Analysis of the technical efficiency of the forms of hospital management based on public-private collaboration of the Madrid Health Service, as compared with traditional management.
The study aims to carry out a comparative analysis of the technical efficiency of hospital management based on public-private collaboration, as compared with traditional management. Specifically, we compare traditionally managed public hospitals, public hospitals managed by a private finance initiative (PFI), public hospitals managed through a public-private partnership (PPP), and hospitals managed through other forms of management, during the period 2009 to 2014, in the hospitals dependent on the Madrid Health Service (SERMAS). The study covers all publicly owned general hospitals under SERMAS, consisting of seven PFI hospitals, three PPP hospitals, 11 traditionally managed public hospitals (with the category of general hospital), and four hospitals managed through other forms of hospital management. The technical efficiency indices of the hospitals were calculated using the data envelopment analysis technique. Subsequently, a sensitivity analysis was performed by bootstrapping and variation of model variables to verify their impact on efficiency. Finally, an analysis of the evolution of efficiency in the analyzed period was carried out using the Malmquist Index. In all the analysis models carried out in the analyzed period, the hospitals managed based on public-private collaboration were more efficient than the hospitals under traditional management. The greater efficiency of hospitals managed based on public-private collaboration, as compared with traditional management, could be attributed to greater organizational and management flexibility.


Fixed-time stability of dynamical systems and fixed-time synchronization of coupled discontinuous neural networks.
In this paper, the fixed-time stability of dynamical systems and the fixed-time synchronization of coupled discontinuous neural networks are investigated under the framework of Filippov solution. Firstly, by means of reduction to absurdity, a theorem of fixed-time stability is established and a high-precision estimation of the settling-time is given. It is shown by theoretic proof that the estimation bound of the settling time given in this paper is less conservative and more accurate compared with the classical results. Besides, as an important application, the fixed-time synchronization of coupled neural networks with discontinuous activation functions is proposed. By designing a discontinuous control law and using the theory of differential inclusions, some new criteria are derived to ensure the fixed-time synchronization of the addressed coupled networks. Finally, two numerical examples are provided to show the effectiveness and validity of the theoretical results.


First-referral presentations of patients with benign paroxysmal positional vertigo who were negative on positional testing and who lacked nystagmus.
The aim of the present study was to explore the demographic, clinical, and pathogenetic features; and treatment outcomes of patients with benign paroxysmal positional vertigo (BPPV) who were negative upon positional testing at their first referral. A total of 133 patients presented with histories of BPPV but were negative, in our hands, upon positional testing. Patients were told to cease taking vestibular suppressant medication (if any) and were to return for re-examination when positional vertigo symptoms recurred. If BPPV was diagnosed, the appropriate repositioning maneuver was applied and patients were re-examined weekly until the characteristic nystagmus and vertigo disappeared. Follow-up was performed 1 week, 4 weeks, 3 months, 6 months, and 1 year after diagnosis. The 133 patients were compared with a group of 250 patients with typical BPPV. Sixty-five of the 133 patients (termed the n-BPPV group) were subsequently identified with typical BPPV. Such diagnoses were made within 10 days of the first referral in 37 (56.9%) cases. Patients of the n-BPPV group had a longer duration of the last episode of vertigo than did others (39.7 ± 38.4 vs. 26.1 ± 36.7 days, p < 0.001), and a higher proportion used vestibular suppressant medication prior to first referral (75.4 vs. 54.8%, p = 0.003). The n-BPPV and typical BPPV patients responded similarly to treatment and exhibited similar recurrence rates. BPPV patients who were negative upon positional testing at first referral were quite common, accounting for 26% of all typical BPPV patients. No significant difference in either treatment outcome or recurrence rate was evident between n-BPPV and typical BPPV positions. Positional vertigo and nystagmus are not always present as BPPV progresses.


[Amino acid bioconversion in the feed for broilers under different breeding rates].
Two experiments were carried out under productional conditions with a total of 69 520 broiler birds (four-line hybrids, crosses of White Plymouth Rock x Cornish ) --one in the spring and one in the summer. The birds were grown in a poultry house at density of 16.6 per sq. m. of floor area and in cage at the rate of 23.6 per sq. m. (an enclosure on the same premise). On another premise the birds were kept at 23.6 and 16.6 per sq. m., respectively. Every 15 days the amino acids and the protein were determined in the white meat, and each feed batch was checked as regards its crude protein and amino acid content. It was found that the bioconversion of the amino acids of the feed into amino acids of the white meat was acted upon by a constellation of biotic and abiotic ecologic factors. Dicisive was the effect of the biotic factors. It is stated that the present approach to optimize only the elements of the microclimate at higher rates of broiler raising is insufficient. It is necessary to study the biotic ecologic factors in detail as the base of optimization of the homotypic and heterotypic reactions.


Hypoglycemia in type 2 diabetes: current controversies and changing practices.
Hypoglycemia is well-recognized to limit the degree of glycemic control possible for many individuals for diabetes. Although the likelihood of hypoglycemia increases as A1c levels decrease in type 1 diabetes, insulin-treated type 2 diabetic persons with higher A1c appear paradoxically to have more hypoglycemia which may explain, in part, the adverse outcome reported in the ACCORD study. Approaches to glucose-lowering that cause lesser degrees of risk for hypoglycemia, technologies to better ascertain hypoglycemic events, and better understanding of patient characteristics associated with greater likelihood of hypoglycemia will all be required to reduce this limiting factor in optimizing glycemic treatment.


Different Design Feature Combinations of Flatfoot Orthosis on Plantar Fascia Strain and Plantar Pressure: A Muscle-Driven Finite Element Analysis With Taguchi Method.
Customized foot orthosis is commonly used to modify foot posture and relieve foot pain for adult acquired flexible flatfoot. However, systematic investigation of the influence of foot orthotic design parameter combination on the internal foot mechanics remains scarce. This study aimed to investigate the biomechanical effects of different combinations of foot orthoses design features through a muscle-driven flatfoot finite element model. A flatfoot-orthosis finite element model was constructed by considering the three-dimensional geometry of plantar fascia. The plantar fascia model accounted for the interaction with the bulk soft tissue. The Taguchi approach was adopted to analyze the significance of four design factors combination (arch support height, medial posting inclination, heel cup height, and material stiffness). Predicted plantar pressure and plantar fascia strains in different design combinations at the midstance instant were reported. The results indicated that the foot orthosis with higher arch support (45.7%) and medial inclination angle (25.5%) effectively reduced peak plantar pressure. For the proximal plantar fascia strain, arch support (41.8%) and material stiffness (37%) were strong influencing factors. Specifically, higher arch support and softer material decreased the peak plantar fascia strain. The plantar pressure and plantar fascia loading were sensitive to the arch support feature. The proposed statistics-based finite element flatfoot model could assist the insole optimization and evaluation for individuals with flatfoot.


Hypertension in pregnancy: An unresectable mediastinal pheochromocytoma.
Hypertension is a relatively common occurrence during pregnancy, which usually has a benign course with an excellent prognosis. However, physicians caring for pregnant women should have a high index of suspicion for underlying medical conditions that could lead to a more perilous outcome. Herein, we present the case of a pregnant woman who was found to have uncontrollable hypertension late in her pregnancy, secondary to a mediastinal pheochromocytoma, which was deemed unresectable at the time of exploration after her delivery.


Crosslinking EEG time-frequency decomposition and fMRI in error monitoring.
Recent studies implicate a common response monitoring system, being active during erroneous and correct responses. Converging evidence from time-frequency decompositions of the response-related ERP revealed that evoked theta activity at fronto-central electrode positions differentiates correct from erroneous responses in simple tasks, but also in more complex tasks. However, up to now it is unclear how different electrophysiological parameters of error processing, especially at the level of neural oscillations are related, or predictive for BOLD signal changes reflecting error processing at a functional-neuroanatomical level. The present study aims to provide crosslinks between time domain information, time-frequency information, MRI BOLD signal and behavioral parameters in a task examining error monitoring due to mistakes in a mental rotation task. The results show that BOLD signal changes reflecting error processing on a functional-neuroanatomical level are best predicted by evoked oscillations in the theta frequency band. Although the fMRI results in this study account for an involvement of the anterior cingulate cortex, middle frontal gyrus, and the Insula in error processing, the correlation of evoked oscillations and BOLD signal was restricted to a coupling of evoked theta and anterior cingulate cortex BOLD activity. The current results indicate that although there is a distributed functional-neuroanatomical network mediating error processing, only distinct parts of this network seem to modulate electrophysiological properties of error monitoring.


[Urinary alanineaminopeptidase with reference to age and sex].
In 200 healthy test persons of either sex between 15 and 94 years the excretion of the alanine aminopeptidase (EC 220.127.116.11) and of creatinine with the urine was tested. Female test persons excrete smaller quantities of enzymes with the urine than male ones. In the two sexes the efflux of the alanine aminopeptidase only slightly increases with growing age. With regard of the enzyme activities to the creatinine in the urine the curve of excretion is clearly deformed, since in the senium significantly smaller quantities of creatinine are excreted. When an enzyme/creatinine quotient is used reference values specific to age must be used.


Metastatic Differentiated Thyroid Cancer Survival Is Unaffected by Mode of Preparation for 131I Administration.
Recombinant human thyrotropin (rhTSH) is currently not Food and Drug Administration approved for the treatment of high-risk patients with differentiated thyroid cancer (DTC). The goal of our study was to compare the outcomes in higher-risk patients with metastatic DTC prepared for radioiodine (RAI) therapy with rhTSH vs thyroid hormone withdrawal (THW). A retrospective chart review was performed of patients with metastatic DTC in follow-up at MedStar Washington Hospital Center and MedStar Georgetown University Hospital from 2009 to 2017. Patients were divided according to their preparation for RAI therapy, with assessment of progression-free survival (PFS) and overall survival (OS). Fifty-five patients with distant metastases (16 men, 39 women) were prepared for RAI therapy exclusively either with rhTSH (n = 27) or with THW (n = 28). There were no statistically significant differences between the groups regarding clinicopathological features and history of RAI therapies. The median follow-up time for patients with rhTSH-aided therapies was 4.2 years (range, 3.3-5.5 years) and for patients with THW-aided therapies was 6.8 years (range, 4.2-11.6 years) (P = .002). Multivariate analysis showed that the method of thyrotropin stimulation was not associated with a difference in PFS or OS. As has been shown previously for low-risk DTC, this study indicates that the mode of preparation for RAI therapy does not appear to influence the outcomes of patients with metastatic DTC. PFS and OS were similar for patients with THW-aided or rhTSH-aided RAI therapies.


