontal junction led participants to be much less proactive, with such a dissociation suggesting that both prefrontal regions differentially contribute to the adjustment of cognitive control modes. tDCS of the left-DLPFC failed to modulate cognitive control. These results partially support the predictions derived from the dual mechanisms of control account.


The safety and efficacy of chemotherapy combined with immunotherapy for pancreatic cancer: A meta-analysis.
Since the combination of chemotherapy and immunotherapy, such as new molecular targeted drugs or vaccines, is controversial in terms of survival advantages compared with chemotherapy therapy alone, we conducted a meta-analysis to compare the efficacy and safety of immunotherapy combined with chemotherapy and chemotherapy alone for advanced pancreatic cancer. We searched PubMed, Embase, and Cochrane Library from the establishment of the database to November 2020. We included some studies that reported pancreatic cancer patients receiving immunotherapy, and we excluded duplicate publications, research without full text, incomplete information or inability to conduct data extraction, animal experiments, reviews, and systematic reviews. The risk ratio of the objective response rate and disease control rate was 1.10 (95% confidence interval [CI]: 0.88-1.38) and 1.17 (95% CI: 1.06-1.31), respectively, indicating that there was no significant difference between the objective response rate of combination therapy and chemotherapy alone, while the disease control rate of the combined treatment was higher than that of chemotherapy alone. The hazard ratio of overall survival and progression-free survival was 0.91 (95% CI: 0.82-1.01) and 0.87 (95% CI: 0.77-0.98), respectively, indicating that there was no significant difference between the overall survival of combination therapy and chemotherapy alone, while progression-free survival of the combined treatment was longer than that of chemotherapy alone. We also found that in addition to the combination treatment, the incidence of vomiting in pancreatic cancer was higher than that of chemotherapy alone, and the incidence of other complications was not significantly different from that of treatment alone. Chemotherapy combined with immunotherapy for pancreatic cancer not only improves treatment efficiency but also does not cause serious adverse reactions. This treatment strategy should be widely used clinically.


Interface relaxation in electrophoretic deposition of polymer chains: effects of segmental dynamics, molecular weight, and field.
Using different segmental dynamics and relaxation, characteristics of the interface growth is examined in an electrophoretic deposition of polymer chains on a three (2+1)-dimensional discrete lattice with a Monte Carlo simulation. Incorporation of faster modes such as crankshaft and reptation movements along with the relatively slow kink-jump dynamics seems crucial in relaxing the interface width. As the continuously released polymer chains are driven (via segmental movements) and deposited, the interface width W grows with the number of time steps t, W proportional, variant t(beta), (beta approximately 0.4-0.8), which is followed by its saturation to a steady-state value W(s). Stopping the release of additional chains after saturation while continuing the segmental movements relaxes the saturated width to an equilibrium value (W(s)-->W(r)). Scaling of the relaxed interface width W(r) with the driving field E, W(r) proportional, variant E(-1/2) remains similar to that of the steady-state W(s) width. In contrast to monotonic increase of the steady-state width W(s), the relaxed interface width W(r) is found to decay (possibly as a stretched exponential) with the molecular weight.