LSRN: A PARALLEL ITERATIVE SOLVER FOR STRONGLY OVER- OR UNDERDETERMINED SYSTEMS.
We describe a parallel iterative least squares solver named LSRN that is based on random normal projection. LSRN computes the min-length solution to min x∈ℝ n ‖Ax - b‖2, where A ∈ ℝ m × n with m ≫ n or m ≪ n, and where A may be rank-deficient. Tikhonov regularization may also be included. Since A is involved only in matrix-matrix and matrix-vector multiplications, it can be a dense or sparse matrix or a linear operator, and LSRN automatically speeds up when A is sparse or a fast linear operator. The preconditioning phase consists of a random normal projection, which is embarrassingly parallel, and a singular value decomposition of size ⌈γ min(m, n)⌉ × min(m, n), where γ is moderately larger than 1, e.g., γ = 2. We prove that the preconditioned system is well-conditioned, with a strong concentration result on the extreme singular values, and hence that the number of iterations is fully predictable when we apply LSQR or the Chebyshev semi-iterative method. As we demonstrate, the Chebyshev method is particularly efficient for solving large problems on clusters with high communication cost. Numerical results show that on a shared-memory machine, LSRN is very competitive with LAPACK's DGELSD and a fast randomized least squares solver called Blendenpik on large dense problems, and it outperforms the least squares solver from SuiteSparseQR on sparse problems without sparsity patterns that can be exploited to reduce fill-in. Further experiments show that LSRN scales well on an Amazon Elastic Compute Cloud cluster.


Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.
Rolandic epilepsy (RE) is the most common focal epilepsy in childhood. To date no hypothesis-free exome-wide mutational screen has been conducted for RE and atypical RE (ARE). Here we report on whole-exome sequencing of 194 unrelated patients with RE/ARE and 567 ethnically matched population controls. We identified an exome-wide significantly enriched burden for deleterious and loss-of-function variants only for the established RE/ARE gene GRIN2A. The statistical significance of the enrichment disappeared after removing ARE patients. For several disease-related gene-sets, an odds ratio >1 was detected for loss-of-function variants.


Subdural hemorrhage secondary to extramedullary hematopoiesis in postpolycythemic myeloid metaplasia.
A 64-year-old woman with a 20-year history of polycythemia vera and a 2-month history of postpolycythemic myeloid metaplasia ( PPMM ) became comatose because of bilateral subdural hematomas. Biopsy of the dura mater at operation demonstrated extramedullary hematopoiesis ( EMH ). The subdural hemorrhage was secondary to dural invasion by hematopoietic tissue and vascular dilation with a predisposing element of thrombocytopenia. This is the second case of central nervous system (CNS) EMH in a case of polycythemia vera. Only 8 cases of symptomatic CNS EMH and 16 cases overall have been reported, and these were primarily due to agnogenic myeloid metaplasia. Symptoms were secondary to the mass effect of dural tumor-like hematopoietic tissue or to an elevated cerebrospinal fluid protein content. The survival after a diagnosis of PPMM with CNS EMH has been less than 6 months in all cases. CNS EMH is an unusual and a potentially critical complication of polycythemia vera that should be considered in the evaluation of the patient with polycythemia vera and myeloid metaplasia.


Effects of pregnancy on the febrile responses in sheep.
Pyrogens were injected into unshorn pregnant and non-pregnant Soay and Clun Forest sheep and the effects on rectal temperature and thermoregulatory mechanisms monitored. Plasma concentrations of unconjugated oestrogens, progesterone and cortisol were measured in the sheep tested in late pregnancy. The effect of pyrogens was also examined in ovariectomized ewes treated with oestrogen and with oestrogen plus progesterone. In contrast to reports of work on shorn sheep all sheep developed a fever even when close to term but the increase in peripheral vasomotor tone normally induced by pyrogens was attenuated in the pregnant Clun Forest ewes. The hormone-treated ovariectomized animals developed normal fevers and provided little indication of a possible relation between peripheral levels of ovarian steroids and the degree of fever. The question of whether an endogenous antipyretic substance is present in pregnant sheep is discussed.


Myosin isoform expression and force generation in cultured resistance arteries.
Organ culture of mesenteric resistance arteries results in a loss of force-generating ability, which is prevented by 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3]. We have tested the hypothesis that the culture-induced decrease in active stress is associated with altered myosin isoform expression. Rat mesenteric resistance arteries were studied immediately (fresh) or after incubation at 37 degrees C for 48 h in culture medium (control), with 300 pg/ml 1,25(OH)2D3, or with 5 microg/ml insulin. Isometric force was measured by myography; myosin heavy chain (MHC) and regulatory myosin light chain isoform (MLC) contents were determined using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Maximal active stress to 100 mM K+ (mN/mm2) was greater for fresh (147.8 +/- 4.9) than control (109.2 +/- 4.6, P = 0.001) or insulin (79.6 +/- 8.6, P < 0.001) but not 1,25(OH)2D3 (137.4 +/- 9.5, P = 0.197). Organ culture did not alter MLC or MHC smooth muscle (SM)-1 isoform content. MHC SM-2 content (nmol/mg protein) was greater in fresh (0.038 +/- 0.003) than control (0.026 +/- 0.003, P = 0.012) and insulin (0.027 +/- 0.002, P = 0.018) but not 1,25(OH)2D3 (0.036 +/- 0.003, P = 0.693); nonmuscle MHC (NMM) was observed in insulin. The maximal active stress response to K+ significantly correlated with SM-2 MHC isoform content (r2 = 0.483, P < 0.001). We conclude that 1) arterial organ culture alters MHC isoform content, 2) SM-2 MHC isoform content positively correlates with active stress generation, 3) 1,25(OH)2D3 maintains force-generating capacity by preventing the shift of MHC isoform expression, and 4) insulin impairs force-generating ability by lowering MHC SM-2 content and stimulating NMM expression.


Assessment of sol-gel derived iron oxide substituted 45S5 bioglass-ceramics for biomedical applications.
Magnetic bioactive glass-ceramic (MGC) powders with nominal compositions of (45 - x)SiO224.5CaO24.5Na2O6P2O5xFe2O3 (x = 2, 4, 6, 8, 10, and 15 wt%) have been synthesized by a sol-gel route by systematically substituting silicon dioxide with iron oxide in Hench's 45S5 glass composition. Powder X-ray diffraction studies revealed a variation in the percentage of combeite (Ca2Na2Si3O9), magnetite (Fe3O4), and hematite (Fe2O3) nanocrystalline phases in MGC powders as a function of composition. Zeta potential measurements showed that MGC containing up to 10 wt% iron oxide formed stable suspensions. The saturation magnetization and heat generation capacity of MGC fluids increased with an increase in iron oxide content. Degradation of MGC powders was investigated in phosphate buffered saline (PBS). The in vitro bioactivity of the MGC powders taken in pellet form was confirmed by observing the pH variation as well as hydroxyapatite layer (HAp) formation upon soaking in modified simulated body fluid. These studies showed a decrement in the overall bioactivity in samples with high iron oxide content due to the proportional decrease in the silanol group. Monitoring the proliferation of MG-63 osteoblast cells in Dulbecco's Modified Eagle Medium (DMEM) revealed that MGC with up to 10 wt% iron oxide exhibited acceptable viability. The systematic study revealed that the MGC with 10 wt% iron oxide exhibited optimal cell viability, magnetic properties and induction heating capacity, which were better than those of FluidMag-CT, which is used for hyperthermia treatment.


Chronic hepatitis B virus monoinfection at a university hospital in Zambia.
To characterize antiviral therapy eligibility among hepatitis B virus (HBV)-infected adults at a university hospital in Zambia. Hepatitis B surface antigen-positive adults (n = 160) who were HIV-negative and referred to the hospital after a routine or clinically-driven HBV test were enrolled. Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), platelet count, hepatitis B e-antigen, and HBV DNA were measured. Liver fibrosis/cirrhosis was assessed by physical examination, AST-to-platelet ratio index, and transient elastography. In antiviral therapy-naïve individuals, we described HBV stages and antiviral therapy eligibility per World Health Organization (WHO) and by HBV test (routine vs clinical). Elevated ALT was > 19 in women and > 30 U/L in men. Among treatment-experienced individuals, we described medication side effects, adherence, and viral suppression. The median age was 33 years, 71.9% were men, and 30.9% were diagnosed with HBV through a clinically-driven test with the remainder identified via routine testing (at the blood bank, community events, etc.). Among 120 treatment-naïve individuals, 2.5% were categorized as immune tolerant, 11.7% were immune active, 35.6% were inactive carriers, and 46.7% had an indeterminate phenotype. Per WHO guidelines, 13 (10.8%) were eligible for immediate antiviral therapy. The odds of eligibility were eight times higher for those diagnosed at clinical vs routine settings (adjusted odds ratio, 8.33; 95%CI: 2.26-29.41). Among 40 treatment-experienced HBV patients, virtually all took tenofovir, and a history of mild side effects was reported in 20%. Though reported adherence was good, 12 of 29 (41.4%) had HBV DNA > 20 IU/mL. Approximately one in ten HBV-monoinfected Zambians were eligible for antivirals. Many had indeterminate phenotype and needed clinical follow-up.


Visual analog scales in formats other than a 10 centimeter horizontal line to assess pain and other clinical data.
To analyze visual analog scales (VAS) for pain and patient global estimate on a Multidimensional Health Assessment Questionnaire (MDHAQ) in formats other than a traditional 10 cm horizontal line, designed to facilitate scoring on MDHAQ in usual clinical care. The MDHAQ with VAS for pain and global estimate was completed by each patient at each visit. VAS formats other than a traditional (unnumbered) 10 cm horizontal line based on 21 circles at 0.5 intervals were analyzed. Formats included unnumbered, symbol at the 11th circle, numbers and/or squares (instead of circles) at selected intermittent scores, and numbers at each circle. Analyses were performed to study the time to score MDHAQ with different VAS formats, possible "clustering" of responses in any format, particularly with intermittent numbers and/or symbols, and test-retest reliability of various formats. The median time to score MDHAQ with a 10 cm line VAS was 15.6 seconds, compared to 7.4 seconds for the 21 numbered circle VAS. No other format was scored in fewer seconds. Clustering was seen for scores of VAS formats with intermittent numbers or symbols, which rendered them unsuitable for use. No clustering was seen for the 21 numbered circle VAS format, for which test-retest agreement was significant, and similar to the 10 cm line VAS format. A 21 numbered circle VAS may be a desirable alternative to a 10 cm horizontal line, yielding similar results and requiring less than half the time to score.


Intubation of inoperable tumours of the oesophagogastric junction.
When obstruction occurs in inoperable tumours of the oesophago-cardiac region, intubation with an endoprosthesis is an important palliative measure. Although the endoscopic placing of a prosthesis is preferable, inoperability can often only by established at laparotomy. In this event a Celestin, Mousseau-Barbin or Häring tube can be introduced. The problems surrounding these surgical procedures are discussed on the basis of 42 patients with an average age of 66 1/2 years. There was an operative mortality of 28%. Thirty patients were discharged. The desired palliation was nearly always achieved. The average survival rate was 11 weeks. One patient lived for 80 weeks. The most important postoperative complication of the discharged patients was wound infection. Adequate antibiotic prophylaxis can diminish the complication rate.


The use of cytochemical procedures in the diagnosis and management of acute and chronic myeloid leukemia.
The use of Wright-Giemsa-stained smears alone for the classification of acute leukemias often proves unsatisfactory. Some cases of M1, M5a, M7, and L2 are morphologically similar. In such cases, cytochemical stains can provide an inexpensive and available diagnostic tool. M1 is positive for SBB and MPO. M5a is usually NSE positive, whereas SBB and MPO are negative. M7 usually is ANA esterase, PAS, and AP reactive, and do not stain with SBB, MPO, and ANB esterases. The megakaryocytic lineage usually is confirmed by ultrastructural cytochemistry for PPO or immunocytochemistry for platelet glycoproteins and von Willebrand factor. PAS block positivity and AP dotlike reactivity are suggestive of lymphoid lineage. NSE stains are useful in differentiating M2 from M4. Morphologic and cytochemical techniques also can suggest the presence of certain chromosomal abnormalities such as t(8;21) and inv(16), which may have an influence on prognosis. Because not all cases of acute leukemia are easily subtyped by morphology and cytochemistry, immunophenotyping, karyotyping, and molecular analysis of DNA and RNA of leukemia cells also may be required to define cell lineage.


Animal models in the pathogenesis and treatment of rabies.
Various animal models have been developed for the study of the pathogenesis of rabies and of methods for halting its spread. The long incubation period and the relatively low mortality observed in human rabies can be mimicked by injecting mice in the footpad with rabies virus. To relate the immune response and efficacy of treatment to the situation in humans, however, it is necessary to corroborate the results in rodents with those in subhuman primates. Methods effective and safe in subhuman primates may be considered for use in humans.


[Busulfan and cycosporin in bone graft children].
Most drugs exhibit both inter- and intra-individual pharmacokinetic and pharmacodynamic variability. This variability explains the different responses observed in patients exposed to standard doses and must be taken into consideration when the therapeutic window is narrow. Population pharmacokinetics provides mean (or median) values of pharmacokinetic parameters as well as the distribution pattern and the statistical relationship with covariables in a group of individuals presenting common characteristics. Among the different methods developed for population pharmacokinetics, the data pool method, as well as the two-step and one-step methods (NONMEM and NPEM) are attractive. Population models can then be developed using bayesian logistics to obtain an estimation of the pharmacokinetic parameters of a given patient and predict the most adapted dose in light of the therapeutic target (residual serum concentration, mean concentration.). Busulfan is an alkylizing agent used instead of radiotherapy for pre-graft preparation before bone marrow grafts in children. This compound requires dose monitoring because of its narrow therapeutic window: under-dosing raises the risk of graft rejection; inversely over-dosing can cause potentially fatal complications such as occlusive venous disease. Interindividual variability is characteristic of busulfan kinetics. Several factors can explain part of this variability: age, underlying disease, changes in liver function, drug bioavailability, chronobiology. The short treatments used (most protocols have 16 doses given in four days) require rapid monitoring to propose effective adjustments. In this context, use of bayesian logistics to estimate the patient's pharmokinetic parameters is very useful for correct dosing. This type of monitoring could also be used for other compounds such as cyclosporine, with a narrow therapeutic window.


Intratumor CpG-oligodeoxynucleotide injection induces protective antitumor T cell immunity.
Tumor cells are typically poorly immunogenic. The same mechanisms that evolved to avoid the induction of immune responses against self tissues, and, hence, autoimmune disease, also have to be overcome for immune therapy of cancer. Toll-like receptor-activating microbial products such as CpG motif containing DNA are among the primary stimuli that the immune system uses to distinguish between infectious nonself (that is to be attacked) and noninfectious self (that must not be attacked). We tested in a murine RMA lymphoma/C57BL/6 model whether providing the infectious nonself context in a tumor-by injecting CpG-oligodeoxynucleotides directly into the tumor-would elicit a protective antitumor response. Complete remission of established solid tumors was achieved in immune competent mice, but not in T cell/B cell-deficient RAG-1 knockout mice. Intratumor injection of CpG-oligodeoxynucleotides was shown to induce a tumor-specific CD4(+) and CD8(+) T cell response of the type 1 effector class, and T cells adoptively transferred the protection to RAG-1 knockout mice. The data show that intratumor injection of CpG-oligodeoxynucleotides is a promising strategy for rendering tumors immunogenic.


Heterogeneity of mesenchymal stromal cells in lymphoproliferative disorders.
Accumulating evidence indicates that bone marrow microenvironment plays an important role in the pathogenesis of some myeloid and lymphoid hematological malignancies (HM). Among different environmental associated parameters, those related to functional, cytogenetic and immunological integrity of mesenchymal stromal cells (MSC) are particularly relevant. Functional alterations and immunophenotypic abnormalities have been described in MSC obtained from HM patients. These data seem to confirm the defective biological pattern of MSC especially in myeloid diseases, while MSC cytogenetic profile in HM is still an open question, because it is not clear whether BM stromal cells are "culprit or bystander" displaying or not an abnormal karyotype. Contradictory findings were reported in different HM but the functional implications of altered MSC karyotype need to be further addressed also in light of a clinical use of MSC. A "pathological" in vivo supportive function of endogenous MSC, which provide important survival and drug resistance signals to leukemic cells especially in lymphoproliferative disorders, is suggested. Thus, the mechanisms underlying these protective versus cytotoxic effects exerted by MSC on leukemic cells need further investigations.


Taurolithocholic acid-3 sulfate induces CD95 trafficking and apoptosis in a c-Jun N-terminal kinase-dependent manner.
Prevention of bile acid-induced apoptosis is of therapeutic interest and requires the understanding of underlying mechanisms. The effect of tauroursodeoxycholate (TUDC) on taurolithocholic acid-3 sulfate (TLCS)-induced apoptosis was studied in cultured rat hepatocytes. TLCS induced activation of caspases 8, 9, and 3 and hepatocyte apoptosis. These effects were abolished by TUDC in a PI 3-kinase-/protein kinase B (PKB)-, p38(MAPK)-, and extracellular signal-regulated kinase-2 (Erk-2)-independent manner. These protein kinases were activated by both TLCS and TUDC, however, with different kinetics. TLCS, but not TUDC, led to a sustained activation of c-Jun N-terminal kinase (JNK) and CD95 trafficking to the plasma membrane; both TLCS effects were prevented by TUDC. Inhibition of JNK1 or protein kinase C prevented TLCS-induced CD95 membrane trafficking and blunted the apoptotic response. The apoptotic potency of other bile acids paralleled their ability to induce sustained JNK activation. Protection by TUDC against TLCS-induced apoptosis starts upstream of caspase 8 activation and is independent of a PI 3-kinase-dependent survival pathway. JNK activation may be important for bile acid-induced apoptosis by triggering ligand-independent CD95 surface trafficking and activation of apoptosis.


Epidermal changes following application of 7,12-dimethylbenz(a)anthracene and 12-O-tetradecanoylphorbol-13-acetate to human skin transplanted to nude mice studied with histological species markers.
Effects of the tumor initiator 7,12-dimethylbenz(a)anthracene (DMBA) and of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) on epidermis of human fetal and adult skin were studied in the nude mouse/human skin model. Human skin grafts on NC nude mice were exposed to two topical applications of 1 mg of DMBA in 50 microliter of acetone with an interval of 3 days and/or to applications of 10 micrograms of TPA in 50 microliter of acetone twice weekly. In some animals, it was attempted to augment the susceptibility of the grafts to the tumor-initiating effect of DMBA by pretreatment with TPA or ultraviolet light. The mice were sacrificed 8-32 wk after the initial treatment. Tumors did not appear in the central portions of any of the grafts, but epidermal tumors were seen at the graft border in 34.9% of the DMBA-treated animals. To identify human epidermis on the grafts and to determine the species origin of the induced tumors, two independently working histological marker methods were applied. (a) The first is detection of a human Blood Group B-like antigen present in mouse epidermis and in chemically induced murine epidermal tumors. This antigen cannot be demonstrated in human epidermis and in epidermal tumors of human patients. (b) The second is histological staining with the DNA-specific fluorochrome, bisbenzimide, displaying a characteristic pattern of 5-10 intranuclear fluorescent bodies in murine nonneoplastic epidermal cells and in murine epidermal tumor cells. Such a pattern is not seen in human epidermis and in epidermal tumors of human patients. The studies showed that TPA treatment resulted in epidermal hyperplasia in both the human epidermis and the adjacent mouse epidermis and that the induced tumors were derived from murine tissue. The mechanisms behind the DMBA action in the nude mouse/human skin model are discussed, and suggestions for future carcinogenesis studies on the model are given.


Binding of 99Tcm sulphur colloid to blood components: implications in renal transplant rejection.
The percentage binding of 99Tcm sulphur colloid to blood components (formed elements and plasma proteins) was studied within 1 min of the intravenous injection of the radiopharmaceutical in humans as well as rats. In humans, 68% of the total blood counts were bound to the formed elements (erythrocytes, leucocytes and platelets). The binding pattern (as percentage of plasma counts) among the plasma protein fractions in humans was as follows: albumin, 9.85 +/- 2.06; fibrinogen, 56.70 +/- 7.96; and total proteins, 66.55 +/- 7.32. Activity bound to fibrinogen represented 82.3 +/- 9.1% of the total protein-bound activity in humans. In rats as well fibrinogen was the predominant binding protein (73.8 +/- 5.6). The significant binding of the 99Tcm sulphur colloid to plasma fibrinogen and formed elements of blood may be one of the reasons for the uptake of this radiocolloid in renal transplants before rejection.


A theoretical model of dentinogenesis: dentin and dentinal tubule formation.
Dentinogenesis, odontoblast dentin formation, includes dentinal growth, mineralization and dentinal tubule formation. Odontoblasts synthesize collagen resulting in collagen apposition contributing to dentinogenesis. Furthermore, within the tubule, they express non-collagenous proteins, such as dentin phosphoprotein (DPP), associated with hydroxyapatite crystal formation and growth. The aim of this work was to determine patterns of growth and dentin formation and quantification of its mineralization. Findings from our work are relevant to endodontics for future regenerative treatment. We formulated a 3D domain mathematical model, which recreates the events that lead to dentinal tubule mineralization. As reference we used collagen apposition and DPP activity. We obtained a model depicting predentin's mineralization distribution during dentin development. Furthermore, we verified different DPP diffusion coefficients to test the model's sensitivity. We present a model to shed light on the process of dentin and dentinal tubule formation, and its relation to diffusion and mineralization processes.


Ischemic preconditioning in rat heart: no correlation between glycogen content and return of function.
We tested the hypothesis that glycogen levels at the beginning of ischemia affect lactate production during ischemia and postischemic contractile function. Isolated working rat hearts were perfused at physiological workload with bicarbonate buffer containing glucose (10 mmol/L). Hearts were subjected to four different preconditioning protocols, and cardiac function was assessed on reperfusion. Ischemic preconditioning was induced by either one cycle of 5 min ischemia followed by 5, 10, or 20 min of reperfusion (PC5/5, PC5/10, PC5/20), or three cycles of 5 min ischemia followed by 5 min of reperfusion (PC3 x 5/5). All hearts were subjected to 15 min total, global ischemia, followed by 30 min of reperfusion. We measured lactate release, timed the return of aortic flow, compared postischemic to preischemic power, and determined tissue metabolites at selected time points. Compared with preischemic function, cardiac power during reperfusion improved in groups PC5/10 and PC5/20, but was not different from control in groups PC5/5 and PC3 x 5/5. There was no correlation between preischemic glycogen levels and recovery of function during reperfusion. There was also no correlation between glycogen breakdown (or resynthesis) and recovery of function. Lactate accumulation during ischemia was lowest in group PC5/20 and highest in the group with three cycles of preconditioning (PC3 x 5/5). Lactate release during reperfusion was significantly higher in the groups with low recovery of power than in the groups with high recovery of power. In glucose-perfused rat heart recovery of function is independent from both pre- and postischemic myocardial glycogen content over a wide range of glycogen levels. The ability to utilize lactate during reperfusion is an indicator for postischemic return of contractile function.


The interchangeability of global positioning system and semiautomated video-based performance data during elite soccer match play.
In elite-level soccer, player motion characteristics are commonly generated from match play and training situations using semiautomated video analysis systems and global positioning system (GPS) technology, respectively. Before such data are used collectively to quantify global player load, it is necessary to understand both the level of agreement and direction of bias between the systems so that specific interventions can be made based on the reported results. The aim of this report was to compare data derived from both systems for physical match performances. Six elite-level soccer players were analyzed during a competitive match using semiautomated video analysis (ProZone® [PZ]) and GPS (MinimaxX) simultaneously. Total distances (TDs), high speed running (HSR), very high speed running (VHSR), sprinting distance (SPR), and high-intensity running distance (HIR; >4.0 m·s(-1)) were reported in 15-minute match periods. The GPS reported higher values than PZ did for TD (GPS: 1,755.4 ± 245.4 m; PZ: 1,631.3 ± 239.5 m; p < 0.05); PZ reported higher values for SPR and HIR than GPS did (SPR: PZ, 34.1 ± 24.0 m; GPS: 20.3 ± 15.8 m; HIR: PZ, 368.1 ± 129.8 m; GPS: 317.0 ± 92.5 m; p < 0.05). Caution should be exercised when using match-load (PZ) and training-load (GPS) data interchangeably.


Prenatal and early life diesel exhaust exposure disrupts cortical lamina organization: Evidence for a reelin-related pathogenic pathway induced by interleukin-6.
Several epidemiological studies have shown associations between developmental exposure to traffic-related air pollution and increased risk for autism spectrum disorders (ASD), a spectrum of neurodevelopmental disorders with increasing prevalence rate in the United States. Though animal studies have provided support for these associations, little is known regarding possible underlying mechanisms. In a previous study we found that exposure of C57BL/6J mice of both sexes to environmentally relevant levels (250-300 µg/m3) of diesel exhaust (DE) from embryonic day 0 to postnatal day 21 (E0 to PND21) caused significant changes in all three characteristic behavioral domains of ASD in the offspring. In the present study we investigated a potential mechanistic pathway that may be of relevance for ASD-like changes associated with developmental DE exposure. Using the same DE exposure protocol (250-300 µg/m3 DE from E0 to PND21) several molecular markers were examined in the brains of male and female mice at PND3, 21, and 60. Exposure to DE as above increased levels of interleukin-6 (IL-6) in placenta and in neonatal brain. The JAK2/STAT3 pathway, a target for IL-6, was activated by STAT3 phosphorylation, and the expression of DNA methyltransferase 1 (DNMT1), a STAT3 target gene, was increased in DE-exposed neonatal brain. DNMT1 has been reported to down-regulate expression of reelin (RELN), an extracellular matrix glycoprotein important in regulating the processes of neuronal migration. RELN is considered an important modulator for ASD, since there are several polymorphisms in this gene linked to the disease, and since lower levels of RELN have been reported in brains of ASD patients. We observed decreased RELN expression in brains of the DE-exposed mice at PND3. Since disorganized patches in the prefrontal cortex have been reported in ASD patients and disrupted cortical organization has been found in RELN-deficient mice, we also assessed cortical organization, by labeling cells expressing the lamina-specific-markers RELN and calretinin. In DE-exposed mice we found increased cell density in deeper cortex (lamina layers VI-IV) for cells expressing either RELN or calretinin. These findings demonstrate that developmental DE exposure is associated with subtle disorganization of the cerebral cortex at PND60, and suggest a pathway involving IL-6, STAT3, and DNMT1 leading to downregulation of RELN expression that could be contributing to this long-lasting disruption in cortical laminar organization.


Breast reduction for the older woman.
Breast reduction surgeries are being performed more regularly in older women, ages 65 and older, although the procedure has historically been undertaken in younger patients. If careful assessment determines that the older woman is suitable for this surgery, breast reduction can be as successful and satisfying for her as in a younger woman. Preoperative, intraoperative, and postoperative care provided should be based upon individual needs, no matter what the age of the patient. The purpose of this paper is to focus on the breast reduction experience for the older woman.


Croatian mayflies (Insecta, Ephemeroptera): species diversity and distribution patterns.
Knowledge of the mayfly biodiversity in the Balkan Peninsula is still far from complete. Compared to the neighbouring countries, the mayfly fauna in Croatia is very poorly known. Situated at the crossroads of central and Mediterranean Europe and the Balkan Peninsula, Croatia is divided into two ecoregions: Dinaric western Balkan and Pannonian lowland. Mayflies were sampled between 2003 and 2013 at 171 sites, and a total of 66 species was recorded. Combined with the literature data, the Croatian mayfly fauna reached a total of 79 taxa. Of these, 29 species were recorded for the first time in Croatia while 15 species were not previously recorded in Dinaric western Balkan ecoregion. Based on the mayfly assemblage, sampling sites were first structured by ecoregion and then by habitat type. In comparison with the surrounding countries, the Croatian mayfly fauna is the most similar to the Hungarian and Bosnian fauna. Some morphologically interesting taxa such as Baetis cf. nubecularis Eaton, 1898 and Rhithrogena from the diaphana group were recorded. Ephemera cf. parnassiana Demoulin, 1958, the species previously recorded only from Greece, was also recorded.


Role of Anti-inflammatory Interventions in Coronary Artery Disease: Understanding the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS).
Coronary artery disease (CAD) is the leading cause of death worldwide. Despite notable advances in understanding the nature of atherosclerotic processes and the use of effective medications such as statins, there remains a significant residual risk. Even after optimal medical treatments and precise revascularisations, the recurrence of MI remains at approximately one-third for 5 years after an acute coronary syndrome (ACS). Over the past two decades, compelling data from animal and human studies has clearly identified atherosclerosis as an inflammatory disease of the arterial wall, but clinical applications related to this accumulated knowledge are still scarce. Recently, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) has provided convincing evidence that an anti-inflammatory intervention with the monoclonal antibody canakinumab reduces cardiovascular events in well-treated CAD patients without affecting LDL cholesterol levels. This article presents a brief description of the role of inflammation in atherogenesis and examines selected anti-inflammatory interventions and their potential use in CAD-affected individuals.


Safety-catch approach to orthogonal synthesis of a triazine library.
A novel safety-catch method for orthogonal synthesis of highly pure trisubstituted triazines was developed. Since the polymer-support used in this method is not acid-labile, this strategy can be uniquely applied to the synthesis of acid-sensitive triazine library compounds. This method will dramatically increase the diversity of triazine and other related heterocyclic library compounds.


Gender ambiguity in an elderly man.
To describe the case of an elderly patient with ambiguous genitalia. We report the clinical features of a 72-year-old man with ambiguous genitalia, discuss the possible etiologic factors, and examine the consequences of this diagnosis being determined at such a late stage in life. During surgical hemicolectomy for colon cancer in a 72-year-old man with a past history of hypospadias and hypogonadism, routine exploration of the abdomen and pelvis resulted in the discovery and removal of a large, asymptomatic mass, which was identified by the surgical pathologist as "normal ovaries, adnexa, and uterus." The patient's karyotype was subsequently found to be 46,XX. The diagnosis of ambiguous genitalia in an elderly patient is uncommon. This dilemma poses additional ethical concerns for the physician, related to balancing the obligation to preserve patient autonomy with the obligation to protect patients from potential psychologic harm as a result of such an unusual diagnosis.


Practice patterns of pulmonologists and family physicians for occupational asthma.
The longer the duration of symptoms of occupational asthma (OA) before diagnosis, the poorer the outcome. Physicians can play a key role in the early recognition of occupational lung diseases (OLDs), including OA. Our objective was to document and compare the practice patterns, barriers, and needs for early diagnosis of OA among pulmonologists and family physicians. Based on information from the literature and interviews with pulmonologists and family physicians, a survey was developed to obtain information on practice patterns. The survey was sent to all pulmonologists and a random sample of 600 family physicians in Ontario. Eight percent of pulmonologists and 7% of family physicians report seeing >20 patients a year with OLD. The majority report taking a workplace exposure history. The most commonly stated barrier to obtaining a workplace exposure history was time constraints. Main reasons for referral to specialists for diagnosis include personal lack of expertise, testing facilities, and knowledge about workers' compensation, while lack of timely access to specialists is a barrier for referral. While most physicians identified a need for further education, those who did not identify a need for further occupational respiratory education cited low volume of patients, access to specialists, and time constraints as reasons for not wanting further education. Opportunities are identified to improve health services delivery and educational initiatives for OA, with approaches tailored to each particular physician group.


Different risk factors for bleeding and discontinuation between dabigatran and rivaroxaban.
It is unclear whether risk factors for bleeding and discontinuation are different between dabigatran and rivaroxaban. We enrolled consecutive patients with atrial fibrillation who received dabigatran or rivaroxaban, had a CHADS2 score >1 and creatinine clearance >30ml/min. During this period, only dabigatran and rivaroxaban were available as non-vitamin K oral anticoagulants (NOACs) in our hospital. We compared the clinical and demographic data and the incidence of bleeding for one year between dabigatran group and rivaroxaban group. As a result, the dabigatran group consisted of 177 patients and the rivaroxaban group consisted of 179 patients. The incidence of discontinuation was significantly higher in the dabigatran group than in the rivaroxaban group (27.7% vs. 13.4%, p<0.001). Multivariate analysis, even after propensity score-matching analysis, revealed that there were no independent risk factors for bleeding in the dabigatran group, while in the rivaroxaban group, use of antiplatelet therapy was an independent factor correlating with bleeding. The risk factors for bleeding may be different between dabigatran and rivaroxaban. To avoid bleeding, rivaroxaban should be prescribed with caution or avoided in patients using antiplatelet therapy. Upon discontinuation, rivaroxaban may be more favorable than dabigatran.


Structural elements in alpha-conotoxin ImI essential for binding to neuronal alpha7 receptors.
The neuronal-specific toxin alpha-conotoxin ImI (CTx ImI) has the sequence Gly-Cys-Cys-Ser-Asp-Pro-Arg-Cys-Ala-Trp-Arg-Cys-NH2, in which each cysteine forms a disulfide bridge to produce a constrained two-loop structure. To investigate the structural basis for bioactivity we mutated individual residues in CTx ImI and determined bioactivity. Bioactivity of the toxins was determined by their competition against 125I-labeled alpha-bungarotoxin binding to homomeric receptors containing alpha7 sequence in the major extracellular domain and 5HT-3 sequence elsewhere. The results reveal two regions in CTx ImI essential for binding to the alpha7/5HT-3 receptor. The first is the triad Asp-Pro-Arg in the first loop, where conservative mutations of each residue diminish affinity by 2-3 orders of magnitude. The second region is the lone Trp in the second loop, where an aromatic side chain is required. The overall results suggest that within the triad of the first loop, Pro positions the flanking Asp and Arg for optimal interaction with one portion of the binding site, while within the second loop, Trp stabilizes the complex through its aromatic ring.


Organic Carbon, Nitrogen Accumulation and Nitrogen Leaching as Affected by Legume Crop Residues on Sandy Loam in the Eastern Baltic Region.
Legumes have a wide range of positive effects on soil properties, including nitrogen and carbon storage, soil structure and the phytosanitary condition of crops. From an agronomic point of view, legumes are most valued for their ability to take up atmospheric nitrogen in symbiosis with nitrogen-fixing bacteria. The aim of this research was to determine the effect of legume residues (peas, fodder beans, narrow-leaved lupins) on the N (Ntotal) and organic carbon (Corg) accumulation in soil and N leaching under temperate climate conditions. The experiment was carried out in lysimetric equipment in 2016-2023. The effect of legumes on Corg and Ntotal accumulation in soil and N leaching were studied in a Fabaceae-Cereals sequence. Three species of legumes-peas, fodder beans and narrow-leaved lupines-were tested; spring barley (Hordeum vulgare L.) was grown as a control treatment. The lysimeter surface area was 1.75 m2 and the experimental soil layer was 0.60 m (sand loam Haplic Luvisol). It was found that after harvesting, more residues were incorporated into the soil with lupines (p < 0.05), which, compared to pea and bean residues, increased Ntotal and Corg concentrations in the soil. There was a strong correlation (r = 0.95) between the Ntotal concentration in the soil and the N amount incorporated with residues. Mineral N released during residue decomposition was leached from the humic horizon under conditions of excess moisture in the autumn-winter period and increased the nitrate concentration in the lysimeter water. The increase in concentration was recorded within 5 to 6 months after the application of the residues. As a result, the N leaching losses increased on average by 24.7-33.2% (p < 0.05) during the year of legume cultivation. In the following year, after legume residue incorporation, the effect of residues on nitrate concentration and N leaching decreased and did not differ significantly from that of barley residues.


Modeling global vector fields of chaotic systems from noisy time series with the aid of structure-selection techniques.
We address the problem of reconstructing a set of nonlinear differential equations from chaotic time series. A method that combines the implicit Adams integration and the structure-selection technique of an error reduction ratio is proposed for system identification and corresponding parameter estimation of the model. The structure-selection technique identifies the significant terms from a pool of candidates of functional basis and determines the optimal model through orthogonal characteristics on data. The technique with the Adams integration algorithm makes the reconstruction available to data sampled with large time intervals. Numerical experiment on Lorenz and Rossler systems shows that the proposed strategy is effective in global vector field reconstruction from noisy time series.


"The times they are a-changin'": A longitudinal, mixed methods case study of a hospital transformation.
Changes to hospital infrastructure are inevitable in ever-evolving healthcare systems. The redevelopment of hospitals and opening of new buildings can be a complex and challenging time for staff as they must find ways to deliver safe and high-quality care while navigating the complexities and uncertainties of change. This study explores the perspectives and experiences of staff and patients before and after the opening of a new hospital building as part of a large public hospital redevelopment in Sydney, Australia. The study comprised a longitudinal mixed methods case study design. Methods included two rounds of staff surveys (n = 292 participants), two rounds of staff interviews (n = 66), six rounds of patient surveys (n = 255), and analysis of hospital data at tri-monthly intervals over two years. Data were compared before (2019) and after (2020) a new hospital building opened at a publicly funded hospital in Sydney, Australia. Four key themes and perspectives emerged from the interviews including change uncertainty, communication effectiveness, staffing adequacy and staff resilience. Significant differences in staff perceptions of change readiness over time was identified. Specifically, perceptions that the organisational change was appropriate significantly decreased (2019: 15.93 ± 3.86; 2020: 14.13 ± 3.62; p < .001) and perceptions that staff could deal with the change significantly increased (2019: 17.30 ± 4.77; 2020: 19.16 ± 4.36; p = .001) after the building opened compared to before. Global satisfaction scores from patient survey data showed that patient experience significantly declined after the building opened compared to before (2020: 81.70 ± 21.52; 2019: 84.43 ± 18.46)), t(254) = -64.55, p < 0.05, and improved a few months after opening of the new facilities. This coincided with the improvement in staff perceptions in dealing with the change. Moving into a new hospital building can be a challenging time for staff and patients. Staff experienced uncertainty and stress, and displayed practices of resilience to deliver patient care during a difficult period of change. Policy makers, hospital managers, staff and patients must work together to minimise disruption to patient care and experience. Key recommendations for future hospital redevelopment projects outline the importance of supporting and informing staff and patients during the opening of a new hospital building.


Effects of graded dietary levels of soy protein concentrate supplemented with methionine and phosphate on the immune and antioxidant responses of gilthead sea bream (Sparus aurata L.).
The effects of a dietary soy protein concentrate (SPC) as a fish meal (FM) substitute, on selected innate immune responses, the oxidative status, hepatic and intestinal morphology of gilthead sea bream, Sparus aurata, were evaluated after a three-month feeding trial. Isonitrogenous (45% crude protein) and isoenergetic (23 kJ/g gross energy) diets with 20% (SPC20), 40% (SPC40) and 60% (SPC60) of SPC inclusion, supplemented with methionine and phosphate, were evaluated against a diet containing FM as the sole protein source. Diets were allocated in triplicate groups of 26-g fish (8 kg m-3/tank) and administered for three months. Immune responses were evaluated by performing immunological assays in blood (respiratory burst activity) and serum (myeloperoxidase content, bacteriolytic and lysozyme activity), as well as by gene expression analysis of immune-associated genes (MHCIIα, β2m, CSF-1R, NCCRP-1, TGF-β1, HSP70) in the head kidney and distal intestine. In addition, oxidative stress was evaluated by measuring the activity of liver enzymes associated with the antioxidant system. The respiratory burst activity of blood was significantly decreased in the SPC40 group, while serum myeloperoxidase content and bacteriolytic and lysozyme activities were affected. Significantly higher expression levels of NCCRP-1 and HSP70 were found in SPC60 head kidneys, while increased intestinal MHCIIα and NCCRP-1 transcripts were observed in SPC40. Hepatic antioxidant enzyme activity of glutathione reductase and glutathione-S-transferase was significantly enhanced in the SPC40 and SPC60 groups, while superoxide dismutase activity was increased only in the SPC40 group. Moreover, increased lipid accumulation in the enterocytes of the distal intestine was observed in the SPC60 group. Overall, a three-month feeding period with diets over 40% of dietary SPC inclusion as a FM substitute, indicated increases on immune and antioxidant enzyme responses, suggesting the dietary SPC levels that gilthead sea bream can tolerate.


Three-dimensional ultrastructural study of oil and astaxanthin accumulation during encystment in the green alga Haematococcus pluvialis.
Haematococcus pluvialis is a freshwater species of green algae and is well known for its accumulation of the strong antioxidant astaxanthin, which is used in aquaculture, various pharmaceuticals, and cosmetics. High levels of astaxanthin are present in cysts, which rapidly accumulate when the environmental conditions become unfavorable for normal cell growth. It is not understood, however, how accumulation of high levels of astaxanthin, which is soluble in oil, becomes possible during encystment. Here, we performed ultrastructural 3D reconstruction based on over 350 serial sections per cell to visualize the dynamics of astaxanthin accumulation and subcellular changes during the encystment of H. pluvialis. This study showcases the marked changes in subcellular elements, such as chloroplast degeneration, in the transition from green coccoid cells to red cyst cells during encystment. In green coccoid cells, chloroplasts accounted for 41.7% of the total cell volume, whereas the relative volume of astaxanthin was very low (0.2%). In contrast, oil droplets containing astaxanthin predominated in cyst cells (52.2%), in which the total chloroplast volume was markedly decreased (9.7%). Volumetric observations also demonstrated that the relative volumes of the cell wall, starch grains, pyrenoids, mitochondria, the Golgi apparatus, and the nucleus in a cyst cell are smaller than those in green coccid cells. Our data indicated that chloroplasts are degraded, resulting in a net-like morphology, but do not completely disappear, even at the red cyst stage.


Effects of Oncostatin M on Invasion of Primary Trophoblasts under Normoxia and Hypoxia Conditions.
To investigate the effect of oncostatin M (OSM) on protein expression levels and enzymatic activities of matrix metalloprotainase (MMP)-2 and MMP-9 in primary trophoblasts and the invasiveness thereof under normoxia and hypoxia conditions. Protein expression levels and enzymatic activities of MMP-2 and MMP-9 in primary trophoblasts under normoxia and hypoxia conditions were examined by Western blot and zymography, respectively. Effects of exogenous OSM on the in vitro invasion activity of trophoblasts according to oxygen concentration were also determined. Signal transducer and activator of transcription 3 (STAT3) siRNA was used to determine whether STAT3 activation in primary trophoblasts was involved in the effect of OSM. OSM enhanced protein expression levels and enzymatic activities of MMP-2 and MMP-9 in term trophoblasts under hypoxia condition, compared to normoxia control (p<0.05). OSM-induced MMP-2 and MMP-9 enzymatic activities were significantly suppressed by STAT3 siRNA silencing under normoxia and hypoxia conditions (p<0.05). Hypoxia alone or OSM alone did not significantly increase the invasiveness of term trophoblasts. However, the invasion activity of term trophoblasts was significantly increased by OSM under hypoxia, compared to that without OSM treatment under normoxia. OSM might be involved in the invasiveness of extravillous trophoblasts under hypoxia conditions via increasing MMP-2 and MMP-9 enzymatic activities through STAT3 signaling. Increased MMP-9 activity by OSM seems to be more important in primary trophoblasts.


Modeling age-specific cancer incidences using logistic growth equations: implications for data collection.
Large scale secular registry or surveillance systems have been accumulating vast data that allow mathematical modeling of cancer incidence and mortality rates. Most contemporary models in this regard use time series and APC (age-period-cohort) methods and focus primarily on predicting or analyzing cancer epidemiology with little attention being paid to implications for designing cancer registry, surveillance or evaluation initiatives. This research models age-specific cancer incidence rates using logistic growth equations and explores their performance under different scenarios of data completeness in the hope of deriving clues for reshaping relevant data collection. The study used China Cancer Registry Report 2012 as the data source. It employed 3-parameter logistic growth equations and modeled the age-specific incidence rates of all and the top 10 cancers presented in the registry report. The study performed 3 types of modeling, namely full age-span by fitting, multiple 5-year- segment fitting and single-segment fitting. Measurement of model performance adopted adjusted goodness of fit that combines sum of squred residuals and relative errors. Both model simulation and performance evalation utilized self-developed algorithms programed using C# languade and MS Visual Studio 2008. For models built upon full age-span data, predicted age-specific cancer incidence rates fitted very well with observed values for most (except cervical and breast) cancers with estimated goodness of fit (Rs) being over 0.96. When a given cancer is concerned, the R valuae of the logistic growth model derived using observed data from urban residents was greater than or at least equal to that of the same model built on data from rural people. For models based on multiple-5-year-segment data, the Rs remained fairly high (over 0.89) until 3-fourths of the data segments were excluded. For models using a fixed length single-segment of observed data, the older the age covered by the corresponding data segment, the higher the resulting Rs. Logistic growth models describe age-specific incidence rates perfectly for most cancers and may be used to inform data collection for purposes of monitoring and analyzing cancer epidemic. Helped by appropriate logistic growth equations, the work vomume of contemporary data collection, e.g., cancer registry and surveilance systems, may be reduced substantially.


Regional variation in the cost effectiveness of childhood hepatitis A immunization.
Routine childhood hepatitis A immunization is recommended in regions with incidence rates twice the national average, but it may be cost-effective in a wider geographic area. To evaluate the costs and benefits of potential hepatitis A immunization of healthy US children in regions with varying hepatitis A incidences. We considered vaccination of the 2000 US birth cohort in states defined by historic hepatitis A incidence rates. Infections among potential vaccinees and their personal contacts were predicted from age 2 through 85 years. Net vaccination costs were estimated from health system and societal perspectives and were compared with life-years saved and quality-adjusted life years (QALYs) gained using a 3% discount rate. RESULTS Nationally vaccination would prevent >75 000 cases of overt hepatitis A disease. Approximately two-thirds of health benefits would accrue to personal contacts rather than to vaccinees themselves. In states with incidence rates of > or =200%, 100 to 199%, 50 to 99% and <50% the national average, societal costs per QALY gained would be <0, <0, 13,800 and 63,000 US dollars, respectively. Nationally vaccination would cost 9100 US dollars per QALY gained from the perspective of the health system and 1400 US dollars per QALY gained from society's perspective. Results are most sensitive to vaccination costs and rates of disease transmission through personal contact. Childhood hepatitis A vaccination is most cost-effective in areas with the highest incidence rates but would also meet accepted standards of economic efficiency in most of the US. A national immunization policy would prevent substantial morbidity and mortality, with cost effectiveness similar to that of other childhood immunizations.


Sliding the Medial Pin: A Safer Approach to Cross-pinning Humerus Supracondylar Fractures?
Many methods have been described to minimize the risk of ulnar nerve injury during the insertion of a medial pin for the percutaneous pinning of pediatric supracondylar humerus fractures (SCHF). The most recent AAOS Clinical Practice Guidelines suggests that physicians might want to avoid the use of medial-entry pins due to considerations of potential injury to the ulnar nerve. However, there are circumstances whereby a cross pin configuration is required. These include cases where there is medial wall comminution or due to the obliquity of the fracture. In this study, we present a group of patients with SCHF in which the medial pin was inserted using a new technique. This is a retrospective case series approved by the local centralized institutional review board. The medical records of all patients who underwent closed reduction and percutaneous pinning for SCHF using a new technique-the sliding method-by a single pediatric orthopedic surgeon from August 2017 till January 2018 were reviewed. Patient demographics, fracture type, operative time, postoperative Baumann's angle, postoperative lateral capitellohumeral angle, and the rate of ulnar nerve palsy were recorded. This new technique was used in a total of 35 patients. Two patients were excluded as one had multiple same limb injuries, while another had a Gustilo 3A humerus supracondylar fracture. The average patient age at the time of surgery was 6.2 years (range: 2 to 12 y). There were 22 children with Gartland grade 3 fractures, 10 with grade 2b fractures, and 1 had a flexion type fracture. The average operative time was 21 minutes (range: 7 to 58 min). The average postoperative Baumann's angle was 73.9 degrees (range: 63.8 to 79.6 degrees) and the average postoperative lateral capitellohumeral angle was 44.6 degrees (range: 31.1 to 56.8 degrees). There were no cases of ulnar nerve palsy. The sliding method is a novel technique of protecting the ulnar nerve during closed reduction percutaneous pinning of SCHF. Level IV.


Age-related changes in muscle strength and spinal kyphosis angles in an elderly Japanese population.
Lumbar kyphosis and the decreased mobility of the lumbar spine increase the risk of falls and impair both the quality of life and the ability to perform activities of daily living. However, in the elderly Japanese population, little is known about the age-related changes and sex-related differences in muscle strength, including of the upper and lower extremities and back extensors. An adequate kyphotic or lordotic angle has also not been determined. In this study, we evaluated the age-related changes in muscle strength and spinal kyphosis in 252 males and 320 females ≥50 years of age. Grip, back extensor, hip flexor, and knee extensor strength; thoracic and lumbar kyphosis; and spinal inclination in the neutral standing position were assessed, together with the range of motion of the thoracic and lumbar spine and spinal inclination. Grip strength, back extensor strength, and the strength of the hip flexors and knee extensors decreased significantly with aging, both in males (P<0.0001) and in females (P=0.0015 to P<0.0001). The lumbar but not the thoracic kyphosis angle decreased significantly with aging, only in females (P<0.0001). Spinal inclination increased significantly with aging in both males (P=0.002) and females (P<0.0001). Back extensor strength and the thoracic kyphosis angle were significant variables influencing the lumbar kyphosis angle in both sexes. Spinal inclination correlated significantly with both the lumbar kyphosis angle and hip flexor strength in males, as well as with the lumbar kyphosis angle in females.


Structural, electronic, and magnetic properties of boron nitride nanotubes filled with iron nanowires.
Under GGA, the structural, electronic, and magnetic properties of Fe(n) nanowire encapsulated in BNNTs have been investigated systematically using the first-principles PAW potential within DFT. We find that the initial shapes (quadratic-prismatic Fe wire and cylindrical (8,8) BNNT) are preserved without any visible changes and no one relative rotation is taken place after optimization for the thin nanowires encapsulated inside BNNTs, and the formation processes of such systems are exothermic due to the weaken interactions between them. The magnetic moments analyses show that no magnetization is found on the B and N atoms, but a significant enhancement of the magnetic moments is found for Fe(n) @ (8,8) systems, especially for thin nanowires encapsulated in (8,8) BNNT due to increased ratio of the surface atoms with less coordination number compared to bulk Fe, and very weak influence of outer nanotubes leading to their magnetic moments are similar to those of the freestanding nanowires. Both the total density of states (DOS) and charge density analyses show that the spin polarization and the magnetic moment of Fe(n) @ (8,8) systems come solely from the Fe(n) nanowire, implying the Fe5 @ (8,8) and Fe9 @ (8,8) systems can be applied to the circuits that demand preferential transport of electrons with a specific spin.


Comparison of the effects of enoximone and isoproterenol on protamine cardiotoxicity in anesthetized dogs.
In this study we investigated the effects of isoproterenol and enoximone on protamine cardiotoxicity because administration of protamine for heparin reversal during open heart surgery depresses left ventricular function. Eighteen mongrel dogs were entered into this study. After induction of general anesthesia and a stabilization period, a thermodilution catheter was inserted via the jugular vein. Another 2 catheters were inserted into the left ventricle and femoral artery. Heparin and protamine were used in all animals. Heparin dosage was 300 U/kg, and protamine dosage was 4.5 mg/kg. The animals were divided into 3 groups. Six animals received enoximone (5 micrograms/kg per min), 6 animals received isoproterenol (0.05 microgram/kg per min), and 6 animals received no inotropic agent. Measurements were performed before treatment, 5 min after protamine administration, and at 15-min intervals for 1 h. Cardiac output (CO), mean arterial pressure, pulmonary capillary wedge pressure, first derivative of left ventricular pressure (1 +/-) left ventricular systolic pressure, and heart rate were measured. CO was 1582 +/- 34 ml/min in the isoproterenol group (I + P), 1684 +/- 61 ml/min in the enoximone group (E + P), and 1471 +/- 37 ml/min in the protamine group (P) (p < 0.05 E + P vs I + P and P) 60 min after protamine administration. The first derivative of left ventricular pressure (dP/dt) was 1995 +/- 61 mmHg/sec in the I + P group, 2320 +/- 85 mmHg/sec in the E + P group, and 1816 +/- 48 mmHg/sec in the P group (p < 0.05 E + P vs I + P and P). In our experimental study, the isoproterenol and protamine combination did not increase hemodynamic activity. However, isoproterenol alone significantly increased hemodynamic activity as determined by dP/dt values. Protamine administration impairs the effects of beta agonists on the myocardium. In the protamine group, CO and pressure-dependent values were significantly reduced. Isoproterenol administration did not reverse this deterioration because of the loss of the beta-receptor activity. Inotropic agents acting through the beta-adrenergic system have partial effects on myocardium. Enoximone, a phosphodiesterase inhibitor, reverses deterioration of cardiac function after protamine administration because it increases myocardial function via the phosphodiesterase system.


Strong dominance of functional alleles over gene deletions in both intensely growing and deeply starved yeast cells.
Previous studies with diploid yeast have shown that the deletion of one allele at a single locus typically has little impact on fitness under conditions promoting fast growth. Here, we confirm and quantify this finding. The strong dominance of functional over nonfunctional alleles is predicted by the metabolic control theory which assumes that the cell is a system of metabolic fluxes and that the total metabolic rate is equivalent to fitness. To test whether these requirements are critical, we tested dominance under conditions of long-term starvation when metabolism is low and thus the metabolic activities of proteins are likely inadequate or imbalanced. More fundamentally, the central assumption of the model, that high metabolic rate translates into high fitness, appears implausible. Contrary to these conjectures, we found that the mean rate of survival of starving heterozygotes was affected only slightly more than was the mean rate of growth under good conditions. Under none of the two treatments the central prediction of the model, that fitness of heterozygous strains is higher for the enzymatic proteins than for nonenzymatic ones, was confirmed. Our data add to growing uncertainty whether the metabolic control theory is sufficient to explain the remarkable ubiquity of strong genetic dominance.


Studies in capillary zone electrophoresis with a post-column multiple capillary device for fraction collection and stepwise increase in electroosmotic flow during analysis.
A new approach involving the stepwise increase in electroosmotic flow during analysis in capillary zone electrophoresis is introduced and evaluated in the rapid separations of proteins and peptides. The stepwise increase in electroosmotic flow is based on the principle of coupled capillaries in series having different flow characteristics, a concept that was introduced recently by our laboratory. To produce stepwise changes in electroosmotic flow during analysis, a post-column multiple capillary device, which allowed the switching between several coupled capillary systems, was designed and constructed in-house. The utility of the multiple capillary device was also demonstrated and extended to fraction collection of separated analytes in short capillary segments. The fraction collection in capillaries facilitated the quantitative transfer of the collected fractions to high performance liquid chromatography (HPLC) for further analysis or to mass spectrometry (MS) for structural determination. The off-line combination of capillary zone electrophoresis with HPLC or MS utilized commercial instruments without the need of expensive interfacing designs.


Emerging Diagnostic Potential of Tumor-derived Exosomes.
Exosomes carry genetic information originating from their parental cells, raising their possibility as novel noninvasive biomarkers for cancer. Tumor-derived exosomes (TEXs) have a variety of endogenous cargos that reflect the pathophysiology status and information of tumor cells. TEXs are increasingly being recognized as potential biomarkers for cancer diagnosis prognosis, and monitoring. It is important to develop a variety of sensitive methods, including probes and biomaterials to isolate exosomes. A variety of approaches for detecting exosomes have been established. By combining exosome DNA and RNA sequencing tools, exosome proteomics analysis and immunoassay technology, it is expected that exosomes will gain widespread use in the diagnosis and treatment of cancer.


A quasi-experimental analysis of the association between family income and offspring conduct problems.
The study presents a quasi-experimental analysis of data on 9,194 offspring (ages 4-11 years old) of women from a nationally representative U.S. sample of households to test the causal hypotheses about the association between family income and childhood conduct problems (CPs). Comparison of unrelated individuals in the sample indicated a robust inverse association, with the relation being larger at higher levels of income and for male offspring, even when statistical covariates were included to account for measured confounds that distinguish different families. Offspring also were compared to their siblings and cousins who were exposed to different levels of family income in childhood to rule out unmeasured environmental and genetic factors confounded with family income as explanations for the association. In these within-family analyses, boys exposed to lower family income still exhibited significantly higher levels of CPs. When considered in the context of previous studies using different designs, these results support the inference that family income influences CPs, particularly in males, through causal environmental processes specifically related to earnings within the nuclear family.


Transport Properties of Protic Ionic Liquids Based on Triazolium and Imidazolium: Development of an Air-Free Conductivity Setup.
The dynamical properties of four protic ionic liquids, based on the ethyltriazolium ([C2HTr124]) and the ethylimidazolium ([C2HIm]) cation, were investigated. The associated anions were the triflate ([TfO]) and the bistriflimide ([TFSI]). Ionic conductivity values and self-diffusion coefficients were measured and discussed, extending the discussion to the concept of fragility. Furthermore, in order to allow the measurement of the ionic conductivity of very small volumes (<0.5 mL) of ionic liquid under an inert and dry atmosphere, a new setup was developed. It was found that the cation nature strongly affected the transport properties, the [C2HTr124] cation resulting in slower dynamics than the [C2HIm] one. This was concluded from both conductivity and diffusivity measurements while for both properties, the anion had a lesser effect. By fitting the conductivity data with the Vogel-Fulcher-Tammann (VFT) equation, we could also estimate the fragility of these ionic liquids, which all fell in the range of very fragile glass-forming materials. Finally, the slower dynamics observed in the triazolium-based ionic liquids can be rationalized by the stronger interactions that this cation establishes with both anions, as deduced from the frequency analysis of relevant Raman signatures and density functional theory (DFT) calculations.


Agonist-induced transfer of the alpha subunits of the guanine-nucleotide-binding regulatory proteins Gq and G11 and of muscarinic m1 acetylcholine receptors from plasma membranes to a light-vesicular membrane fraction.
A clone of a Chinese hamster ovary (CHO) cell line expressing high levels of the human muscarinic M1 acetylcholine (Hm1) receptor undergoes a substantial agonist-specific down-regulation of both Hm1 receptors and the alpha subunits of the guanine-nucleotide-binding (G)-proteins Gq and G11 which is accompanied by a desensitization of inositol-phospholipid-specific-phospholipase-C response [Mullaney, I., Dodd, M. W., Buckley, N. J. & Milligan, G. (1993) Biochem. J. 289, 125-131]. To examine early events in this process, the effect of agonist on subcellular distribution of Gq alpha and G11 alpha and of Hm1 receptors was assessed after short-term and long-term treatment with carbachol. Short-term (30 min) incubation with carbachol (1 mM) induced a simultaneous transfer of a proportion of both Gq alpha and G11 alpha and Hm1 receptors from plasma membranes to distinct light vesicular membranes. The total number of receptors and of Gq alpha and G11 alpha in each cell remained unchanged under these conditions. A similar transfer was noted for the G-protein Gs alpha but not for intrinsic plasma membrane markers. The plasma membrane, as well as light vesicular membrane, pool of Gs alpha subunit was unaffected by further sustained incubation with carbachol (16 h), whereas Hm1 receptors and both Gq alpha and G11 alpha proteins were down-regulated to 25% and 40%, respectively, when compared with untreated cells. Such observations support the idea that down-regulation of both the Hm1 receptor and its associated inositol-phospholipid-specific-phospholipase-C-linked G-proteins is produced by two sequential steps. The first is a transfer of signal-transducing polypeptides from the plasma membrane to a non-plasma membrane light vesicle fraction. The second step is represented by an agonist-specific down-regulation pathway. Both the Hm1 receptor and Gq alpha/G11 alpha appear to follow similar sequestration and down-regulation patterns.


Extrauterine adenomyoma with atypical (symplastic) smooth muscle cells: a report of 2 cases.
Adenomyomas are circumscribed tumorlike masses most often involving the uterus and consisting of endometrioid glands, stroma, and smooth muscle tissue. They are uncommon in extrauterine sites and in this situation it may be unclear whether such lesions represent foci of endometriosis with marked smooth muscle hyperplasia/metaplasia, uteruslike mass lesions, or leiomyomas with entrapped endometriotic glandular and stromal elements. In this report 2 cases of extrauterine adenomyoma are presented in which the smooth muscle component showed focal atypical (symplastic) cytologic appearances.


Outgassing of oxygen from polycarbonate.
A manometric permeation apparatus was used to study the "outgassing" or desorption of oxygen from polycarbonate (PC). A PC film was placed in the apparatus. Both sides were exposed to oxygen until the film was saturated. To simulate inert gas purging of a closed container or "microenvironment", oxygen was pumped from one side of the apparatus to reduce the concentration on that side to nearly zero. Oxygen concentrations on the freshly purged side rose quickly at first but then slowed. Eventually, a steady state was established and oxygen concentrations increased linearly with time. Mass-transport coefficients (permeation, diffusion, and solubility coefficients) were also estimated and then used to successfully predict the postpurge rise of the oxygen concentration.


Femoral Bone Plug in Total Knee Replacement.
The intramedullary alignment guides used in total knee replacement disrupt the intramedullary vessels, resulting in greater postoperative blood loss. The use of an autologous bone plug to seal the intramedullary femoral canal has been shown to be effective in reducing postoperative bleeding. The authors present a simple technique to create a bone plug from the anterior chamfer femoral cut to perfectly seal the intramedullary canal of the femur.


SYPL1 overexpression predicts poor prognosis of hepatocellular carcinoma and associates with epithelial-mesenchymal transition.
Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality worldwide, which is mainly due to relapse and metastasis. Synaptophysin-like 1 (SYPL1), a member of SYP family proteins, exerts complicated functions, which prompted us to wonder whether SYPL1 contributed to HCC progress. Herein, we performed integrative experiments of quantitative real-time polymerase chain reaction (qRT-PCR), western blot analysis and immunohistochemistry (IHC), and found that SYPL1 overexpression in HCC tissues was closely correlated with several malignant clinicopathologic features of HCC. The results from IHC in serial sections of HCC tissues further indicated that SYPL1 expression was associated with epithelial-mesenchymal transition (EMT) biomarkers of HCC cells. Additionally, Kaplan-Meier survival analysis showed that SYPL1 overexpression was significantly associated with reduced overall survival (OS) (p<0.001) and disease-free survival (DFS) (p=0.002). Furthermore, univariate and multivariate Cox proportional hazards analysis identified SYPL1 as an independent prognostic factor for OS [hazard ratio (HR), 2.443, 95% confidence interval (CI), 1.429-4.177, p=0.001] and DFS (HR, 1.680, 95% CI=1.012-2.788, p=0.045) of HCC patients. Collectively, SYPL1 overexpression predicts poor prognosis of HCC and may associate with EMT of HCC cells. Therefore, SYPL1 could serve as a future novel biomarker and potential therapy target for HCC.


Mesoscale modeling of multi-protein-DNA assemblies: the role of the catabolic activator protein in Lac-repressor-mediated looping.
DNA looping plays a key role in the regulation of the lac operon in Escherichia coli. The presence of a tightly bent loop (between sequentially distant sites of Lac repressor protein binding) purportedly hinders the binding of RNA polymerase and subsequent transcription of the genetic message. The unexpectedly favorable binding interaction of this protein-DNA assembly with the catabolic activator protein (CAP), a protein that also bends DNA and paradoxically facilitates the binding of RNA polymerase, stimulated extension of our base-pair level theory of DNA elasticity to the treatment of DNA loops formed in the presence of several proteins. Here we describe in detail a procedure to determine the structures and free energies of multi-protein-DNA assemblies and illustrate the predicted effects of CAP binding on the configurations of the wild-type 92-bp Lac repressor-mediated O3-O1 DNA loop. We show that the DNA loop adopts an antiparallel orientation in the most likely structure and that this loop accounts for the published experimental observation that, when CAP is bound to the loop, one of the arms of LacR binds to an alternative site that is displaced from the original site by 5 bp.


Measurement of electrostatic potential fluctuation using heavy ion beam probe in large helical device.
Heavy ion beam probe (HIBP) for large helical device (LHD) has been improved to measure the potential fluctuation in high-temperature plasmas. The spatial resolution is improved to about 10 mm by controlling the focus of a probe beam. The HIBP is applied to measure the potential fluctuation in plasmas where the rotational transform is controlled by electron cyclotron current drive. The fluctuations whose frequencies change with the time constant of a few hundreds of milliseconds and that with a constant frequency are observed. The characteristics of the latter fluctuation are similar to those of the geodesic acoustic mode oscillation. The spatial profiles of the fluctuations are also obtained.


[Effects of vitamin E deficiency on bleomycin-induced pulmonary fibrosis in hamsters].
We examined the effect of free radicals on lung defense mechanism in bleomycin (BLM)-induced pulmonary fibrosis in hamsters. The concentration of vitamin E (VE) in the lung tissue increased significantly after intratracheal BLM administration. VE deficient hamsters showed increased lipid peroxide values in the lung tissue at a very early stage after BLM treatment. This was followed by decreased superoxide dismutase activities in the lung tissue. The results indicate that; 1) VE appears to be necessary for the prevention of lipid peroxidation in BLM-induced oxidant lung injury, 2) VE deficiency produces a large number of free radicals at the early stage after BLM treatment, and might induce protease-antiprotease imbalance within the lung, which probably causes an emphysematous change in the BLM-treated lung at a late stage after BLM administration.


Regulation of redox metabolism in the mouse oocyte and embryo.
Energy homeostasis of the oocyte is a crucial determinant of fertility. Following ovulation, the oocyte is exposed to the unique environment of the Fallopian tube, and this is reflected in a highly specialised biochemistry. The minute amounts of tissue available have made the physiological analysis of oocyte intermediary metabolism almost impossible. We have therefore used confocal imaging of mitochondrial and cytosolic redox state under a range of conditions to explore the oxidative metabolism of intermediary substrates. It has been known for some time that the early mouse embryo metabolises external pyruvate and lactate but not glucose to produce ATP. We now show at the level of single oocytes, that supplied glucose has no effect on the redox potential of the oocyte. Pyruvate is a cytosolic oxidant but a mitochondrial reductant, while lactate is a strong cytosolic reductant via the activity of lactate dehydrogenase. Unexpectedly, lactate-derived pyruvate appears to be diverted from mitochondrial oxidation. Our approach also reveals that the level of reduced glutathione (GSH) in the oocyte is maintained by glutathione reductase, which oxidises intracellular NADPH to reduce oxidised glutathione. Surprisingly, NADPH does not seem to be supplied by the pentose phosphate pathway in the unfertilised oocyte but rather by cytosolic NADP-dependent isocitrate dehydrogenase. Remarkably, we also found that the oxidant action of pyruvate impairs development, demonstrating the fundamental importance of redox state on early development.


Stimulus-dependent variability and noise correlations in cortical MT neurons.
Population codes assume that neural systems represent sensory inputs through the firing rates of populations of differently tuned neurons. However, trial-by-trial variability and noise correlations are known to affect the information capacity of neural codes. Although recent studies have shown that stimulus presentation reduces both variability and rate correlations with respect to their spontaneous level, possibly improving the encoding accuracy, whether these second order statistics are tuned is unknown. If so, second-order statistics could themselves carry information, rather than being invariably detrimental. Here we show that rate variability and noise correlation vary systematically with stimulus direction in directionally selective middle temporal (MT) neurons, leading to characteristic tuning curves. We show that such tuning emerges in a stochastic recurrent network, for a set of connectivity parameters that overlaps with a single-state scenario and multistability. Information theoretic analysis shows that second-order statistics carry information that can improve the accuracy of the population code.


Differentiation of Superoxide Radical Anion and Singlet Oxygen and Their Concurrent Quantifications by Nuclear Magnetic Resonance.
While there have been various techniques, assays, and commercial kits developed to measure reactive oxygen species (ROS) with varying degrees of success, there is a lack of innovative methods to differentiate and quantify them simultaneously. In this work, we demonstrate a 19F nuclear magnetic resonance (NMR)-based method to differentiate two important types of ROS, superoxide radical anion and singlet oxygen, and to quantify them concurrently. By taking advantage of the unique chemical reactivity of two fluorine-containing molecules, 4-fluoro-3-methylphenyl boronic acid and 4-fluoro-3-methylphenol, serving as 19F NMR probes, we are able to differentiate and quantify, for the first time, superoxide radical anion and singlet oxygen generated by photosensitizers (PSs) concurrently. The results reveal that relative amounts of superoxide radical anion and singlet oxygen generated by a PS under light illumination are oftentimes sensitive to the environment, such as the presence or absence of electron donors. This method provides a means to identify the type of mechanism by which a PS functions under a given condition. We envision that this relatively simple, yet robust, method would be beneficial to a broad range of ROS-pertinent studies, such as photodynamic therapy and photoredox reactions.


27‑Gauge vitrectomy vs. 25‑gauge vitrectomy in the management of proliferative diabetic retinopathy with preoperative intravitreal injection of conbercept.
Small-gauge vitrectomy has become popular due to its notable advantages, including less trauma, shortened convalescence and improved manoeuvrability. The aim of the present study was to compare the surgical outcomes of 27-gauge (27-G) vitrectomy with those of 25-gauge (25-G) vitrectomy in the management of proliferative diabetic retinopathy (PDR) with preoperative intravitreal injection of conbercept. The data of 48 consecutive patients with PDR (48 eyes) were retrospectively collected. The patients underwent conbercept intravitreal injection and pars plana vitrectomy with a 27-G group (23 eyes) or 25-G group (25 eyes) vitrectomy system. The operating time, suturing rate, endodiathermy rate, postoperative best-corrected visual acuity (BCVA), intraocular pressure (IOP) and complications were recorded. The mean postoperative BCVA at final follow-up was significantly improved compared with that at the baseline in both groups (P<0.001 for both). The differences in the mean BCVA changes between the two groups were not significant (P>0.99), and no differences were observed in the final central foveal thickness (P=0.51) between the two groups. The final IOP remained stable compared with that at the baseline in the 27-G group (P=0.36) and the 25-G group (P=0.05). The suturing rate was significantly decreased in the 27-G group compared with the 25-G group (P=0.04). There were no significant differences between the two groups in terms of the operating time (P=0.18), rate of endodiathermy use (P>0.99), iatrogenic retinal breaks (P=0.42) or postoperative recurrent vitreous haemorrhage (P>0.99). In addition, no case of ocular hypotony was observed in either group. In conclusion, 27-G vitrectomy was as efficient and safe as 25-G vitrectomy in the management of PDR in terms of operating time and complications. With reference to the literature, preoperative conbercept injection appears to assist in decreasing the incidence of intraoperative and postoperative complications.


A meta-synthesis of studies of patients' experience of living with terminal cancer.
The aim of this research was to produce a synthesis of phenomenological studies of the experience of living with the awareness of having terminal cancer to gain a more complete understanding of the parameters of this experience. This research used meta-synthesis as a method for integrating the results of 23 phenomenological studies of the experience of living with the awareness of having terminal cancer published between 2011 and 2016. The meta-synthesis generated 19 theme clusters that informed the construction of four master themes: trauma, liminality, holding on to life, and life as a cancer patient. Each master theme captures a distinct experiential dimension of living with the awareness of having terminal cancer. Each dimension brings with it significant and distinctive psychological challenges. The results from the present meta-synthesis suggest that the experience of living with the awareness of having terminal cancer is a multidimensional experience that patients actively negotiate as they search for ways in which they can rise to the psychological challenges associated with it. A better understanding of the parameters of this experience can help health care professionals provide appropriate support for this client group. (PsycINFO Database Record